Léa Montégut

Carlos Lopez-Otin

Christophe Magnan

Guido Kroemer
email: kroemer@orange.fr

Old paradoxes and new opportunities for appetite control in obesity

Human obesity is accompanied by alterations in the blood concentrations of multiple circulating appetite regulators. Paradoxically, most of the appetite-inhibitory hormones are elevated in non-syndromic obesity, while most of the appetite stimulatory hormones are reduced, perhaps reflecting vain attempts of regulation by inefficient feedback circuitries. In this context, it is important to understand which appetite regulators exhibit a convergent rather than paradoxical behavior and hence are likely to contribute to the maintenance of the obese state. Pharmacological interventions on obesity should preferentially consist in the supplementation of deficient appetite inhibitors or the neutralization of excessive appetite stimulators. Here, we critically analyze the current literature on appetite-regulatory peptide hormones. We propose a short-list of appetite modulators that may constitute the best candidates for therapeutic interventions.

Highlights

• Multiple protein and peptide hormones produced outside of the central nervous system control food intake. In this review, we postulate that peripheral appetite inhibitors that are actually downregulated in human obesity -or conversely appetite stimulators that are upregulated in this condition -should be particularly important for the pathogenesis of obesity.

• Paradoxically, most appetite inhibitors (exemplified by leptin) are upregulated in obesity while most appetite stimulators (exemplified by ghrelin) are downregulated, perhaps reflecting homeostatic adaptation.

• Only three endogenous appetite inhibitors follow a 'coherent' pattern and are downregulated in obesity. This applies to PP, PYY and VIP.

• Among the numerous appetite-stimulatory hormones only three behave in a 'coherent' fashion and are upregulated in obesity: ACBP, asprosin and NAMPT.

• Remarkably, these factors, ACBP, asprosin and NAMPT, are phylogenetically ancient (from worms to mammals) and are ubiquitously expressed.

• We speculate that ACBP, asprosin and NAMPT may constitute the backbone of a phylogenetically ancient appetite-stimulatory system that is causally involved in human obesity.

Introduction

Obesity is the most prevalent pathological condition of the 21 st century. In itself a disease, obesity predisposes to other pathologies including metabolic syndrome, diabetes, hypertension, arteriosclerosis and cancer [START_REF] Blüher | Obesity: global epidemiology and pathogenesis[END_REF]. Thus, obesity can be viewed as the most important risk factor for accelerating the manifestation of age-related diseases, causing a drastic reduction in healthspan and lifespan [START_REF] Global | Body-mass index and all-cause mortality: individual-participantdata meta-analysis of 239 prospective studies in four continents[END_REF][START_REF] Bhaskaran | Association of BMI with overall and cause-specific mortality: a population-based cohort study of 3•6 million adults in the UK[END_REF][START_REF] Lopez-Otin | Hallmarks of Health[END_REF].

Given its socioeconomic impact and its individual consequences, the pathophysiology of obesity has come under close scrutiny. Multiple theories have been advanced to explain the mechanisms of obesity. Such theories may invoke psychosocial and behavioral parameters, alterations in central nervous reward centers, shifted endocrine and neuroendocrine circuitries, as well as changes in the composition of the intestinal microbiota affecting the meta-organism [START_REF] Maclean | Biological control of appetite: A daunting complexity[END_REF]. Interestingly, once an individual has transited from normal weight through overweight to obesity, the person appears to be 'locked' in the state of pronounced adiposity, meaning that even drastic dieting and exercising usually only leads to a transient correction of the body mass [START_REF] Foster | A randomized trial of a low-carbohydrate diet for obesity[END_REF][START_REF] Arterburn | Weight Outcomes of Sleeve Gastrectomy and Gastric Bypass Compared to Nonsurgical Treatment[END_REF]. Thus, although the US gives home to more than 100 million obese adults, the National Weight Control Registry (http://www.nwcr.ws) monitors a rather small number (just above 10,000 cases) of durable weight losers.

The primary cause of lack of durable weight reduction is the excessive caloric intake observed in overweight or obese patients, a tendency that can be explained in part by the weakening of satiation after food intake [START_REF] Delgado-Aros | Independent influences of body mass and gastric volumes on satiation in humans[END_REF]. Control of food intake by central nervous system involves many regions that respond to sensory (smell, hearing, sight), endocrine (gastrointestinal hormones, leptin, insulin...) and nervous (vagal afferences) signals [START_REF] Heisler | An appetite for life: brain regulation of hunger and satiety[END_REF]. Specific centers such as the hypothalamus and the brainstem participate in homeostatic control (i.e. in response to calorie deficit or plethora). Other structures (ventral tegmental area, nucleus accumbens, striatum...) are more involved in the non-homeostatic control of food intake, responding to motivational or reward stimuli [START_REF] Clemmensen | Gut-Brain Cross-Talk in Metabolic Control[END_REF]. Figure 1 summarizes the most important actors involved in this homeostatic control of food intake, mainly detailing the hypothalamus towards which many endocrine signals converge. In brief, two major hypothalamic populations of neurons were firstly identified to control appetite in the hypothalamic arcuate nucleus (ARC): an orexigenic population that secretes agouti-related peptide (AgRP), neuropeptide Y (NPY) and γ-aminobutyric acid (GABA), and an anorexigenic population that secretes melanocortin (processed from the polypeptide precursor POMC) and cocaine-and amphetamine-regulated transcript (CART). These hypothalamic neurons assimilate a wide range of signals such as chemical inputs from circulating peptides or neuropeptides, neuronal input from various brain areas [START_REF] Druce | The regulation of appetite[END_REF], and peripheral physiological information that is carried by the vagus nerve via the nucleus of the solitary tract (NTS).

Several other populations of neurons were identified in hypothalamic areas such as the paraventricular nucleus (PVN) and lateral hypothalamic area (LHA). Moreover, additional factors such as the neuropeptide kisspeptin, melanin concentrating hormone (MCH), brain derived neurotrophic factor (BDNF), and oxytocin play major signaling functions (Figure 1). Beyond this homeostatic control of food intake by the hypothalamus, other regions (such as the reward circuits, the cerebral cortex, the limbic system…) trigger behavioral and metabolic responses [START_REF] Berthoud | Blaming the Brain for Obesity: Integration of Hedonic and Homeostatic Mechanisms[END_REF]. In addition, neurons close to circumventricular organs (CVOs, such as area postrema, subfornical organ, organum vasculosum of lamina terminalis or median eminence) are also able to sense blood-borne signals such as homones due to the particular anatomy of the blood brain barrier in these CVOs and its highly fenestrated capillaries [START_REF] Fry | The sensory circumventricular organs: brain targets for circulating signals controlling ingestive behavior[END_REF]. Finally, non-neuronal cells such as astrocytes, microglia, and tanycytes of the median eminence act in close interaction with neurons to contribute to the fine control of energy balance [START_REF] Garcia-Caceres | Role of astrocytes, microglia, and tanycytes in brain control of systemic metabolism[END_REF].

Modulate by all these mechanisms, the activation of anorexigenic neurons activation promotes meal termination and activates catabolic pathways, whereas orexigenic neurons circuits will stimulate food intake and decrease metabolic energy expenditure [15]. The central appetite system receives inputs from the periphery at short and long-term. Thus, the nutrient composition, duration and volume of a meal as well as the levels of circulating nutrients (glucose, fatty acids) and body fat mass are among the many factors that modulate food intake [START_REF] Augustine | Neural Control and Modulation of Thirst, Sodium Appetite, and Hunger[END_REF].

The information from these distant organs is transmitted electrically, by the vagal afferent nerves, and chemically, by circulating hormonal factors. Leptin is one of the first hormones that was found to modulate food intake and that was explored at the genetic level: sequenced in 1994 by Friedman et al., the protein is secreted by adipocytes in quantities proportional to the fat mass and acts as a potent appetite inhibitor in mice or patients with defects in the leptin/leptin receptor (R) system [START_REF] Considine | Serum immunoreactive-leptin concentrations in normal-weight and obese humans[END_REF]. Initially, this discovery raised hope for obesity therapy, but it was soon discovered that leptin regulation is dysfunctional in obese subjects [START_REF] Ozata | Human leptin deficiency caused by a missense mutation: multiple endocrine defects, decreased sympathetic tone, and immune system dysfunction indicate new targets for leptin action, greater central than peripheral resistance to the effects of leptin, and spontaneous correction of leptin-mediated defects[END_REF][START_REF] Myers | Mechanisms of leptin action and leptin resistance[END_REF]. Since then, many other factors capable of inflecting or inducing hunger have been discovered. While several of them are under clinical investigations, the hunt for a magical appetite controller is still under way.

This review aims at identifying the known stimulators and inhibitors of appetite and their regulation in the pathological context of obesity. Given the entanglement of the central circuitries of hunger and satiety, we will limit the scope of study to the proteins and peptides that are produced by peripheral cells, outside from the central nervous system (Figure 2A) and demonstrate effects when administered peripherally while acting on central or peripheral receptors (Figure 2B). Rather than giving a detailed description of the mechanism of action for each factor, we seek to understand if their regulatory functions are altered in the context of obesity, in order to identify the most reliable candidates as a leverage for weight loss in obese subjects. Driven by elementary logics and Occam's razor (Text Box 1), we postulate that peripheral appetite inhibitors that actually downregulated in human obesity -or conversely appetite stimulators that are upregulated in this condition -should be particularly important for the pathogenesis of obesity and hence constitute good targets for therapeutic intervention.

7

Peripheral appetite inhibitors

Assuming that obesity is linked to the failure of homeostatic circuitries that limit caloric intake, it appears logical to identify appetite inhibitors and to supply them to obese patients, hoping to inhibit appetite. Indeed, a number of endogenous appetite inhibitors have been identified (Table 1, Figure 3).

However, the only agent that has undergone successful Phase 3 evaluation and has recently (Nov. 2020) been FDA approved is liraglutide, an injectable glucagon-like peptide-1 (GLP-1) receptor agonist that likely acts on the central nervous system to reduce appetite [START_REF] Perez-Montes De Oca | Obesity and GLP-1[END_REF].

The leptin axis

Leptin, the historical satiety factor, and its receptor were cloned by exploring the genomes of spontaneously obese and diabetic mice: the ob/ob strain, which lacks leptin and the db/db strain which lacks the leptin receptor. These strains exhibit severe hyperphagia and a tendency to develop type-2 diabetes due to the lack of stimulation of the "leptin axis". Indeed, the leptin receptor (LepR) is involved in all major steps of appetite regulation: binding of Lep on LepR-expressing neurons in the NTS amplifies the signal from the vagus nerve in the NTS, while it has activating effects on the POMC/CART neurons and inactivating effects on the AgRP/NPY neurons in the hypothalamus, inhibits adrenal corticosteroids secretion and increases energy expenditure [21].

In humans, genetic defects in the leptin gene or its receptor also cause extreme early-onset obesity [START_REF] Montague | Congenital leptin deficiency is associated with severe early-onset obesity in humans[END_REF]. The severity of leptin deficiency can be partially reduced by oral leptin supplementation [START_REF] Paz-Filho | Congenital leptin deficiency: diagnosis and effects of leptin replacement therapy[END_REF].

Although extensively studied, these cases of obesity are extremely rare, and only a few dozen cases have been reported. Instead, cohort studies reveal a clear positive correlation between plasma leptin levels and BMI or subcutaneous fat mass, meaning that obesity is usually accompanied by a hyperleptinemia [START_REF] Considine | Serum immunoreactive-leptin concentrations in normal-weight and obese humans[END_REF]. Leptin levels drop drastically when adipose tissue mass is decreased, increasing hunger sensations for as long as one year after bariatric surgery or diet-induced weight loss according to one report [START_REF] Sumithran | Long-term persistence of hormonal adaptations to weight loss[END_REF]. Indeed, the individuals with the highest initial leptin levels have the highest chances of regaining weight after diet interventions [START_REF] Crujeiras | Weight regain after a diet-induced loss is predicted by higher baseline leptin and lower ghrelin plasma levels[END_REF]. The high basal leptin levels found in obese patients are thought to cause leptin resistance, rendering leptin treatment inefficient in most obese subjects [START_REF] Myers | Mechanisms of leptin action and leptin resistance[END_REF]. However, at largely supraphysiological levels, recombinant leptin therapies allow mild reduction in appetite which can help with weight maintenance [START_REF] Kissileff | Leptin reverses declines in satiation in weight-reduced obese humans[END_REF]. Co-administration of both leptin and amylin might be also a promising approach [START_REF] Levin | Amylin and Leptin: Co-Regulators of Energy Homeostasis and Neuronal Development[END_REF].

The increase of an appetite-inhibitory factor in the context of obesity appears paradoxical, especially if it assumed that this appetite-inhibitory factor plays a major role in appetite control. However, in view of the current knowledge that appetite is regulated by dozens of different factors, the paradox may be resolved by invoking a failing homeostatic control. Since obesity causes a deviation in body composition that is sensed by the system, homeostatic mechanisms intended to reduce appetite are activated, yet fail either because of resistance mechanisms or because they are superseded in importance by the true -yet to be defined -dominant drivers of obesity. Despite the great expectation it caused at the end of the twentieth century, leptin proved disappointing as a hormonal therapy for obesity. However, the study of its hypothalamic targets helped building the foundations of the current knowledge of appetite regulation. Many other hormonal regulators were subsequently found to regulate food intake through leptin-related or independent pathways.

Intestinal appetite regulators

The intestine and the brain are the first organs to sense food intake, making the gut hormones a natural starting point to discover appetite-regulatory factors.

Glucagon-like peptide-1

Glucagon-like peptide-1 (GLP-1) and oxyntomodulin (OXM) are two of the many peptides derived from alternative cleavage of glucagon, which can both affect blood glucose levels. The most studied one, GLP-1, is known to increase after a meal proportionally to its caloric content, slow down gastric emptying and potentiate the glucose-dependent effects of insulin [START_REF] Holst | Truncated glucagon-like peptide I, an insulin-releasing hormone from the distal gut[END_REF]. Through its receptor GLP-1R, it exerts strong anorectic effects at the peripheral level, likely by an action on afferent nerves, but may also reach the CNS when its levels are high. These effects have been extensively studied in animals and proved to be able to induce durable weight loss [START_REF] Abbott | The inhibitory effects of peripheral administration of peptide YY(3-36) and glucagon-like peptide-1 on food intake are attenuated by ablation of the vagal-brainstemhypothalamic pathway[END_REF][START_REF] Baggio | A recombinant human glucagon-like peptide (GLP)-1-albumin protein (albugon) mimics peptidergic activation of GLP-1 receptor-dependent pathways coupled with satiety, gastrointestinal motility, and glucose homeostasis[END_REF]. However, neutralization of GLP-1R by systemic (i.p. or s.c.) injection of blocking antibodies inhibits high-fat diet induced obesity in mice [START_REF] Svendsen | Pharmacological antagonism of the incretin system protects against diet-induced obesity[END_REF], suggesting that the GLP-1/GLP-1R system may have different roles in the in the periphery and in the central nervous system (which is not attained by antibodies). In humans, polymorphisms in the GLP-1R gene have been linked to obesity-related pathologies such as type-2 diabetes mellitus (T2DM) and cardiovascular diseases [START_REF] Scott | A genomic approach to therapeutic target validation identifies a glucoselowering GLP1R variant protective for coronary heart disease[END_REF]33], while the GLP-1 axis appears to be more frequently mutated in binge-eating disorders [START_REF] Lutter | Novel and ultra-rare damaging variants in neuropeptide signaling are associated with disordered eating behaviors[END_REF]. However, the study of circulating GLP-1 levels in the context of obesity leads to inconsistent results: some studies establish a positive correlation between BMI and GLP-1 levels [35,[START_REF] Bowes | Lifestyle change reduces cardiometabolic risk factors and glucagon-like peptide-1 levels in obese first-degree relatives of people with diabetes[END_REF], others report attenuated GLP-1 responses to meals in obese compared to lean subjects [START_REF] Adam | Glucagon-like peptide-1 release and satiety after a nutrient challenge in normal-weight and obese subjects[END_REF][START_REF] Carroll | Influence of BMI and gender on postprandial hormone responses[END_REF], and a third set of studies simply finds no significant link between GLP-1 response and obesity [START_REF] Vilsbøll | Incretin secretion in relation to meal size and body weight in healthy subjects and people with type 1 and type 2 diabetes mellitus[END_REF]. Thus, the causative implication of GLP-1 in obesity has not been established.

Nonetheless, there are multiple GLP1R agonists in the pharmacopeia currently under trial, either alone or in combination, for the treatment of obesity and T2DM [START_REF] Gerstein | Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial[END_REF][START_REF] Knudsen | The Discovery and Development of Liraglutide and Semaglutide[END_REF]. Some of them, like liraglutide or exenatide are prescribed to diabetic patients, yielding promising weight-loss results beyond their insulinotropic effects [START_REF] Fadini | Comparative effectiveness of exenatide once-weekly versus liraglutide in routine clinical practice: A retrospective multicentre study and meta-analysis of observational studies[END_REF] and liraglutide has recently been FDA approved for the treatment of obesity [START_REF] Perez-Montes De Oca | Obesity and GLP-1[END_REF]. Dual agonists acting on the receptors for glucagon and glucagon-like peptide-1 are being developed for the treatment of obesity, and MEDI0382 as well as SAR425899 caused weight reduction in obese patients with Type 2 diabetes [START_REF] Ambery | MEDI0382, a GLP-1 and glucagon receptor dual agonist, in obese or overweight patients with type 2 diabetes: a randomised, controlled, double-blind, ascending dose and phase 2a study[END_REF][START_REF] Tillner | A novel dual glucagon-like peptide and glucagon receptor agonist SAR425899: Results of randomized, placebo-controlled first-in-human and first-in-patient trials[END_REF].

There is now more and more convincing evidence that intestinal peptides like GLP-1 not only regulate the quantity of calories ingested but also their quality. In fact, the signaling pathways of these peptides (GLP-1 but also GIP) are not only activated in the homeostatic regions of the central nervous system (hypothalamus or brainstem), but also in non-homeostatic regions [START_REF] Adriaenssens | The glucose-dependent insulinotropic polypeptide signaling axis in the central nervous system[END_REF][START_REF] Da Porto | Dulaglutide reduces binge episodes in type 2 diabetic patients with binge eating disorder: A pilot study[END_REF] such as certain areas of the limbic system (striatum, ventral tegmental area), the hippocampus or the olfactory bulb ,which strongly expresses GLP-1 receptors [START_REF] Thiebaud | A unique olfactory bulb microcircuit driven by neurons expressing the precursor to glucagon-like peptide 1[END_REF]. Thus, these peptides control the quantity of food ingested but also participate in our food choices and preferences [START_REF] Nielsen | Oxyntomodulin and Glicentin May Predict the Effect of Bariatric Surgery on Food Preferences and Weight Loss[END_REF]49]. It is therefore conceivable that future classes of compounds that target receptors of these peptides (alone, in combination, or in the form of di-triagonists) may impact our feeding behavior, thus inducing a preference for, or an aversion to, certain types of food with equal caloric intake acting in addition to their effects on homeostatic regulation [50] GIP Gastric inhibitory polypeptide (also called glucose-dependent insulinotropic polypeptide, GIP) was initially considered as the orexigenic member of the incretin family, given that chemical inhibition of the GIP receptor (GIPR) or its genetic deletion in mice protected them from diet and geneticallyinduced obesity by reducing food intake and stimulating catabolism. However, its metabolic actions are twofold: after a meal, it stimulates insulin release, but in the fasted state, it enhances glucagon release [51]. Moreover, in mice activation of GIPR-positive neurons in the hypothalamus reduced food intake, suggesting that the role of GIP in central appetite control is complex, in line with the fact that GLP-1 positive neurons can co-express GIPR [START_REF] Adriaenssens | Glucose-Dependent Insulinotropic Polypeptide Receptor-Expressing Cells in the Hypothalamus Regulate Food Intake[END_REF].

Pharmacological GIPR agonists, especially if combined with GLP-1R agonists, reduce food intake in mice [START_REF] Coskun | LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: From discovery to clinical proof of concept[END_REF]54]. Indeed, dual agonists that activate both GIPR and GLP-1R such as LY3298176 (also called tirzepatide) has been shown to reduce body weight in Type 2 diabetes patients [START_REF] Coskun | LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: From discovery to clinical proof of concept[END_REF][START_REF] Frias | Efficacy and safety of LY3298176, a novel dual GIP and GLP-1 receptor agonist, in patients with type 2 diabetes: a randomised, placebo-controlled and active comparatorcontrolled phase 2 trial[END_REF],

suggesting that GIP actually may serve as an anorexigen when acting in the presence of GLP-1. A phase 3 study that evaluates LY3298176 for the treatment of obesity is underway.

Increased levels of circulating GIP are measured in obese patients, especially after a meal [51,[START_REF] Jones | Obesity is associated with increased post-prandial GIP levels which are not reduced by dietary restriction and weight loss[END_REF].

Genetic perturbations in GIP signaling favor the development of obesity: polymorphisms near the GIPR locus are associated to an increased risk of obesity and perturbations in glucose metabolism [START_REF] Speakman | Functional analysis of seven genes linked to body mass index and adiposity by genome-wide association studies: a review[END_REF]58], while variants in the GIP gene have been linked with increased adiposity [START_REF] Nakayama | Common variants of GIP are associated with visceral fat accumulation in Japanese adults[END_REF][START_REF] Wang | The effect of glucose-dependent insulinotropic polypeptide (GIP) variants on visceral fat accumulation in Han Chinese populations[END_REF].

Oxyntomodulin OXM more recently emerged as an alternative to GLP-1 because of their overlapping activity: OXM activates GLP1-R and the glucagon receptor (GCGR), causing both satiation and an increase in energy expenditure [START_REF] Scott | Oxyntomodulin analogue increases energy expenditure via the glucagon receptor[END_REF]. Like other anorexigenic gut hormones, OXM strongly increases after bariatric surgery. However, its basal level does not seem to be disturbed in obese compared to lean patients, suggesting that OXM cannot be involved in the etiology of obesity [62]. Notwithstanding this limitation, OXM administration to obese subjects successfully dampened appetite and improved energy expenditure, leading to a significant loss in body weight [START_REF] Wynne | Oxyntomodulin increases energy expenditure in addition to decreasing energy intake in overweight and obese humans: a randomised controlled trial[END_REF]. Such a "dual agonism" is a tempting approach to compensate the decrease in energy expenditure usually caused by a decreased food intake, but still requires a better understanding of the balance between its metabolic and anorexigenic effects.

Cholecystokinin

Cholecystokinin (CCK), a hormone secreted by the intestine after ingestion of lipids and proteins, slows gastric emptying and triggers satiety in a wide variety of species [START_REF] Dockray | Cholecystokinin[END_REF]. Its effects are additive or even synergic to leptin, perhaps because of the colocalization of LepR and CCK receptors on vagal afferent fibers and in the NTS [65], but is also likely to involve to descending projections from the hypothalamus to the hindbrain that are activated by leptin acting in the hypothalamus [START_REF] Morton | Evidence against hypothalamic-pituitary-adrenal axis suppression in the antidiabetic action of leptin[END_REF]. Rats bearing a genetic deletion of CCK receptor are hyperphagic and obese [START_REF] Moran | Disordered food intake and obesity in rats lacking cholecystokinin A receptors[END_REF]. However, such a clear effect has not been reproduced in mice [START_REF] Lo | Characterization of mice lacking the gene for cholecystokinin[END_REF]. Despite a dose-dependent acute diminution of meal size with CCK administration [START_REF] Gibbs | Cholecystokinin elicits satiety in rats with open gastric fistulas[END_REF], in the long term, this CCK effect is compensated by an increase in meal frequency, and no weight loss is achieved [START_REF] West | Cholecystokinin persistently suppresses meal size but not food intake in free-feeding rats[END_REF][START_REF] West | Infusion of cholecystokinin between meals into free-feeding rats fails to prolong the intermeal interval[END_REF]. Other mechanisms, such as the impaired vagal sensitivity measured in high-fat diet-fed mice, may contribute to lack of efficacy of CCK in animal models [START_REF] Crawley | Rapid development of tolerance to the behavioural actions of cholecystokinin[END_REF], as well as in patients [START_REF] Dockray | Cholecystokinin[END_REF]. Indeed, obese subjects who durably lose weight decrease their post-prandial CCK secretion, even after a stabilization period of a year [START_REF] Sumithran | Long-term persistence of hormonal adaptations to weight loss[END_REF].

Polymorphisms in the genes coding for CCK or its receptors have been linked to body fat content [START_REF] Funakoshi | Gene structure of human cholecystokinin (CCK) type-A receptor: body fat content is related to CCK type-A receptor gene promoter polymorphism[END_REF], larger meal sizes [START_REF] De Krom | Common genetic variations in CCK, leptin, and leptin receptor genes are associated with specific human eating patterns[END_REF], and higher risk of weight regain [START_REF] Larsen | Analyses of single nucleotide polymorphisms in selected nutrientsensitive genes in weight-regain prevention: the DIOGENES study[END_REF]. However, BMI and other obesity-related indicators do not seem to be related to CCK circulating levels [START_REF] Butler | Plasma cholecystokinin levels in Prader-Willi syndrome and obese subjects[END_REF], suggesting that CCK is not a major contributor to the pathogenesis of obesity.

Peptide YY

Peptide tyrosine-tyrosine (PYY) is a member of the NPY family [77], but it is mostly secreted in the gut upon lipid and protein ingestion in the form of 2 major forms: PYY and PYY [START_REF] Essah | Effect of macronutrient composition on postprandial peptide YY levels[END_REF].

PYY binds to Y1, Y2, Y4, and Y5 receptors; PYY is a high-affinity ligand for Y2 receptors with low affinity for Y1 and Y5 receptors [START_REF] Keire | Structure and receptor binding of PYY analogs[END_REF]. Influenced by a positive control loop with CCK, PYY appears to be co-secreted and have complementary effects with GLP-1 (and OXM) [START_REF] Gimeno | Leveraging the Gut to Treat Metabolic Disease[END_REF].

Early studies proved the anorexigenic effect of central and peripheral PYY injections in various animal models, as well as in humans [START_REF] Batterham | Gut hormone PYY(3-36) physiologically inhibits food intake[END_REF][START_REF] Morley | Peptide YY (PYY), a potent orexigenic agent[END_REF]. In the context of obesity, PYY variations are coherent with the hypothesis that high caloric intake is driven by an excessive appetite: fasting levels and PYY meal responses are lower in obese subjects compared to their lean counterparts and PYY levels decrease after diet-induced weight-loss (for a review, see [START_REF] Karra | The role of peptide YY in appetite regulation and obesity[END_REF]). Of note, polymorphisms in the PYY gene or its regulatory regions have been linked to obesity-related phenotypes [84,[START_REF] Shih | Peptide YY (PYY) gene polymorphisms in the 3'-untranslated and proximal promoter regions regulate cellular gene expression and PYY secretion and metabolic syndrome traits in vivo[END_REF], while high circulating PYY levels are seen in restrictive-type anorexia nervosa (AN) [START_REF] Misra | Elevated peptide YY levels in adolescent girls with anorexia nervosa[END_REF]. Based on studies that confirmed comparable short-term sensitivity to PYY-induced satiation between lean and obese subjects [START_REF] Le Roux | The putative satiety hormone PYY is raised in cardiac cachexia associated with primary pulmonary hypertension[END_REF], larger scale clinical studies were launched by pharmaceutical companies since the early 2000s. Merck's Nastech trial was abandoned due to a lack of results as well as adverse effects such as constant nausea for the highest doses [START_REF] Gantz | Efficacy and safety of intranasal peptide YY3-36 for weight reduction in obese adults[END_REF]. More recently, combination therapies of PYY with GLP-1R agonists have been successful with less side events in primates [START_REF] Rangwala | A Long-Acting PYY(3-36) Analog Mediates Robust Anorectic Efficacy with Minimal Emesis in Nonhuman Primates[END_REF] and are still under clinical investigation (Novo Nordisk trials NCT03707990 and NCT03574584).

Apolipoprotein A-IV

Apolipoproteins are a family of proteins that bind to lipids: by regulating their transport, they are key actors in lipid metabolism [START_REF] Hayashi | Transport of lipid and apolipoproteins A-I and A-IV in intestinal lymph of the rat[END_REF]. Among them, apolipoprotein A-IV (Apo-A4) is secreted by the small intestine in response to dietary lipids [START_REF] Apfelbaum | Apolipoprotein A-IV synthesis in rat intestine: regulation by dietary triglyceride[END_REF]. In rodents, peripheral injection of recombinant Apo-A4, suppressed appetite while central injection of anti-Apo-A4 antibody elicited unusual food intake during the light period [START_REF] Fujimoto | Suppression of food intake by apolipoprotein A-IV is mediated through the central nervous system in rats[END_REF]. Mechanistically, Apo-A4 requires and interacts positively with the CCK circuits [START_REF] Lo | Apolipoprotein AIV requires cholecystokinin and vagal nerves to suppress food intake[END_REF] and its secretion is down-regulated by leptin [START_REF] Liu | Regulation of intestinal and hypothalamic apolipoprotein A-IV[END_REF].

Various human studies found associations between variations in the apo-A4 gene and obesity or obesity-related traits [START_REF] Ejchel | Association of the apolipoprotein A-IV: 360 Gln/His polymorphism with cerebrovascular disease, obesity, and depression in a Brazilian elderly population[END_REF][96][START_REF] Fiegenbaum | Further evidence for the association between obesityrelated traits and the apolipoprotein A-IV gene[END_REF]. However, no general trend can be outlined from the few data available on the variation of Apo-A4 plasma levels in obesity [START_REF] Sun | Effects of age, gender, and lifestyle factors on plasma apolipoprotein A-IV concentrations[END_REF][START_REF] Vergès | Increased plasma apoA-IV level is a marker of abnormal postprandial lipemia: a study in normoponderal and obese subjects[END_REF]. This lack of consistency between studies may be explained by the influence of sexual hormones [100] but also by a retro-active mechanism in the regulation of Apo-A4. Thus, studies in rats and in humans show that Apo-A4 increases proportionally to the lipid intake in short term, although a constant high fat diet leads to a return to Apo-A4 basal levels within weeks [101]. Moreover, the anorectic response to Apo-A4 is blunted in high fat diet-induced obesity of rats [102].

Bombesin-like peptides

The bombesin-like family of peptides is comprised of two anorectic peptides: gastrin-releasing peptide (GRP) and neuromedin beta (NMB), which target specific G-coupled receptors (GRP-R and MNB-R, GRP-R; a third receptor, bombesin receptor subtype 3, BRS-3, has no known endogenous ligand) in order to cause systemic effects that include increased thermogenesis, decreased appetite and inhibition of gastric emptying [103]. While GRP-R (and BRS-3) deficient mice tend develop hyperphagia, metabolic imbalance and obesity [104], NMB-R-deficient mice rather manifest impaired adipogenesis, which protects them from diet-induced obesity [105]. Observed in a large set of species, the anorexigenic effects of bombesin-related peptides seem to be mostly mediated by GRP through activation of hypothalamic neurons [104], while NMB regulates food intake through an effect on adipose tissue [106].

The impact of this axis on appetite is confirmed by human genetic studies: polymorphisms in NMB are more frequent in obese patients [107][108][109], and some sequence and copy number variations in the GRP gene have been linked to early-onset obesity [110]. Nevertheless, activation of GRP-R was able to cause food suppression in lean but not in obese women [111], and sex differences were also highlighted in the consequences of a mutation in the NMB gene on long-term caloric intake [112].

BRS-3 agonists are currently under investigation with apparently more systematic results in obese patients, but its endogenous ligand remains unknown [113], and non-specific effects triggering adverse events will have to be taken into account [114]. Altogether, the implication of bombesin-like peptides in obesity is far from being fully understood, calling for further investigation before clinical applications can be envisioned.

Secretin

Historically seen as a digestive peptide that controls gastric acidification and motility, secretin (SCT) recently regained interest as an anorexigenic peptide. Previous studies on appetite regulation led to conflicting results: meal reduction was achieved upon central and peripheral injection of SCT in mice and was accompanied by increased lipolysis [115], but such results are inconsistent with earlier findings in rats [116] and sheep [117]. A predominant role in the regulation of lipid metabolism was inferred by the fact that SCT-receptor-deficient mice did not modify their eating patterns, but were still protected from HFD-induced obesity because of faulty lipogenesis [118]. A study by Li et al. reconciled the metabolic and appetite-regulatory effects of SCT with a model of SCTR-expressing brown adipocytes, which, once activated, increase thermogenesis and send hormonal signals to the hypothalamic appetite control centers [119]. This study also confirmed the effects of SCT-induced BAT activation on appetite and energy regulation in seven human subjects, opening the way for the use of adipose tissue-based strategies for the regulation of food intake [119]. Further studies, especially in the context of obesity, will be needed to elucidate the SCT-mediated crosstalk between intestinal and adipose tissues.

VIP/PACAP

Vasoactive intestinal peptide (VIP) and adenylate cyclase activating polypeptide 1 (ADCYAP1, hereafter referred to as PACAP) are homologous pleiotropic neuropeptides from the glucagon family.

Highly expressed in the intestinal and central nervous systems, they target the hypothalamic centers of food regulation and decrease food intake when administered centrally to vertebrates [120]. Except for one experiment in fish [121], there is no proof that peripheral injection of VIP diminishes caloric intake. However, peripheral PACAP administration consistently inhibited food intake in mice [122].

This difference can be explained by the fact that VIP and PACAP share the VPAC1 and VPAC2 receptors, while the PAC1 receptor which mediates appetite inhibitory effects is specific to PACAP [122,123].

As confirmed by genetic association studies that linked the VIP axis to obesity [124] and PACAP polymorphisms to addictive and binge-eating behaviors [125], these two peptides play a role in central control of food intake but are not strictly anorexigenic. Indeed, the knockout of both VIP and PACAP results in unexpected effects on the metabolism of mice: instead of the expected increase in caloric intake, appetite-related hormones are dysregulated, leading to a decrease in food intake and fat mass [126,127]. In a review that reconciles the opposed effects between normal and extreme conditions, Gargiulo et al. proposed a model in which a finely regulated feedback loop linking PACAP to the control of normal feeding cycles, is broken when overfeeding increases the basal PACAP levels [125].

Other peripheral anorectic peptides

Hormones secreted by the pancreas, the liver, or multiple other cell types can participate to the regulation of the peripheral metabolic response and affect with appetite and energy homeostasis.

Insulin

Insulin secretion increases in response to a meal and the concomitant hyperglycemia, which allows the body to manage caloric intake by promoting energy storage and reducing food intake. The short-term inhibitory effect of insulin on food intake was first demonstrated experimentally in the 1980s [128].

Although the molecular mechanisms have not yet been fully elucidated, it is known that insulin acts in the hypothalamus via the inhibition of NPY/AgRP/GABA neurons and the activation of POMC/CART neurons, both populations expressing the insulin receptor. Recent results indicate that insulin activates POMC neurons via transient receptor potential (TRPC)5 channels [129,130]. Conversely, insulin inhibits NPY/AgRP/GABA neurons through activation of K(ATP) channels, leading to their hyperpolarization [130].

Like leptin, insulin is believed to act as an adiposity signal, contributing to the long-term brain control of body weight in addition to its short-term effects. Thus, a change in plasma leptin or insulin levels is detected as an altered state of energy homeostasis and adiposity, to which the brain responds by adjusting food intake to restore the basal fat mass level. These long-term effects may partly explain the seasonal changes in weight and fat mass. Because of its effect on energy storage and weight gain (which is a side effect of insulin therapy for type 2 diabetics), insulin cannot be considered as an effective treatment for obesity. However, approaches combining a co-injection of amylin (see "calcitonin-related peptides" below) and insulin (or leptin) may act synergistically to effectively reduce food intake and body weight [131,132].

Pancreatic polypeptide

The pancreatic polypeptide (PP) is secreted postprandially by PP cells in the islets of Langerhans. PP belongs to the family of NPY and causes central anorectic effects through Y4 and Y5 receptors. PP secretion is impaired in ob/ob mice [133]. PP injections limit food intake and weight gain in both leptin-competent and leptin-deficient mice [134]. The translation of these findings to humans is not perfect, with reports of diminished food intake at short term [135] but no differences in hunger ratings in another study [136]. Nonetheless, consistent diminution of PP levels is confirmed in syndromic obesity such as the Prader-Willi Syndrome (PWS) [137], in non-syndromic obese patients [138] and in large-scale studies, with negative correlations between PP levels and fat mass/BMI [139]. Conversely, in patients with anorexia nervosa, the PP response to a meal is abnormally high [140]. Despite diverging reports on its variations upon weight loss [START_REF] Sumithran | Long-term persistence of hormonal adaptations to weight loss[END_REF]141,142], in the context of obesity, PP follows a trend that fits an increase in hunger and sensitivity to PP treatment does not seem to be compromised [143]. In conclusion, PP appears as a good candidate for an anti-obesity drug, though with the limitations of its short half-life in circulation and the complexity of its interactions with the NPY and PYY receptor networks [144].

Calcitonin-related peptides

The family of calcitonin-related peptides (CRP) is comprised of peptides that are primarily secreted in the pancreas and in the brain: amylin (also called islet amyloid peptide, IAPP), adrenomedullin (ADM), calcitonin (CT) and calcitonin gene-related peptide (CGRP). Each of them has been studied and will be presented separately, but they share two receptors, the CT-receptor (CTR) and CT-like receptor (CLR), which makes them highly interdependent [145].

Amylin is released by β-cells of the pancreas along with insulin. After an abnormal increase in the early phase of the disease, amylin blood levels are durably decreased in diabetes and amylin analogues have been approved for diabetes treatment [146]. In terms of food intake, amylin decreases meal sizes when administered centrally and peripherally, with no resistance effects known on long-term, through a direct central activation of CTR as well as the potentiation of CCK circuits [147]. Different analogues with increased effects are currently under preclinical and clinical investigation, either alone or in combination [START_REF] Levin | Amylin and Leptin: Co-Regulators of Energy Homeostasis and Neuronal Development[END_REF]. In the context of obesity, basal amylin levels tend to increase, but the postprandial rise is maintained and no desensitization to its anorexic effect has been reported [132]. Upon weight loss, amylin levels reportedly decrease [START_REF] Sumithran | Long-term persistence of hormonal adaptations to weight loss[END_REF], adding up to many other hunger signals.

Adrenomedullin is a ubiquitous peptide with multiple functions including growth, endocrine regulation, neurotransmission and antimicrobial activity [148,149]. Evidence for altered ADM function was found in fa/fa obese rats [150]. Peripheral injections of ADM inhibit gastric emptying and decrease food intake in rats [151]. In human, variations in the gene for ADM receptor were linked to a smaller BMI [150]. Long-term studies found associations between weight gain and high plasma levels of ADM in women but not in men [152]. These cues indicate a role for ADM in body weight regulation, although it is not univocally anorexigenic.

The calcitonin related polypeptide alpha (CALCA) encodes for the last two members of the family, CT and CGRP. Elevated plasma levels of their common prepropeptide, procalcitonin, has been associated to higher BMI in the general population [153], but differential effects occur for each peptide. On one hand, calcitonin has been most intensively studied for its calcium-related properties, but recent evidence from knockout studies in mice describes it as potentially orexigenic and lipogenic Altogether, the CRP family definitely plays a role in appetite regulation and acts at the central and peripheral levels. Given the wide spectrum of their biological roles and the complexity of their interactions, it may be difficult to develop CRP analogues for a specific obesity treatment, and further studies are required to precisely understand their appetite inhibitory effects.

Apelin

Apelin (APLN) is a 77 amino-acids protein belonging to the family of adipokines. It is mainly produced by adipocytes but also by gastric mucosa and Kupffer cells in the liver [161]. Several active forms arise from this common precursor and are detected in bloodstream (13, 17 or 36 amino acids).

Apelin is the ligand of the former orphan APJ receptor, a seven-transmembrane G-protein-coupled receptor. APJ is widely distributed in various tissues (heart, blood vessels, stomach, etc.) including the central nervous system, especially in the hypothalamus. APLN appears to be pleiotropic, with evidence of dietary inhibition in rodents (mice and rats) when a synthetic analogue, pyroglutamylated apelin-13, is administered centrally [162]. However, the doses and routes of administration may lead to conflicting results on dietary intake [163]. The duration of treatment may affect treatment efficacy, since peripheral administration of apelin-13 for 28 days induced a decrease in food intake and body weight in obese Swiss mice on high-fat diet [164].

In parallel with insulin, APLN rises in response to blood glucose increase and has a glucose-lowering effect. Recently, APLN analogues showed encouraging preclinical results, with a strong insulinotropic effect and food intake suppression mice. [165]. Across studies, APLN plasma level are consistently increased in obese patients compared to their lean counterparts, possibly to compensate or delay their insulin resistance [166].

Fibroblast growth factor 21

Fibroblast growth factor 21 (FGF21) is secreted in the liver upon sugar ingestion. It has been found to correct genetic and diet-induced obesity in mice [167], to decrease food intake and to limit sweet preference in mice and non-human primates [168]. Metabolically, it stimulates glucose uptake and thermogenesis in the BAT and fatty acid oxidation in the liver through the activation of hypothalamic and adrenal circuits which release corticosterone [169]. Accordingly, variants in the human FGF21 locus are associated with increased carbohydrate preference in adults [170] as well as with total macronutrient intake [171]. However, circulating FGF21 is positively correlated with BMI and high levels are associated with metabolic syndrome and T2DM [172,173]. Seen as a protective mechanism against nutrient-induced hepatotoxicity [174], the FGF21 axis seems to be overactive in obese patients. Thus, FGF21 exemplifies yet another appetite inhibitor that cannot be involved in the etiology of obesity since it is upregulated (rather than downregulated). Despite this pattern of dysregulation, many FGF21 analogues are under trial to treat obesity, diabetes and their comorbidities. Some of them lead to moderate weight loss [168,175], but their main effect appears to be the limitation of hepatic lipid accumulation [176], establishing FGF21 analogues as candidates for the treatment of non-alcoholic fatty liver disease.

Nesfatin

Nesfatin is a broadly expressed peptide derived from the protein nucleobidin-2, the anorectic effects of which were discovered in the early 2000s when it was injected peripherally into mice and rats. These effects are leptin-independent and rely on activation of the vagus nerve and on direct hypothalamic signaling, leading to the inhibition of NPY neurons and the activation of the melanocortin system [177,178]. Metabolically, it enhances glucose-induced insulin secretion [179]. In line with this, a polymorphism of the NUCB2 gene is associated with a decreased risk of T2DM (in heterozygosity) as well as of obesity (in homozygosity) [180,181]. However, nesfatin can be detrimental when overexpressed: in mice, genetically-induced overexpression leads to insulin resistance, increased body mass and fat deposition in the liver upon high-fat diet [179]. Such a dysregulation is observed in human obesity: while nesfatin appears to be negatively correlated with BMI in normal-weight subjects

Oxytocin

Oxytocin, the "social hormone", falls into the scope of this review because it triggers anorectic responses when injected peripherally into rodents [186]. In humans, central and metabolic effects of oxytocin complement each other to induce weight loss: they include snacking reduction, improved insulin sensitivity, fatty acid oxidation and increased energy consumption [187]. Oxytocin signaling is crucial for weight regulation: genetic defects in oxytocin receptor have been linked to precocious obesity [188], while, on the contrary, patients with PWS have significantly lower oxytocin-expressing neurons and are moderately sensitive to oxytocin-driven weight loss [189,190]. Not all studies agree on the variations of oxytocin in obese patients, with reported positive and negative correlations between oxytocin levels and body or fat mass [191]. Nevertheless, intranasal oxytocin treatments of non-syndromic obese patients yielded promising results even in the case of high basal levels of this hormone [192,193].

Peripheral appetite stimulators

As a general rule, in pharmacology, receptor agonists/activators have more side effects than receptor antagonists/inhibitors, calling for the identification of appetite-stimulatory pathways (Table 2, Figure 4) that might be overactivated in obesity and hence constitute attractive targets for therapeutic intervention.

Ghrelin and intestinal factors

Ghrelin

The historical counterpart of leptin, ghrelin, is a hormone that apparently rises upon fasting and declines upon satiation. Its receptor (growth hormone secretagogue receptor, GHSR) is expressed centrally, directly activating the AgRP/NPY orexigenic neurons in the hypothalamus, and peripherally, for example in the adipose tissues where it increases fat storage. Strong orexigenic effects are seen in animal models and lead to obesity when ghrelin is chronically administrated [194], while selective inhibition of ghrelin signaling in the brain leads to hypophagia and resistance to high-fat diet-induced weight gain [195]. Translation of these clear-cut observations into human treatments proved disappointing. On one hand, ghrelin inactivation by recombinant or endogenous antibodies lead to moderate weight loss [196]. On the other hand, supraphysiological doses of ghrelin are necessary to increase hunger [197,198]. Moreover, a large number of studies revealed a negative correlation between ghrelin levels and BMI in humans (reviewed in [199]). With the notable exception of PWS patients, who have abnormally high ghrelin levels [200], the (paradoxically) lower levels of ghrelin observed in non-syndromic obesity indicate yet another feedback mechanism that is thwarted by the general hormonal deregulation associated with obesity.

Two directions may be helpful to better control ghrelin effects on appetite. The first one is the discovery that acylation by ghrelin O-acyl-transferase (GOAT) is necessary to appetite-inhibitory ghrelin activity, which led in the past decade to the development of GOAT inhibitors still under study [201,202]. Importantly, only non-acylated, but not acylated, ghrelin increases with fasting, shedding doubts on the participation of ghrelin in a 'hunger reflex' [203]. The second one is the alternative posttranslational product of the ghrelin gene, obestatin. First seen as an appetite suppressor with effects opposed to ghrelin, it is now more often described as a metabolic regulator that modulates insulin sensitivity and adiposity through GHSR-dependent mechanism [204]. Most studies report that obestatin levels are downregulated in obesity and T2DM, as well as a negatively correlated with BMI, making it a possible (but controversial) target for the treatment of obesity and diabetes [205].

Motilin

Motilin is secreted between meals and stimulates peristaltic waves following the pattern of migrating motor complex (MMC) contractions: its peak provokes the entry into phase III (the maximum of mechanical and electrical activity causing active peristalsis for 5-10 min), which may induce the feeling of hunger through vagal nerve activation [206]. The administration of motilin or erythromycin, an antibiotic that also acts as a motilin receptor agonist, induces premature MMC phase III and increases the declared appetite in healthy subjects [207]. Given the potential role of motilin and gastric motility in driving hunger, plasma levels of obese patients have been compared to their lean counterparts under fasted or refed conditions, yielding alternatively higher or lower levels [207,208].

However, obese subjects seem to lack a clear motilin peak and MMC phase III induction across studies, indicating an impairment of gastric motility. One genome-wide association study indicated that single nucleotide polymorphisms in the motilin gene are among the mutations that are most strongly associated with extreme obesity [209].

Adipose tissue peptides

Adiponectin

Adiponectin is an adipocyte-secreted hormone that is obesogenic in mice, and which genetic inactivation leads to resistance to HFD-induced obesity. The absence of adiponectin led to a decrease in food intake, increased energy expenditure, insulin desensitization and reduction in adiposity [210].

In a multi-ethnic meta-analysis spanning more than 45,000 subjects, alleles involved in the diminution of adiponectin levels were strongly associated with lower BMI but also with an increased risk of T2DM and insulin resistance [211]. In effect, lower adiponectin levels have been consistently measured in obese patients and shown to be inversely correlated with BMI and fat mass [212].

Therefore, the obesity-associated decrease in adiponectin can be interpreted as an attempt of metabolic adaptation to increase energy intake, resulting in limited effects on feeding behavior and adipose tissue accumulation, though deleterious consequences in terms of insulin resistance and hypertension.

Asprosin

Another adipokine, called asprosin, is secreted upon fasting. Subcutaneous injection of this factor into mice stimulated food intake, likely through central effects because peripherally injected asprosin crosses the blood-brain barrier [213]. Its main metabolic effect is to trigger glycogenolysis in the liver, thus elevating circulating glucose levels during fasting, but it is also able to directly activate orexigenic AgRP neurons [214]. Asprosin levels are associated with high BMI and insulin resistance: it was found to be upregulated in obese versus lean individuals in most recent studies, with one exception in obese children [215,216]. The Marfan lipodystrophy syndrome, associated with severe leanness, originates from mutations in the FBN1 gene, which codes for asprosin as well as a structural protein called Fibrilin1 [217]. Other polymorphisms in the asprosin-coding part of FBN1 have been associated with decreased asprosin plasma levels and hypophagic, extremely underweight and lipodystrophic phenotypes [213]. Interestingly, one study on anorexia nervosa patients found elevated levels of asprosin in patients with bulimic behaviors, reflecting a possible detrimental adaptation to their reduced caloric intake [218]. Altogether, asprosin is a peptide whose variations reliably dictate the alimentary behavior and metabolic resilience in both lean and obese subjects, making it a new potential target for obesity treatments.

Ubiquitously secreted proteins NAMPT Nicotinamide phosphoribosyltranferase (NAMPT, also known as Visfatin) is a ubiquitous intracellular enzyme that contributes to nicotinamide adenine dinucleotide (NAD + ) synthesis, conferring it with important metabolic and nutrient-sensing. Beyond its enzymatic activity, NAMPT is secreted by a large number of cells. Its endocrine role is the subject of much debate, especially in the pathophysiology of obesity [219]. A central effect of circulating NAMPT can be hypothesized, based on the fact that, in chicks and rats, central injections of NAMPT activate hypothalamic circuits and increase food intake [220,221]. Given that adipose tissue-specific Nampt knockout is sufficient to render mice completely resistant to HFD-induced obesity and to improve their glucose tolerance, adipocytes appear to contribute to the obesogenic effects of NAMPT [222]. Human studies tend to confirm the orexigenic role of NAMPT as its plasma level is increased in obesity [223]. Notably, a rare allelic form of NAMPT was found to be protective against extreme obesity in a cohort enrolling more than 6000 subjects [224], raising hopes for targeting NAMPT as a suitable strategy against obesity.

ACBP

Acyl-coenzyme A binding protein (ACBP), also called diazepam binding inhibitor (DBI), is a ubiquitous protein that is present in the cytoplasm of all nucleated cells, where it affects long-chain fatty acyl-CoA esters metabolism and mitochondrial fatty acid oxidation. Upon autophagy induction, for instance in response to fasting, ACBP is secreted from cells and the consequent rise in extracellular and circulating ACBP activates orexigenic and lipogenic responses in mice. Thus, the intravenous or intraperitoneal injection of ACBP causes an immediate (30 min) hyperphagic response that does not require the binding of ACBP to acyl-coenzyme A (because mutant proteins losing this function conserve their potential to stimulate appetite), yet requires the function of the γ-aminobutyric receptor (GABA) A receptor (GABAAR) because mice bearing a mutation in this receptor abolishing its interactions with ACBP fail to mount a hyperphagic response [225]. Transgenic expression expression of ACBP in hepatocytes is sufficient to cause significant weight gain and an increase in adiposity in mice [226]. Conversely, antibody-mediated inactivation of circulating ACBP is anorexigenic, meaning that it reduces hyperphagy in starved mice and leptin-deficient ob/ob mice as it reduces weight gain of mice fed a high-fat diet or increases weight loss when obese mice are switched from a high-fat to a normal diet [226]. Thus, the relocation of ACBP from the intracellular to the extracellular space can be viewed as a cellular sensor of nutrient scarcity that triggers appetite. It appears improbable that peripherally administered ACBP acts on the central nervous system to induce appetite because central injection of ACBP or its peptide fragments (in particular the octadecaneuropeptide, ODN) is anxiogenic and anorexigenic [227,228]. Thus, intracerebroventricular injection of ODN into the fourth ventricle inhibits the swallowing reflex controlled by the brainstem [229]. Similarly, intraparenchymal unilateral injection of OP into the arcuate nucleus of the hypothalamus reduces food intake. These effects are not mediated by GABAAR but rather by ODN-GPCR signaling, since they are blunted by co-treatment with a selective 231]. Moreover, the orexigenic effects of intraperitoneally injected ACBP can be blunted by a glucose clamp, again pleading against a direct central nervous action of ACBP [226].

Dampened ACBP signals may be linked to insufficient food intake, as indicated by lower ACBP levels in patients with anorexia nervosa [226,232] and by a predisposition to weight gain after antipsychotic treatment for patients bearing a polymorphism in the gene coding for the γ2 subunit of GABAAR [233]. Overexpression of ACBP is found in the tissues and the plasma of rodent models of obesity [234], as well as in human obese cohort studies, in which circulating ACBP levels strongly correlate with BMI. Thus, the obesity-induced overexpression of this orexigenic factor potentially drives a feed-forward mechanism to increase food consumption and to sustain the self-maintenance of obesity [235].

Conclusions and Perspectives

Although obesity has become the most prevalent pathological conditions afflicting humanity, its pathophysiology has not been elucidated to a level that would facilitate its management. Thus, a whole economic sector promises a myriad of diets or exercise regimens, psychosocial interventions, supplements of micronutrients or specific concoctions, though without tangible results. Bariatric surgery has major side effects and often provides only transient benefits. Pharmacological interventions have also been unsuccessful because anti-obesity drugs were either ineffective or produced major side effects precluding their general use [236]. In particular, anorexiants that targeted central-nervous appetite control have turned out to induce psychiatric side effects including suicide [237]. For this reason, peripheral appetite regulatory circuitries may offer new opportunities for an etiological treatment of obesity.

Here, we reviewed an extensive list of appetite regulators that are produced in peripheral locations and then regulate food intake through a variety of mechanisms that may be peripheral (for instance by effects on vagal afferences, by effects on other (neuro)endocrine factors, or by metabolic effects on major organs including the liver and adipose tissue) or central (by direct effects on appropriate brain centers). Of note, manipulation of some of appetite regulators mentioned here yields ambiguous results. Thus, neutralization of GIPR and GLP-1R by systemically injected antibodies (that in principle cannot cross the blood-brain barriers) inhibits diet-induced obesity in mice, but injection of dual agonists of GIPR and GLP-1R (which reach the brain) has marked anorexigenic effects, both in preclinical and clinical settings (Table 1). Similarly, injection of ACBP/DBI into the brain has anorexigenic effects, contrasting with the orexigenic consequences of its intravenous or intraperitoneal injection. These results underscore the fact that brain-permeable and -impermeable agonist and antagonists may have rather distinct effects. Future preclinical research should explore this conjecture, which, if correct, will affect the development of drugs for the treatment of obesity.

In this review, we attempted to identify those endogenous appetite inhibitors that are reduced in the circulation of obese patients as well as those appetite stimulators that are increased, driven by the believe that pharmacological manipulations of such mediators would have particularly high chances to be successful. Obviously, this rationale has some major caveats that result from persistent uncertainties: Are the methods used for the quantification of factors accurate? This question is particularly pertinent when distinct peptide fragments act on different receptors (as found for PYY) or post-translational modifications affect the bioactivity of appetite regulators (as illustrated for acylated ghrelin). Is the measurement of the factor in the plasma/serum physiologically relevant? This question is legitimate, taking into account that some of the factors mostly act as paracrine, not endocrine, factors (as gastrointestinal peptides that locally act on vagal afferences) and have a short half-live. Does the measurement occur during the dynamic phase of obesity (i.e., the phase with weight gain) or the static phase of obesity (i.e., the phase with stable weight and energy balance)? Unfortunately, longitudinal studies that would distinguish these phases are uncommon, but would be useful to distinguish possible differences in the role of appetite regulators in weight gain versus weight maintenance. Could alterations in circadian rhythms affecting peripheral appetite regulators contribute to the development of obesity? Again, the clinical exploration of disease-related, time-dependent fluctuations of appetite regulators is in its infancy. Finally, could deregulations in food preferences (for instance for high-sugar items, which likely are intrinsically obesogenic) be dictated by peripheral appetite regulators? Thus, specific factors (such as GIP and GLP) could determine a qualitative rather than a quantitative disequilibrium in food intake that contributes to the obese phenotype.

As summarized here, most factors that are generally considered as endogenous appetite inhibitors (such as leptin and many others) are increased in obese patients, and most endogenous appetite stimulators (such a ghrelin and many others) are reduced in non-syndromic obesity, likely reflecting a failing homeostatic circuitry that translates into this 'paradoxical' pattern. Thus, at difference with normal physiology (before obesity occurs), in which appetite stimulators or inhibitors participate in homeostatic pathways to limit caloric uptake (Figure 5A), once obesity has established, such circuitries appear to be unable to link excessive caloric intake and body mass to a reduction of appetite stimulatory hormones (or an increase in appetite inhibitor effects). Instead, they are replaced by disease amplifying feedforward loops in which excessive adiposity stimulates appetite (or suppresses appetite inhibition) (Figure 5B). Hypothetically, these latter feedforward loops would be truly pathogenic and would be accompanied by a 'coherent' pattern, i.e. an increase in appetite stimulators or a decrease of appetite inhibitors.

For this reason, it is important to identify peripheral modulators of appetite that behave in a 'coherent' rather than 'paradoxical' fashion. Thus, it may be advisable to concentrate research efforts on appetite inhibitors that are indeed reduced (not increased or unaltered) in obese subjects and to investigate whether their artificial supplementation (or, alternatively, the administration of agents that have agonistic effects on their receptors) would be able to reduce excessive caloric uptake. Similarly, it appears logical to neutralize appetite-stimulatory factors that are 'coherently' elevated (rather than 'paradoxically' reduced or unaltered) in obesity.

Apparently, only three endogenous appetite inhibitors follow a 'coherent' pattern: PP, PYY and VIP (Table 1). Given the fact that these potential anorexiants also have multiple other functions outside of appetite control, which would yield side effects, it will be important to choose among these agents the one that is the most 'specific' appetite controller. Using this criterion, which however is based on scarce knowledge, it appears that PP would be the best candidate for development. Nonetheless, at this point no active clinical trials are recruiting patients for PP administration.

Among the numerous appetite-stimulatory hormones that have been characterized over the past three decades, only three behave in a 'coherent' fashion: ACBP, asprosin and NAMPT (Table 2). These three factors are the only appetite-stimulatory effects with a ubiquitous expression pattern (Fig. 2A) and that are also phylogenetically ancient (Fig. 6). Thus, ACBP is the sole protein factor secreted by yeast (Saccharomyces cerevisiae) upon starvation and stimulates sporulation, which is the only possibility for yeast cells to search for new food sources. ACBP also stimulates pharyngeal pumping and nutrient uptake in the nematode Caenorhabditis elegans [238]. Asprosin/FBN1 possesses an orthologue in nematodes. NAMPT has a functional homologue, PNC-1, in yeast [239] and nematodes, where this protein can be secreted and has cell non-autonomous developmental functions [240]. It appears intriguing that such ubiquitous, phylogenetically ancient factors may be particularly important for the pathogenesis of human obesity.

In a highly speculative scenario (see Outstanding Questions), one or several among these three factors would have evolved to generate the 'core' of appetite control, which would have been complemented during evolution by many additional factors (that do not exist in invertebrates). However, only the 'core' is indeed endowed with the capacity to impose long-term deviations from normal body mass. Among these three putative 'core' appetite stimulators (ACBP, asprosin and NAMPT), the one that apparently has the most specific relationship to obesity is ACBP, in thus far that it is both an orexigenic factor and stimulates lipo-anabolism. In contrast, since asprosin binds to the insulin receptor, this factor may be expected to play a major role in glucose metabolism. Moreover, NAMPT is an enzyme that participates to the biosynthesis of nicotinamide adenine dinucleotide (NAD + ), a vital cofactor of many enzymes, suggesting that NAMPT inhibition might result in major side effects. As a possible strategy, 'core' appetite stimulators might be inactivated by blocking antibodies or by the blockade of their receptors. However, clinical trials that would explore this possibility are still elusive (Text Box 2).

In summary, well over two dozen peptide hormones participate in peripheral appetite control.

However, in human obesity, the serum concentrations of only three appetite inhibitors are reduced and only three appetite stimulators are enhanced, contrasting with all the other factors that often exhibit an inverse, paradoxical behavior. We surmise that this ensemble of six hormones constitutes the short list of agents that are the best potential targets for pharmacological interventions on appetite control.

Outstanding questions

• A systematic longitudinal analysis of changes in the plasma concentration of neuroendocrine appetite regulators is still elusive.

• It remains to be determined which appetite regulators contribute to the dynamic phase of obesity (i.e., the phase with weight gain) versus the static phase of obesity (i.e., the phase with stable weight and energy balance).

• It is important to explore the question as to whether appetite regulatory neuroendocrine factors determine food preferences and hence influence the quality of ingested food items beyond the quantity of calories.

• The optimal strategy to control appetite by pharmacological interventions is an open conundrum.

Text Box 1: Coherent versus paradoxical patterns of peripheral appetite regulators in obesity:

We propose to distinguish two patterns in the variation of appetite controlling regulators as they occur in human obesity.

We refer to a "paradoxical" pattern when obesity is associated with the increase of measurable concentrations of appetite-inhibitory factors or a decrease in the levels of appetite-stimulatory factors.

Indeed, such factors are either misclassified (for instance as a result of differences between humans and rodents, taking into account that most studies on appetite control are performed in mice or rats) or their variations cannot be the cause of obesity. At best, their fluctuation constitutes a futile attempt of the organism to return from the pathological (obese) state to the physiological (lean) condition. Of note, most known appetite regulators follow this pattern, as prominently exemplified by leptin (an appetite inhibitor that increases in non-syndromic obesity) or ghrelin (an appetite stimulator that usually is reduced in obese subjects). It can be attempted to shift the problem to aberrant responses to such mediators ("leptin resistance" or "ghrelin sensitivity"). Moreover, it can be postulated that without the "paradoxical" behavior of such mediators, obesity actually would be worse.

We consider that appetite stimulatory molecules that increase in obesity or appetite inhibitor that decrease follow a "coherent" pattern, because such variations may indeed explain the development of obesity and the maintenance of the obese state. Hence, they are potentially involved in the causation of obesity. For this reason, we suggest that appetite regulators that respect a "coherent" pattern should be considered as prime targets for therapeutic interventions on obesity.

Text Box 2: Outstanding clinical trials for the modulation of core appetite regulators:

Clinical trials for the treatment of obesity have been hampered for long because obesity has only recognized by the American Medical Association as a "disease" in 2013. For this reason, most clinical trials have been dealing with the treatment of comorbidities of obesity such as type-2 diabetes and non-alcoholic fatty liver disease. Moreover, the standards for safety are particularly stringent for clinical trials designed to achieve weight loss, because obesity (as opposed to, for example, cancer) is not considered as an acutely life-threatening condition. The clinical management of obesity demands a combination of pharmacological treatments with nutritional and behavioral interventions (diet & exercise), requiring compliance by the patient. The problem of compliance can be overcome by monitoring drug administration (or by providing injectable drugs), as well as continuous measuring of cardiometabolic parameters. However, it is notoriously difficult to induce and maintain stable modifications of eating habits and physical (in)activity.

The notion of a "core" of appetite-modulatory factors that exhibit a "coherent" behavior, suggesting a causative implication in obesity, is rather new. Appetite-inhibitory agents that are reduced in human obesity have been supplemented in clinical trials. This applies to subcutaneous injections of PP (https://www.clinicaltrials.gov NCT01052493, NCT02221765), as well as oral, nasal or intravenous administration of PYY (e.g. NCT00331175, NCT00537420, NCT00822705, NCT00940134), that were completed in the past, showing that appetite control can be achieved (see Table 1). However, specific inhibitors of appetite stimulators such as asprosin, NAMPT and ACBP have not yet been evaluated in clinical trials for the treatment of obesity. For this, it would be necessary to develop specific receptor antagonists or humanized neutralizing antibodies that are currently not yet available. [START_REF] Svendsen | Pharmacological antagonism of the incretin system protects against diet-induced obesity[END_REF][START_REF] Vilsbøll | Incretin secretion in relation to meal size and body weight in healthy subjects and people with type 1 and type 2 diabetes mellitus[END_REF][START_REF] Coskun | LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: From discovery to clinical proof of concept[END_REF]54,[START_REF] Jones | Obesity is associated with increased post-prandial GIP levels which are not reduced by dietary restriction and weight loss[END_REF][START_REF] Speakman | Functional analysis of seven genes linked to body mass index and adiposity by genome-wide association studies: a review[END_REF][58][START_REF] Nakayama | Common variants of GIP are associated with visceral fat accumulation in Japanese adults[END_REF][START_REF] Wang | The effect of glucose-dependent insulinotropic polypeptide (GIP) variants on visceral fat accumulation in Han Chinese populations[END_REF][251][252][253][254] Glucagon-like peptide 1

Tables

Peripheral injections of GLP-1 or agonist reduces feeding in rodents.

GLP-1 circuits are more frequently mutated in binge-eating population.

Increased / Decreased / Unchanged GLP-1R agonists induce weight loss by diminution of food [START_REF] Abbott | The inhibitory effects of peripheral administration of peptide YY(3-36) and glucagon-like peptide-1 on food intake are attenuated by ablation of the vagal-brainstemhypothalamic pathway[END_REF][START_REF] Baggio | A recombinant human glucagon-like peptide (GLP)-1-albumin protein (albugon) mimics peptidergic activation of GLP-1 receptor-dependent pathways coupled with satiety, gastrointestinal motility, and glucose homeostasis[END_REF][START_REF] Svendsen | Pharmacological antagonism of the incretin system protects against diet-induced obesity[END_REF][START_REF] Lutter | Novel and ultra-rare damaging variants in neuropeptide signaling are associated with disordered eating behaviors[END_REF][35][START_REF] Bowes | Lifestyle change reduces cardiometabolic risk factors and glucagon-like peptide-1 levels in obese first-degree relatives of people with diabetes[END_REF][START_REF] Adam | Glucagon-like peptide-1 release and satiety after a nutrient challenge in normal-weight and obese subjects[END_REF][START_REF] Carroll | Influence of BMI and gender on postprandial hormone responses[END_REF][START_REF] Vilsbøll | Incretin secretion in relation to meal size and body weight in healthy subjects and people with type 1 and type 2 diabetes mellitus[END_REF] In turn, neuronal projections to other populations located in lateral hypothalamic area (LHA), paraventricular nucleus (PVN) or ventromedian nucleus (VMN) together with other brain areas involved in nutrient sensing and reward will lead to finely control food intake and feeding behavior.

Legends to Figures

Neurons from circumventricular organs such as area postrema (AP), median eminence (ME),

  [154]. In addition, CT levels are positively correlated with BMI in elderly women [155]. On the other hand, CGRP is a neuropeptide of clinical interest for migraine treatments, which may contribute to appetite regulation [156]. CGRP neurons in the PVN are key mediators of anorexia [157, 158]. Food consumption can be reduced in mice upon peripheral injection of CGRP [159] or a long-lasting analogue, but these observations may result from indirect effects such as the activation of GLP-1 secretion [160].

[

  182], several in obese cohorts studies show either positive[183], negative[182] or no correlations[184]. The variation of the ratio between cerebral and plasma nesfatin may explain the observed differences: an exaggerated secretion in the plasma may not systematically result in the accumulation of the anorexigenic peptide in the brain[185].

Figure 1 .

 1 Figure 1. Central control of food intake. The central nervous system integrates mechanical, nervous, hormonal and metabolic signals from the periphery via the nucleus of the solitary tract (NTS), which receives afferent signals from the vagal nerve, and via direct binding of messenger peptides on their receptors located in different neuronal population within the arcuate (ARC) nucleus of hypothalamus.

2 .

 2 subfornical organ (SFO) and the organum vasculosum of the lamina terminalis (OVLT) are also able to sense blood-borne signals. AgRP: agouti related peptide; BDNF: brain derived neurotrophic factor; CART: cocaine/amphetamine related transcript; CRH: corticotrophin releasing hormone; GABA: gamma aminobutyric acid; NAc: Nucleus Accumbens; NPY: neuropeptide Y; MCH: melanin concentrating hormone; NTS: nucleus of the solitary tract; POMC: proopiomelanocortin; TRH: thyroid releasing hormone; VTA: ventral tegmental area. Expression patterns of peripheral appetite modulators and their receptors. Results on protein expression levels (www.proteinatlas.org) were listed for appetite inhibitory (red protein symbols) or stimulatory (blue protein symbols) peptides (A) and their receptors (B) in different human tissues, as determined by immunohistochemistry. Asterisks mark those proteins that rhythmically change their expression level in at least two distinct tissues from mice, according to the CircaDB database (http://circadb.hogeneschlab.org/mouse).

Figure 3 . 1 (

 31 Figure 3. Central targets of major anorexigenic factors. Leptin is secreted by the white adipose tissue and acts through its receptor LepR both peripherally, on the vagal afferences, and centrally. It potentiates the input from the vagal nerve in the NTS, activates anorexigenic neurons in the hypothalamus and inhibits the orexigenic response. The pancreatic polypeptide (PP) and the intestinal peptide YY (PYY) share the family of Y-receptors and exert their anorexigenic effects through vagal and hypothalamic regulation. Cholecystokinin, in a positive control loop with PYY, exerts most of its function by vagal nerve activation though its receptor CCK-1R. Finally, glucagon-like peptide-1 (GLP-1) activates the vagal nerve, increases the integration of its signals by the NTS and exerts direct anorexigenic actions on hypothalamic nuclei though a leptin-independent pathway which relies on the GLP-1R receptor. AgRP: Agouti-Related Peptide; CART: cocaine-and amphetamine-regulated transcript; CRH: Corticotropin-releasing hormone ; DMH: dorsomedial hypothalamic; GABA: γ-

Figure 4 .

 4 Figure 4. Central targets of major orexigenic factors. Ghrelin activates orexigenic signals in the hypothalamus and inhibits the vagal nerve response though the growth-hormone secretagogue receptor (GHSR). Adipocyte-secreted factors, adiponectin and asprosin, respectively mediate POMC/CART neurons inhibition though the adiponectin receptor 1 (AdipoR1) and AgRP/NPY neurons activation through a GHSR-independent pathway (unknown receptor). Soluble factors such as NAMPT and ACBP have been proven to mediate the activation of the lateral hypothalamic area (LHA), but whether this activation is direct or indirect remains to be understood. AgRP: Agouti-Related Peptide; CART: cocaine-and amphetamine-regulated transcript; DMH: dorsomedial hypothalamic area; GABA: γamino butyric acid; GH: growth hormone; LHA: lateral hypothalamic area; MCH: Melaninconcentrating hormone; NPY: Neuropeptide Y; POMC: pro-opiomelanocortin; PVH: paraventricular hypothalamic; VMH: ventromedial hypothalamic nuclei.

Figure 5 .

 5 Figure5. Peripheral appetite-regulatory circuitries. A. In the normal starvation response, appetitestimulatory hormones are upregulated or appetite-inhibitory mediators are downregulated, causing a raise in appetite and feeding that ultimately abolishes the starvation-elicited alterations in appetiterelevant hormones, thus closing a homeostatic feedback loop. B. In obesity, this feedback loops fails and may be superseded in importance by disease amplifying feedforward loops that involve either appetite stimulators that are upregulated or appetite inhibitors that are downregulated due to an increase in adiposity.

Figure 6 .

 6 Figure 6. Phylogenomic analysis of genes related to appetite (green for inhibitors, orange for stimulators). Numbers represent functional copies of each gene. Black stands for no-copies. Numbers were obtained from orthology tables at Ensembl. Where stated, these numbers were corrected using published results, manual annotation of genomic assemblies or specific databases, such as Wormbase. SCER -Saccharomyces cerevisiae; HVUL -Hydra vulgaris; CELE -Caenorhabditis elegans; DMEL -Drosophila melanogaster; NFUR -Nothobranchius furzeri; CAUR -Carassius auratus; XTRO -Xenopus tropicalis; GGAL -Gallus gallus; CLUP -Canis lupus familiaris; BTAU -Bos primigenius taurus; SSCR -Sus scrofa; HGLA -Heterocephalus glaber; RNOR -Rattus norvegicus; MMUS -Mus musculus; CJAC -Callithrix jacchus; MMUL -Macaca mulatta; PTRON -Pan troglodytes; HSAP -Homo sapiens. * Genetically, OXM and GLP-1 are identical; ** Values change depending on gender (male/female). *** One functional copy, five additional copies seem to have underwent a pseudogenization proccess. **** Wormbase annotates additional members (~7 for ACBP and ~30 for INS). Their functionality remains elusive.

Table 1 .

 1 Appetite inhibitory hormones with peripheral metabolic effects

	Hormone	In vivo	Genetic perturbations in human	General trend in obesity	Human studies	Ref.
	Adrenomedullin	Central injections reduce food intake in	rs574603859 polymorphism in ADM	Increased in women	ADM antibody, which increases	[150-152,
	(ADM)	rodents	receptor is associated with a smaller BMI		long-term plasma ADM, is in	241]
		Deficient ADM signaling in fa/fa rats			phase II trial for the treatment of
					sepsis with a good safety profile
	Amylin	Daily subcutaneous injection of apelin	Greater occurrence of a missense mutation	Increased	Amylin agonists decrease food	[132, 147,
		analogue decreases food intake and body	in subjects with T2DM		intake in obese patients, alone or	242, 243]
		weight in rodents			in combination
		Antagonists increase food intake
	Apelin (APLN)	APLN analogues have glucose-lowering and	Single-nucleotide polymorphisms are	Increased	APLN analogue under clinical	[165, 244-
		appetite suppressive effects in mice	associated with obesity in women cohorts		trial for type II diabetic patients	247]
					(NCT02724566)
	Apolipoprotein	Peripheral injections reduce meal sizes in	Apo-A4 polymorphisms linked to obesity in	Increased / Decreased	-	[95-99,
	A-IV	rats	adult and elderly populations			248]
	(Apo-A4)
	Cholecystokinin	CCK-1R deficiency causes hyperphagy and	CCK alleles associated with increased meal	Unchanged	CCK terminal octapeptide	[67, 68,
	(CCK)	obesity in rats but not in mice.	size in obese carriers	Postprandial secretion is	reduces meal size and duration	70, 71, 73,
		Acute peripheral reduction of food intake in	Homozygous polymorphism in the promoter	increased after bariatric	in lean men	74, 76,
		rodents with long-term tolerance to CCK.	of CCK type A receptor is associated with	surgery		249, 250]
			body fat mass
	Fibroblast growth	Peripheral injections decrease food intake	Variants in FGF21 gene associated with	Increased	FGF21 analog induces weight	[167, 168,
	factor 21	and reverse obesity in mice	carbohydrate and global intake		loss in T2DM patients	170-173]
	(FGF21)
	Glucose-	Augmenting GIPR signaling, especially in	Polymorphisms in the GIP receptor gene are	Increased post-prandial	Systemic infusion increases
	dependent	combination with GLP-1R signaling,	linked to obesity, increase BMI and visceral	responses, likely as a result	hunger and subcutaneous fat
	insulinotropic	reduces food intake in mice.	fat accumulation	of exaggerated meal size	metabolism in lean but not obese
	polypeptide	However, GIPR deficient mice strains are			subjects
	(GIP)	resistant to obesity. Inhibition of GIPR by			Tirzepatide, a dual agonist of
		means of a systemically injected antibody			GIPR and GLP-1R biased
		reduces high-fat diet-induced weight gain			towards GIPR, induces weight
		GIP neutralization decreases weight gain in			loss in T2DM obese subjects
		animal models [251].			(phase 3 clinical trial
					NCT03954834)

Table 2 .

 2 Appetite stimulatory hormones with peripheral metabolic effects

	Hormone	In vivo	Genetic perturbations in human	General trend in obesity	Human studies	Ref.
	Acyl-CoA	Peripheral injections are orexigenic and	A polymorphism (rs279858) in GABAA	Increased	-	[226, 233]
	binding protein	obesogenic in mice. Antibody-mediated	receptor predisposes to weight gain after
	(ACBP)	neutralization and knockout are anorexigenic	treatment with antipsychotics.
	Adiponectin	Peripheral injections increase food intake	Adiponectin-decreasing allelic variations are	Decreased	Numerous adiponectin-increasing	[210, 211,
		after refeeding in mice. Adiponectin-	associated with lower BMI and decreased		molecules have been tested for their	283-286]
		deficient mice have decreased food intake	appetite		insulin-sensitizing properties
		and increased energy expenditure.
		Serum adiponectin levels are decreased in
		ob/ob mice and restored in POMC-deficient
		obese mice
	Asprosin	Subcutaneous injection into mice stimulated	Mutations in the Fbn1 gene cause the	Increased / Inconsistent	-	[213, 215,
		food intake. Its antibody-mediated	Marfan syndrome, associated with extreme	results in children		217, 287-
		neutralization decreases appetite and body	thinness and hypophagia			291]
		weight in obese mice.
		Peripheral injections cause hyperglycemia
		and hyperlipidemia with no changes in body
		weight
	Ghrelin	Peripheral injections increase food intake	Ghrelin is upregulated in patients with	Decreased	Appetite and food intake is	[194-200,
		and are obesogenic at long term in rodents	Prader-Willi syndrome		increased upon high but not	292]
		Ghrelin-receptor-deficient mice strains are hypophagic and resistant to high-fat diet-induced obesity	Rare allelic forms of preproghrelin may be protective against fat accumulation		physiological doses Anti-ghrelin vaccination studies led to marginal weight loss
	Motilin	Peripheral injections stimulate food intake in	rs2274459 polymorphism in the MLN gene	Absence of MLN peak	Motilin receptor agonist	[206, 208,
	(MLN)	rats	is associated with an increased odds-ratio for	during MMC phase III	erythromycin increases appetite	209, 293-
		Extremely high doses inhibit feeding,	obesity	coupled to increased /		296]
		probably due to nausea		decreased levels at
				baseline
	Nicotinamide	Central injections have orexigenic effects in	rs10487818, a rare polymorphism in Nampt,	Increased	-	[220, 222-
	phosphoribosyl-	chicks	may be protective against obesity			224]
	transferase	NAMPT-deficient mice are resistant to high-
	(NAMPT)	fat diet-induced obesity

Acknowledgments: GK is supported by the Ligue contre le Cancer (équipe labellisée); Agence National de la Recherche (ANR) -Projets blancs; ANR under the frame of E-Rare-2, the ERA-Net for

Research on Rare Diseases; AMMICa US23/CNRS UMS3655; Association pour la recherche sur le cancer (ARC); Association "Ruban Rose"; Cancéropôle Ile-de-France; Chancelerie des universités de Paris (Legs Poix), Fondation pour la Recherche Médicale (FRM); a donation by Elior; European Research Area Network on Cardiovascular Diseases (ERA-CVD, MINOTAUR); Gustave Roussy Odyssea, the European Union Horizon 2020 Project Oncobiome; Fondation Carrefour; High-end Foreign Expert Program in China (GDW20171100085), Institut National du Cancer (INCa); Inserm (HTE); Institut Universitaire de France; LeDucq Foundation; the LabEx Immuno-Oncology (ANR-18-IDEX-0001); the RHU Torino Lumière; the Seerave Foundation; the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE); and the SIRIC Cancer Research and Personalized Medicine (CARPEM). CM is supported by Agence Nationale de la Recherche (ANR); ANR-15-CE14-0027 betadiamark, ANR-16-CE14-0026 Fat4Brain; ANR-17-CE14-0020 PogSiDiab; Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115881 (RHAPSODY). This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA.

Conflicts of interest:

GK is listed as an inventor on a patent application dealing with ACBP/DBI as a target for therapeutic appetite control.