Q Leyrolle

Direct and indirect effects of lipids on microglia function

Keywords: Microglia, Fatty acids, Obesity, Gut microbiota, Hormones, Inflammation

niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Introduction

Microglia are the resident macrophages of the brain. They have been studied for decades for their role as primary immune cells of the central nervous system (CNS) [START_REF] Thion | Microglia and early brain development: An intimate journey[END_REF] . They orchestrate the local inflammatory response to maintain tissue homeostasis. Exaggerated activation of microglial inflammation is yet observed in several disorders such as Alzheimer's Disease (AD), Parkinson's Disease (PD), Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis (MS) or obesity, where it can lead to further damage [START_REF] Salter | Microglia emerge as central players in brain disease[END_REF] . Microglia are also involved in the resolution phase of inflammation by phagocyting dying cells or debris and by releasing cytokines and some lipid mediators exerting anti-inflammatory and pro-repair properties [START_REF] Jeon | Plasminogen activator inhibitor type 1 regulates microglial motility and phagocytic activity[END_REF] .

More generally, microglia are extremely sensitive to their local environment, which they continuously scan with highly motile processes [START_REF] Davalos | ATP mediates rapid microglial response to local brain injury in vivo[END_REF][START_REF] Nimmerjahn | Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo[END_REF] . One reason for that is the wide array of receptors microglia expressed at their membrane, known as "microglia sensome", that give them the ability to "sense" and respond to lots of endogenous as well as exogenous signals [START_REF] Hickman | The microglial sensome revealed by direct RNA sequencing[END_REF] . Among all receptors identified, several of them can bind to lipids, including membrane phospholipids such as phosphatidylserine (PS) or oxidized lipids. This can promote phagocytosis of myelin, spines, apoptotic cells, protein aggregates, etc. More generally, many factors including nutrition can modulate microglia functions through the activation of their sensome [START_REF] Layé | Anti-Inflammatory Effects of Omega-3 Fatty Acids in the Brain: Physiological Mechanisms and Relevance to Pharmacology[END_REF][START_REF] Hanamsagar | Environment matters: microglia function and dysfunction in a changing world[END_REF] . Depending on the brain structure, sex and the type of environmental stimulus, microglia acquire diverse phenotypes characterized by singular transcriptomic signatures [START_REF] Bennett | A Combination of Ontogeny and CNS Environment Establishes Microglial Identity[END_REF][START_REF] Hanamsagar | Generation of a microglial developmental index in mice and in humans reveals a sex difference in maturation and immune reactivity[END_REF][START_REF] Matcovitch-Natan | Microglia development follows a stepwise program to regulate brain homeostasis[END_REF][START_REF] Thion | Microbiome Influences Prenatal and Adult Microglia in a Sex-Specific Manner[END_REF] .

The combination of several studies helped to draw the gene profile of microglia, so-called "Disease Associated Microglia" or DAM [START_REF] Deczkowska | Disease-Associated Microglia: A Universal Immune Sensor of Neurodegeneration[END_REF][START_REF] Keren-Shaul | A Unique Microglia Type Associated with Restricting Development of Alzheimer's Disease[END_REF][START_REF] Krasemann | The TREM2-APOE Pathway Drives the Transcriptional Phenotype of Dysfunctional Microglia in Neurodegenerative Diseases[END_REF] . Interestingly, some of these genes, such as trem2, apoe, lpl are related to lipid transport and metabolism [START_REF] Deczkowska | Disease-Associated Microglia: A Universal Immune Sensor of Neurodegeneration[END_REF][START_REF] Keren-Shaul | A Unique Microglia Type Associated with Restricting Development of Alzheimer's Disease[END_REF][START_REF] Krasemann | The TREM2-APOE Pathway Drives the Transcriptional Phenotype of Dysfunctional Microglia in Neurodegenerative Diseases[END_REF] . Likewise, diseases such as obesity and metabolic disorders, characterized by profound alterations in lipid metabolism, display microglial inflammatory activation [START_REF] Cope | Microglia Play an Active Role in Obesity-Associated Cognitive Decline[END_REF][START_REF] Gao | Lipoprotein Lipase Maintains Microglial Innate Immunity in Obesity[END_REF][START_REF] Newcombe | Inflammation: the link between comorbidities, genetics, and Alzheimer's disease[END_REF][START_REF] Valdearcos | Microglia Dictate the Impact of Saturated Fat Consumption on Hypothalamic Inflammation and Neuronal Function[END_REF] . Overall, regulation of brain homeostasis is likely to involve some lipid-mediated mechanisms aimed at modulating microglia functions.

A new field of research has hence emerged, aiming at deciphering how lipids affect microglia using a wide variety of protocols (in vitro lipid application or in vivo dietary approaches) and analyzing outcomes such as inflammation, phagocytosis, density, proliferation, etc. [START_REF] Nadjar | Role of metabolic programming in the modulation of microglia phagocytosis by lipids[END_REF][START_REF] Nadjar | Bioactive lipids as new class of microglial modulators: When nutrition meets neuroimunology[END_REF] . While in vitro experiments address a potential direct effect of fatty acids on microglial function, in vivo experiments must considered indirect actions of lipids through "secondary actors", including hormones, peripheral immune cells or gut microbiota, that in turn affect microglia function. This review summarizes the current knowledge on direct and indirect effects of lipids on microglial cells and highlights different aspects of this complex relationship.

Direct effect of fatty acids on microglia function

Several lines of evidence suggest a link between microglia and fatty acids: 1) Fatty acids are present at high amount in cellular membranes, including microglial cells [START_REF] Rey | Maternal n-3 polyunsaturated fatty acid dietary supply modulates microglia lipid content in the offspring[END_REF] , and many of them can be metabolized into bioactive derivatives [START_REF] Bazinet | Polyunsaturated fatty acids and their metabolites in brain function and disease[END_REF][START_REF] Serhan | Treating inflammation and infection in the 21st century: new hints from decoding resolution mediators and mechanisms[END_REF] , modulate proteins localization and function as well as downstream signaling pathways [START_REF] Bazinet | Polyunsaturated fatty acids and their metabolites in brain function and disease[END_REF] . 2) Microglia express many lipid-sensitive receptors such as TREM2, CD36, Toll-Like Receptors (TLRs), receptors for fatty acids derivatives such as endocannabinoids, oxylipins, etc. [START_REF] Mauerer | Comprehensive mRNA profiling of lipid-related genes in microglia and macrophages using taqman arrays[END_REF] ; 3) Macrophages can store fatty acids within lipid droplets, that are known to control their inflammatory response and phagocytic activity [START_REF] Melo | Lipid droplets in leukocytes: Organelles linked to inflammatory responses[END_REF] , suggesting that lipids are potential regulators of microglial function [START_REF] Nadjar | Role of metabolic programming in the modulation of microglia phagocytosis by lipids[END_REF] . All these observations suggest a potential role of fatty acids on microglial physiology.

Three main families of fatty acids have been studied, based on the number of double bonds: the saturated (SFA), monounsaturated (MUFA) or polyunsaturated (PUFA) fatty acids.

Subfamilies are distinguished by the position of unsaturation and the length of the hydrocarbon chain. In the following chapters, we extensively review the literature on the effects of SFA, MUFA and PUFA on microglial cells.

Microglia and SFA

SFA are present in great quantities in obesity-inducing diets, among which palmitate (C16:0) is the most abundant. Hence, high-fat diet (HFD) intake rises brain SFA levels, and more specifically those of palmitate [START_REF] Valdearcos | Microglia Dictate the Impact of Saturated Fat Consumption on Hypothalamic Inflammation and Neuronal Function[END_REF] . Several studies showed that HFD modulates brain inflammatory status [START_REF] Maldonado-Ruiz | Microglia activation due to obesity programs metabolic failure leading to type two diabetes[END_REF] , in a body weight-independent [START_REF] Valdearcos | Microglia Dictate the Impact of Saturated Fat Consumption on Hypothalamic Inflammation and Neuronal Function[END_REF][START_REF] Thaler | Obesity is associated with hypothalamic injury in rodents and humans[END_REF] and microglia-dependent fashion [START_REF] Cope | Microglia Play an Active Role in Obesity-Associated Cognitive Decline[END_REF][START_REF] Valdearcos | Microglia Dictate the Impact of Saturated Fat Consumption on Hypothalamic Inflammation and Neuronal Function[END_REF][START_REF] André | Inhibiting Microglia Expansion Prevents Diet-Induced Hypothalamic and Peripheral Inflammation[END_REF][START_REF] Valdearcos | Microglial Inflammatory Signaling Orchestrates the Hypothalamic Immune Response to Dietary Excess and Mediates Obesity Susceptibility[END_REF] . This supports the newly developed concept that microglia act as nutrient sensors within the brain in basal conditions, so that when levels of dietary nutrients suddenly rise, these cells are among the first to react, long before metabolic alterations occur [START_REF] Valdearcos | Hypothalamic microglia as potential regulators of metabolic physiology[END_REF] . Once obesity develops, the increase in adiposity and associated metabolic disturbances and inflammatory processes will contribute to the second phase of microglial microglia activation [START_REF] Maldonado-Ruiz | Microglia activation due to obesity programs metabolic failure leading to type two diabetes[END_REF] . Microglial activation and neuroinflammatory processes are initiated within the hypothalamus, before spreading to other structures such as amygdala, hippocampus and cerebellum [START_REF] Guillemot-Legris | Obesity-Induced Neuroinflammation: Beyond the Hypothalamus[END_REF][START_REF] Hao | Dietary obesity reversibly induces synaptic stripping by microglia and impairs hippocampal plasticity[END_REF][START_REF] Jeon | Plasminogen activator inhibitor type 1 regulates microglial motility and phagocytic activity[END_REF] .

In terms of mechanisms, the pioneer study of Valdearcos and colleagues revealed that in animals fed a SFA-rich diet, fatty acids, including palmitic acid, are rapidly conveyed to the brain after ingestion. There, they are directly taken up by microglia within the hypothalamus to trigger an inflammatory response [START_REF] Valdearcos | Microglia Dictate the Impact of Saturated Fat Consumption on Hypothalamic Inflammation and Neuronal Function[END_REF] . Palmitic acid in return induces central insulin and leptin resistance and impairs glucose and lipid metabolism [START_REF] Benoit | Palmitic acid mediates hypothalamic insulin resistance by altering PKC-theta subcellular localization in rodents[END_REF][START_REF] Cheng | Palmitic acid induces central leptin resistance and impairs hepatic glucose and lipid metabolism in male mice[END_REF] . In vitro studies on microglial cell cultures confirmed the ability of SFA to initiate an inflammatory reaction, characterized by the production of pro-inflammatory cytokines and oxidative stress response [START_REF] Valdearcos | Microglia Dictate the Impact of Saturated Fat Consumption on Hypothalamic Inflammation and Neuronal Function[END_REF][START_REF] Button | Microglial cell activation increases saturated and decreases monounsaturated fatty acid content, but both lipid species are proinflammatory[END_REF][START_REF] Tracy | Exposure to the Saturated Free Fatty Acid Palmitate Alters BV-2 Microglia Inflammatory Response[END_REF][START_REF] Wang | Saturated fatty acids activate microglia via Toll-like receptor 4/NF-κB signalling[END_REF][START_REF] Yanguas-Casás | Sex differences in the phagocytic and migratory activity of microglia and their impairment by palmitic acid[END_REF] .

However, a more recent study using a lower dose of palmitate showed that application of this fatty acid on BV2 and IMG cells, two immortalized microglial cell lines, induces an antiinflammatory response [START_REF] Kim | Palmitate induces an anti-inflammatory response in immortalized microglial BV-2 and IMG cell lines that decreases TNFα levels in mHypoE-46 hypothalamic neurons in co-culture[END_REF] . This study pinpoints the potential neuroprotective action of palmitate-treated microglia, that release interleukin-13 (IL-13) and in turn induce an antiinflammatory response in co-cultured hypothalamic neurons [START_REF] Kim | Palmitate induces an anti-inflammatory response in immortalized microglial BV-2 and IMG cell lines that decreases TNFα levels in mHypoE-46 hypothalamic neurons in co-culture[END_REF] . Beyond the fact that the relevance of in vitro models of microglia, and especially the use of cell lines, must be questioned [START_REF] Butovsky | Identification of a Unique TGF-? Dependent Molecular and Functional Signature in Microglia[END_REF] , these results highlight the importance of the dose, duration of treatment and type of SFA considered when studying their effects on microglial physiology [START_REF] Kim | Palmitate induces an anti-inflammatory response in immortalized microglial BV-2 and IMG cell lines that decreases TNFα levels in mHypoE-46 hypothalamic neurons in co-culture[END_REF][START_REF] Ono-Moore | Is palmitate truly pro-inflammatory? Experimental confounders and context-specificity[END_REF] . Moreover, none of these studies ever considered and/or studied potential modulations of lipid transport into the brain, as well as their local synthesis and metabolism within the CNS.

How SFA affect microglial phagocytosis is still a matter of debate. While a BV2-based study showed that palmitate enhances phagocytosis [START_REF] Tracy | Exposure to the Saturated Free Fatty Acid Palmitate Alters BV-2 Microglia Inflammatory Response[END_REF] , this has been recently challenged by another study using primary microglia culture [START_REF] Yanguas-Casás | Sex differences in the phagocytic and migratory activity of microglia and their impairment by palmitic acid[END_REF] . In the latter, they showed that application of palmitate does not increase basal phagocytic activity and suppresses interferon-γ (IFN-γ) induced phagocytosis [START_REF] Yanguas-Casás | Sex differences in the phagocytic and migratory activity of microglia and their impairment by palmitic acid[END_REF] . Of note, these two groups used different experimental conditions: palmitate dissolved in ethanol vs methanol, different doses (125 µM vs 100-200µM), different duration of phagocytic assays (5h vs 1h). Further studies are thus needed to understand how palmitate and other SFA, if they do, modulate microglial phagocytosis.

Of importance, a recent study conducted on macrophages highlighted various pitfalls in palmitate studies [START_REF] Ono-Moore | Is palmitate truly pro-inflammatory? Experimental confounders and context-specificity[END_REF] . Indeed, fatty acids require specific carriers (e.g. BSA) or solvents (e.g. ethanol) to increase their solubility, both factors having a strong effect on cellular activity. Moreover, Bohlen et al. demonstrated that the composition of culture medium is a potent modulator of microglial function, hence adding another potential bias to in vitro studies 44 . Overall,combining different approaches (in vitro,ex vivo and in vivo) as well as using cell components (dead neurons, synaptosomes) in phagocytic assay rather than beads seems essential to conclude on the (direct) effects of SFA on microglia function.

Microglia and MUFA

The beneficial inflammation in BV2 cells [START_REF] Oh | Oleamide suppresses lipopolysaccharide-induced expression of iNOS and COX-2 through inhibition of NF-kappaB activation in BV2 murine microglial cells[END_REF][START_REF] Oh | Oleic acid reduces lipopolysaccharide-induced expression of iNOS and COX-2 in BV2 murine microglial cells: possible involvement of reactive oxygen species, p38 MAPK, and IKK/NF-kappaB signaling pathways[END_REF] . Based on the same microglial cell line, Debabbi and collaborators reported that oleate (18:1) prevents7-ketocholesterol-inducedcytotoxicity [START_REF] Debbabi | Comparison of the effects of major fatty acids present in the Mediterranean diet (oleic acid, docosahexaenoic acid) and in hydrogenated oils (elaidic acid) on 7ketocholesterol-induced oxiapoptophagy in microglial BV-2 cells[END_REF] .

In microglia primary cultures, oleic acid does not trigger pro-inflammatory cytokines release while SFA do [START_REF] Valdearcos | Microglia Dictate the Impact of Saturated Fat Consumption on Hypothalamic Inflammation and Neuronal Function[END_REF] . MUFA have greater affinity than SFA for the transcription factor peroxisome proliferator-activated receptor (PPAR), that mainly promotes anti-inflammatory processes [START_REF] Hostetler | Peroxisome proliferator-activated receptor alpha interacts with high affinity and is conformationally responsive to endogenous ligands[END_REF] .

Thus, it could represent a mechanism through which oleate exerts its anti-inflammatory effects. Data also show that the oleate derivatives oleamide increases phagocytic activity of microglia towards amyloid beta (Aβ) particles both in vitro and in vivo [START_REF] Ano | Preventive effects of a fermented dairy product against Alzheimer's disease and identification of a novel oleamide with enhanced microglial phagocytosis and anti-inflammatory activity[END_REF] .

Microglia and polyunsaturated fatty acids (PUFA)

We focus here on the two main PUFA families, n-3 and n-6 PUFAs, that differ by the position of the first double-bound [START_REF] Bazinet | Polyunsaturated fatty acids and their metabolites in brain function and disease[END_REF] . The main PUFA that constitute the mammalian brain are the long chain (LC) fatty acids arachidonic acid (AA) and docosapentaenoic acid (DPA, 22:5 n-6) from n-6 family and docosahexaenoic acid (DHA, 22:6 n-3) from the n-3 group 50 . The n-3 PUFA eicosapentaenoic acid (EPA, 20:5 n-3) is present at very low oncentration in the CNS, yet it is enriched in the membrane of microglial cells [START_REF] Rey | Maternal n-3 polyunsaturated fatty acid dietary supply modulates microglia lipid content in the offspring[END_REF] . LC-PUFA are either biosynthesized from their dietary precursors, respectively linoleic acid (18:2n-6 or LA) and α-linolenic acid (18:3n-3 or ALA) or can be directly sourced from the diet (mainly meat and dairy products for AA/DPA, fat fishes for DHA/EPA) [START_REF] Lands | Quantitative effects of dietary polyunsaturated fats on the composition of fatty acids in rat tissues[END_REF][START_REF] Abedi | Long-chain polyunsaturated fatty acid sources and evaluation of their nutritional and functional properties[END_REF] . PUFA are mainly esterified into phospholipids within cell membranes [START_REF] Bazinet | Polyunsaturated fatty acids and their metabolites in brain function and disease[END_REF] . They can also be released from these membranes in a phospholipase A2-dependent manner. Once free from the membrane, PUFA can act directly on specifics targets or can be enzymatically metabolized, leading to the production of a wide variety of derivatives, such as docosanoids, eicosanoids or endocannabinoids [START_REF] Layé | Anti-Inflammatory Effects of Omega-3 Fatty Acids in the Brain: Physiological Mechanisms and Relevance to Pharmacology[END_REF] . PUFA and their bioactive mediators exert numerous biological properties, from immunomodulation to neuronal plasticity or regulation of gene expression 3 .

Westernization of dietary habits not only led to an increase in SFA intake but also to a decrease of the n-3/n-6 PUFA ratio (both from a decrease in n-3 PUFA consumption and an increase in n-6 PUFA) [START_REF] Stark | Global survey of the omega-3 fatty acids, docosahexaenoic acid and eicosapentaenoic acid in the blood stream of healthy adults[END_REF] . Consequently, AA brain concentration rose while DHA content diminished [START_REF] Layé | Anti-Inflammatory Effects of Omega-3 Fatty Acids in the Brain: Physiological Mechanisms and Relevance to Pharmacology[END_REF][START_REF] Stark | Global survey of the omega-3 fatty acids, docosahexaenoic acid and eicosapentaenoic acid in the blood stream of healthy adults[END_REF] . Moreover, our data show that lifelong dietary n-3 PUFA deficiency specifically alters microglia composition in mice [START_REF] Rey | Maternal n-3 polyunsaturated fatty acid dietary supply modulates microglia lipid content in the offspring[END_REF] . Numerous groups also studied the effect of PUFA on microglia inflammatory activity in vitro, knowing that n-3 PUFAs and their derivatives are considered rather anti-inflammatory while n-6 PUFAs and their derivatives are anti-inflammatory [START_REF] Layé | Anti-Inflammatory Effects of Omega-3 Fatty Acids in the Brain: Physiological Mechanisms and Relevance to Pharmacology[END_REF] . DHA, and to a lesser extent EPA, decrease the production and release of pro-inflammatory cytokines, oxidative stress and NO production after treatment with LPS, cytokines or Aβ [START_REF] Ajmone-Cat | Docosahexaenoic acid modulates inflammatory and antineurogenic functions of activated microglial cells[END_REF][START_REF] Chen | n-3 PUFA supplementation benefits microglial responses to myelin pathology[END_REF][START_REF] Corsi | Supplementation of omega 3 fatty acids improves oxidative stress in activated BV2 microglial cell line[END_REF][START_REF] Smedt-Peyrusse | Docosahexaenoic acid prevents lipopolysaccharide-induced cytokine production in microglial cells by inhibiting lipopolysaccharide receptor presentation but not its membrane subdomain localization[END_REF][START_REF] Inoue | Omega-3 polyunsaturated fatty acids suppress the inflammatory responses of lipopolysaccharide-stimulated mouse microglia by activating SIRT1 pathways[END_REF] . In vivo studies confirmed that DHA and/or EPA attenuate neuroinflammation and microglial activation triggered by various inflammatory challenge (HFD, LPS, aging, maternal immune activation) [START_REF] Cintra | Unsaturated fatty acids revert diet-induced hypothalamic inflammation in obesity[END_REF][START_REF] Delpech | Dietary n-3 PUFAs Deficiency Increases Vulnerability to Inflammation-Induced Spatial Memory Impairment[END_REF][START_REF] Delpech | Transgenic Increase in n-3/n-6 Fatty Acid Ratio Protects Against Cognitive Deficits Induced by an Immune Challenge through Decrease of Neuroinflammation[END_REF][START_REF] Fourrier | Docosahexaenoic acid-containing choline phospholipid modulates LPSinduced neuroinflammation in vivo and in microglia in vitro[END_REF][START_REF] Hopperton | Brain omega-3 polyunsaturated fatty acids modulate microglia cell number and morphology in response to intracerebroventricular amyloid-beta 1-40 in mice[END_REF][START_REF] Labrousse | Dietary omega-3 deficiency exacerbates inflammation and reveals spatial memory deficits in mice exposed to lipopolysaccharide during gestation[END_REF][START_REF] Labrousse | Short-term long chain omega3 diet protects from neuroinflammatory processes and memory impairment in aged mice[END_REF][START_REF] Moranis | Long term adequate n-3 polyunsaturated fatty acid diet protects from depressive-like behavior but not from working memory disruption and brain cytokine expression in aged mice[END_REF][START_REF] Orr | Unesterified docosahexaenoic acid is protective in neuroinflammation[END_REF][START_REF] Madore | Nutritional n-3 PUFAs deficiency during perinatal periods alters brain innate immune system and neuronal plasticity-associated genes[END_REF] . Among the pathways activated by n-3 PUFA, DHA and EPA have been shown to inhibit the inflammatory signaling cascades NFκB, and MAPK and to activate the anti-inflammatory factors PPAR, retinoid X receptor (RXR) and the G-protein coupled receptor 120 (GPR120) [START_REF] Layé | Anti-Inflammatory Effects of Omega-3 Fatty Acids in the Brain: Physiological Mechanisms and Relevance to Pharmacology[END_REF][START_REF] Ajmone-Cat | Docosahexaenoic acid modulates inflammatory and antineurogenic functions of activated microglial cells[END_REF][START_REF] Smedt-Peyrusse | Docosahexaenoic acid prevents lipopolysaccharide-induced cytokine production in microglial cells by inhibiting lipopolysaccharide receptor presentation but not its membrane subdomain localization[END_REF][START_REF] Inoue | Omega-3 polyunsaturated fatty acids suppress the inflammatory responses of lipopolysaccharide-stimulated mouse microglia by activating SIRT1 pathways[END_REF] . Another property of DHA is to remodel lipid bodies inside microglia cells, counteracting the effect of inflammation by restoring mitochondrial function [START_REF] Chang | Docosahexaenoic acid (DHA): a modulator of microglia activity and dendritic spine morphology[END_REF][START_REF] Tremblay | Remodeling of lipid bodies by docosahexaenoic acid in activated microglial cells[END_REF] .

PUFA can also modulate the phagocytic activity of microglia. Two in vitro studies observed similar results, i.e. an increase in phagocytic activity against Aβ particles and myelin debris in response to EPA or DHA application [START_REF] Chen | n-3 PUFA supplementation benefits microglial responses to myelin pathology[END_REF][START_REF] Hjorth | Omega-3 fatty acids enhance phagocytosis of Alzheimer's disease-related amyloid-beta42 by human microglia and decrease inflammatory markers[END_REF] . Moreover, we showed in vivo that perinatal dietary n-3 PUFA deficiency increases microglia-mediated phagocytosis of synaptic elements in the CA1 region and of apoptotic neurons in the dentate gyrus of juvenile mice [START_REF] Abiega | Neuronal Hyperactivity Disturbs ATP Microgradients, Impairs Microglial Motility, and Reduces Phagocytic Receptor Expression Triggering Apoptosis/Microglial Phagocytosis Uncoupling[END_REF] . Altogether, these data suggest that n-3 PUFA differentially regulates the phagocytic response of microglial cells depending on the context (physiology vs pathology, cellular elements vs exogenous stimuli, etc.). Further studies are needed to clarify how the n-3/n-6 PUFA balance controls microglial phagocytic activity, such as exploring the role of PUFA derivatives that are known to influence microglial function as well [START_REF] Layé | Anti-Inflammatory Effects of Omega-3 Fatty Acids in the Brain: Physiological Mechanisms and Relevance to Pharmacology[END_REF] .

PUFA derivatives are produced through a wide range of enzymatic and non-enzymatic pathways [START_REF] Layé | Anti-Inflammatory Effects of Omega-3 Fatty Acids in the Brain: Physiological Mechanisms and Relevance to Pharmacology[END_REF] . A positive correlation between DHA and EPA intake and blood level of their derivatives has been observed, meaning that dietary PUFA intake directly influences the amount of bioactive compounds [START_REF] Markworth | Divergent shifts in lipid mediator profile following supplementation with n-3 docosapentaenoic acid and eicosapentaenoic acid[END_REF][START_REF] Schuchardt | Modulation of blood oxylipin levels by long-chain omega-3 fatty acid supplementation in hyper-and normolipidemic men[END_REF] . Oxylipins such as n-6 PUFA-derived prostaglandins, thromboxanes or lipoxins and n-3 PUFA-derived resolvins, maresins or neuroprotectin are synthesized by the cyclooxygenase (COX), lipoxygenase (LOX), cytochromes P450 (CYP) and epoxide hydrolase (EH) [START_REF] Layé | Anti-Inflammatory Effects of Omega-3 Fatty Acids in the Brain: Physiological Mechanisms and Relevance to Pharmacology[END_REF][START_REF] Serhan | Treating inflammation and infection in the 21st century: new hints from decoding resolution mediators and mechanisms[END_REF][START_REF] Gabbs | Advances in Our Understanding of Oxylipins Derived from Dietary PUFAs[END_REF] . A differential expression of lipid mediators is observed across inflammation in parallel of cytokine expression [START_REF] Serhan | Treating inflammation and infection in the 21st century: new hints from decoding resolution mediators and mechanisms[END_REF][START_REF] Sugimoto | Resolution of Inflammation: What Controls Its Onset?[END_REF] . Decreasing n-3 PUFA-derived pro-resolutive species might have detrimental effects, leading to chronic inflammation [START_REF] Serhan | Treating inflammation and infection in the 21st century: new hints from decoding resolution mediators and mechanisms[END_REF] .

Resolvins from the D-(DHA-derived) or the E-series (EPA-derived) decrease neuroinflammation and counteract microglial activation [START_REF] Harrison | Resolvins AT-D1 and E1 differentially impact functional outcome, posttraumatic sleep, and microglial activation following diffuse brain injury in the mouse[END_REF][START_REF] Rey | Resolvin D1 and E1 promote resolution of inflammation in microglial cells in vitro[END_REF][START_REF] Serhan | docosatrienes, and neuroprotectins, novel omega-3-derived mediators, and their aspirin-triggered endogenous epimers: an overview of their protective roles in catabasis[END_REF][START_REF] Wang | Effects of n-3 FA supplementation on the release of proresolving lipid mediators by blood mononuclear cells: the OmegAD study[END_REF] . The release of neuroprotectins and maresins also protect from microglial inflammatory activation. Moreover, maresins facilitate phagocytosis of Aβ by microglia [START_REF] Bazan | Novel aspirin-triggered neuroprotectin D1 attenuates cerebral ischemic injury after experimental stroke[END_REF][START_REF] Zhu | Pro-Resolving Lipid Mediators Improve Neuronal Survival and Increase Aβ42 Phagocytosis[END_REF] . The situation is more complex for n-6 PUFA derivatives. While prostaglandins can be either pro-or anti-inflammatory, thromboxanes and leukotrienes promote microglial activation and neuroinflammation 3 . AA-derived prostaglandin E2 (PGE2) for instance has been shown to decrease microglia phagocytosis of Aβ through its receptor EP2 [START_REF] Nagano | Prostaglandin E2 reduces amyloid beta-induced phagocytosis in cultured rat microglia[END_REF] . Likewise, AA-derived lipoxin A4 is anti-inflammatory in various models of CNS inflammation [START_REF] Guo | Lipoxin A4 Reduces Inflammation Through Formyl Peptide Receptor 2/p38 MAPK Signaling Pathway in Subarachnoid Hemorrhage Rats[END_REF][START_REF] Jin | Lipoxin A4 methyl ester ameliorates cognitive deficits induced by chronic cerebral hypoperfusion through activating ERK/Nrf2 signaling pathway in rats[END_REF][START_REF] Medeiros | Aspirin-triggered lipoxin A4 stimulates alternative activation of microglia and reduces Alzheimer disease-like pathology in mice[END_REF] .

PUFA can also be metabolized into endocannabinoids. Microglia possess all the machinery to produce these molecules and express their receptors, namely CB1 and CB2 [START_REF] Layé | Anti-Inflammatory Effects of Omega-3 Fatty Acids in the Brain: Physiological Mechanisms and Relevance to Pharmacology[END_REF][START_REF] Stella | Endocannabinoid signaling in microglial cells[END_REF] . The most abundant AA-derived endocannabinoids, anandamide and 2-arachidonoylglycerol, dampen microglial inflammation [START_REF] Mecha | Endocannabinoids drive the acquisition of an alternative phenotype in microglia[END_REF] . Endocannabinoids can also be produced from DHA and EPA. The DHA-derived DHEA (or synaptamide) and EPA-derived EPEA exert anti-inflammatory activity on microglial cells, yet only few data are available in the literature [START_REF] Mcdougle | Anti-inflammatory ω-3 endocannabinoid epoxides[END_REF][START_REF] Park | N-Docosahexaenoylethanolamine ameliorates LPS-induced neuroinflammation via cAMP/PKA-dependent signaling[END_REF] . Overall, and regardless of their precursor, endocannabinoids are likely to exert anti-inflammatory action on microglia notably through CB2 receptors but more extensive studies are needed to decipher the mechanisms underlying these effects [START_REF] Stella | Endocannabinoid signaling in microglial cells[END_REF][START_REF] Mecha | Endocannabinoids drive the acquisition of an alternative phenotype in microglia[END_REF] .

Microglia and other lipids

Other lipids modulate microglia function. Cholesterol, lipoproteins, lipid-related enzymes or receptors can control microglia phenotype and phagocytic activity. As we described above, DAM are characterized by altered expression of lipid transport and metabolism related genes such as apoe, trem2 or lpl [START_REF] Deczkowska | Disease-Associated Microglia: A Universal Immune Sensor of Neurodegeneration[END_REF][START_REF] Keren-Shaul | A Unique Microglia Type Associated with Restricting Development of Alzheimer's Disease[END_REF][START_REF] Krasemann | The TREM2-APOE Pathway Drives the Transcriptional Phenotype of Dysfunctional Microglia in Neurodegenerative Diseases[END_REF] . In this part, we explore the literature linking microglia functions with these factors.

Trem2 and APOE. TREM2 is specifically expressed by microglial cells in the brain. It binds to phospholipids, LPS, lipoproteins such as LDL, and apolipoproteins including APOE and APOJ [START_REF] Hickman | The microglial sensome revealed by direct RNA sequencing[END_REF][START_REF] Ulland | TREM2 -a key player in microglial biology and Alzheimer disease[END_REF][START_REF] Yeh | TREM2 Binds to Apolipoproteins, Including APOE and CLU/APOJ, and Thereby Facilitates Uptake of Amyloid-Beta by Microglia[END_REF] . Interaction of TREM2 with apoliporoteins is involved in microglia-mediated Aβ phagocytosis and could explain why mutations in trem2 and apoe have been associated with neurodegenerative diseases [START_REF] Ulland | TREM2 -a key player in microglial biology and Alzheimer disease[END_REF][START_REF] Yeh | TREM2 Binds to Apolipoproteins, Including APOE and CLU/APOJ, and Thereby Facilitates Uptake of Amyloid-Beta by Microglia[END_REF] . APOE is also pivotal in the polarization of microglial phenotype during development, aging and neurodegenerative disorders [START_REF] Butovsky | Identification of a Unique TGF-? Dependent Molecular and Functional Signature in Microglia[END_REF][START_REF] Kang | Microglial translational profiling reveals a convergent APOE pathway from aging, amyloid, and tau[END_REF] . Concomitantly, its expression is high during development and decreases across brain maturation [START_REF] Butovsky | Identification of a Unique TGF-? Dependent Molecular and Functional Signature in Microglia[END_REF] . APOE and TREM2 both promote microglia protective effects in contexts such as neurodegenerative diseases, stroke, MS or brain development [START_REF] Krasemann | The TREM2-APOE Pathway Drives the Transcriptional Phenotype of Dysfunctional Microglia in Neurodegenerative Diseases[END_REF][START_REF] Ulland | TREM2 -a key player in microglial biology and Alzheimer disease[END_REF][START_REF] Yeh | TREM2 Binds to Apolipoproteins, Including APOE and CLU/APOJ, and Thereby Facilitates Uptake of Amyloid-Beta by Microglia[END_REF][START_REF] Filipello | The Microglial Innate Immune Receptor TREM2 Is Required for Synapse Elimination and Normal Brain Connectivity[END_REF][START_REF] Hickman | Microglia in neurodegeneration[END_REF][START_REF] Jay | Disease Progression-Dependent Effects of TREM2 Deficiency in a Mouse Model of Alzheimer's Disease[END_REF][START_REF] Kleinberger | The FTD-like syndrome causing TREM2 T66M mutation impairs microglia function, brain perfusion, and glucose metabolism[END_REF][START_REF] Mazaheri | TREM2 deficiency impairs chemotaxis and microglial responses to neuronal injury[END_REF][START_REF] Pang | Apolipoprotein E Exerts a Whole-Brain Protective Property by Promoting M1? Microglia Quiescence After Experimental Subarachnoid Hemorrhage in Mice[END_REF][100] . While the specific mechanisms are not fully understood, several reports suggest that these molecules are necessary for microglia reactivity to injuries, by controlling their inflammatory response and metabolism [START_REF] Ulland | TREM2 -a key player in microglial biology and Alzheimer disease[END_REF][101][102][103] .

Lipoprotein lipase (LPL).

Another lipid-related gene that appears to modulate microglia phenotype and function is lpl [START_REF] Keren-Shaul | A Unique Microglia Type Associated with Restricting Development of Alzheimer's Disease[END_REF][START_REF] Gao | Lipoprotein Lipase Maintains Microglial Innate Immunity in Obesity[END_REF] . This gene encodes the protein LPL, which hydrolyzes triglycerides that are bound to lipoproteins. In mice models of neurodegenerative and neuroinflammatory diseases, lpl expression is increased [START_REF] Keren-Shaul | A Unique Microglia Type Associated with Restricting Development of Alzheimer's Disease[END_REF]104 . These observations were confirmed in brain samples of AD patients [START_REF] Keren-Shaul | A Unique Microglia Type Associated with Restricting Development of Alzheimer's Disease[END_REF]105 . Increased expression of lpl has been observed during remyelination and its role in promoting microglia phagocytosis has also been revealed 104,[106][107][108] . Inhibition or suppression of LPL skews microglia phenotype towards proinflammation and decreases their phagocytic activity 104,107 . HFD increases lpl expression in hypothalamic microglia [START_REF] Gao | Lipoprotein Lipase Maintains Microglial Innate Immunity in Obesity[END_REF] . In this context, inhibiting LPL activity aggravates HFD-induced metabolic alterations [START_REF] Gao | Lipoprotein Lipase Maintains Microglial Innate Immunity in Obesity[END_REF] .

Cholesterol. Cholesterol is synthesized de novo in the brain, mainly by astrocytes 109,110 . It is then transferred to surrounding cells through APOE, the main cholesterol-carrier of the CNS, that is expressed by both astrocytes and microglia 111,112 . Cholesterol uptake by microglia, that follows APOE-TREM2 interaction, ensures survival of cultured cells [START_REF] Bohlen | Diverse Requirements for Microglial Survival, Specification, and Function Revealed by Defined-Medium Cultures[END_REF][START_REF] Yeh | TREM2 Binds to Apolipoproteins, Including APOE and CLU/APOJ, and Thereby Facilitates Uptake of Amyloid-Beta by Microglia[END_REF] . Even though the mechanisms remain unclear, cholesterol metabolism modulates microglial phagocytic capacity [START_REF] Bohlen | Diverse Requirements for Microglial Survival, Specification, and Function Revealed by Defined-Medium Cultures[END_REF]109,113 . When present at high concentration, engulfed cholesterol (cellular debris, myelin), can no longer be digested by microglia so that it accumulates within lipid bodies or cholesterol crystals 114 . Cholesterol efflux capacity is overwhelmed in these conditions 114 , impairing the normal induction of remyelination processes in a context of lysolecithininduced demyelination in aged mice 114 . This maladaptive immune response (cholesterol efflux impairment) could explain why alterations in the expression of genes like apoe or trem2 are associated with greater risks of neurodegenerative disorders.

Cholesterol can be metabolized in bioactive derivatives, namely oxysterols. These latter modulate microglial inflammatory response in vitro as well as MS and AD brains 111,115,116 .

Many oxysterols are anti-inflammatory as they decrease LPS-induced inflammatory response in microglia primary culture 116 . Conversely, 25-hydroxycholesterol (25-OH) promotes neuroinflammation in a model of adrenoleukodystrophy 117 . Mechanisms through which oxysterols modulate brain inflammation remain unknown. Some reports suggest that they could act through LXRs 116,117 . Interestingly, LXRs activation is beneficial in AD progression as it decreases Aβ burden and as a consequence cognitive impairments [118][119][120] . Oxysterols have been recently showed to stimulate microglial expression of ABCA1 and APOE, two targets of LXR signaling, hence favoring cholesterol efflux [121][122][123] .

Other lipid carriers have been studied for their ability to control microglia function. A recent paper highlighted the role of Apolipoprotein A-I binding protein (AIBP) in microglial activation in a context of neuropathic pain 124 . HDL and APOA-I, its principal protein component, are known to bind AIBP which interacts with TLR4, leading to cholesterol efflux and remodeling of lipid rafts 124,125 . Overall AIBP and cholesterol efflux exert antiinflammatory action on microglia and macrophages 124,126,127 .

Indirect effects of lipids on microglia function

The levels of body lipids are controlled by two main factors: 1) dietary intake and 2) endogenous lipid synthesis and metabolism, which are themselves regulated by a wide variety of genetic or environmental factors 128 . Some reports suggest that peripheral lipids can influence microglia function as well, through indirect mechanisms including microbialderived metabolites, hormonal control and inflammation. In a second part, we are summarizing current knowledge on the potential candidates involved in lipid-mediated indirect modulation of microglial activity. We concentrate on experimental contexts in which lipid intake and/or metabolism are disturbed such, as HFD feeding, obesity and n-3 PUFA deficiency. We more specifically discuss the role of hormones and gut-derived messengers in these aspects (as the role of inflammation has been extensively reviewed in the past).

Microglia and gut physiology

Microbiota and their metabolites. Diet is one of the main modulator of gut microbiota composition and function. Relative intake of proteins, lipids and carbohydrates as well as fiber consumption not only controls the diversity of microbial species but also their activity (e.g. metabolites production) [129][130][131][132][133] . More specifically, the quantity and quality of lipid intake can modulate intestinal permeability, low-grade inflammation, fat storage and endocrine activity 132,[134][135][136]134,137,138 . Conversely, microbiota controls fat absorption, storage and metabolism 139,140 . Furthermore, microbiota composition and function influences behavior, neuronal activity and neuroinflammatory processes [START_REF] Thion | Microbiome Influences Prenatal and Adult Microglia in a Sex-Specific Manner[END_REF][141][142][143][144][145][146][147] .Notably, microbiota transfer from HFD-fed mice to standard chow-fed animals triggers behavioral deficits and neuroinflammation in the acceptor mice 148 . Recent studies have shown that microglia are sensitive to microbial activity [START_REF] Thion | Microbiome Influences Prenatal and Adult Microglia in a Sex-Specific Manner[END_REF]142,145,149 . In a pioneering study, Erny and colleagues showed that germ-free mice display alterations in microglial morphology 142 . Knocking-out TLR receptors did not reverse the phenotype, suggesting that the effect of microbiota on microglia is independent of microbial ligands recognition 142 . Authors also showed that short-chain fatty acids (SCFA), which are bacterial metabolites, are involved in gut-microglia communication through activation of the free-fatty acid receptor 2 (FFAR2) 142 . More recently, Thion et al. showed that microbiota modulates microglia transcriptome in a sex and age-dependent manner [START_REF] Thion | Microbiome Influences Prenatal and Adult Microglia in a Sex-Specific Manner[END_REF] . Moreover, they revealed that maternal microbiota influences the maturation of fetal microglia [START_REF] Thion | Microbiome Influences Prenatal and Adult Microglia in a Sex-Specific Manner[END_REF] . Overall, these studies highlighted for the first time the role of gut bacteria and associated metabolites on microglia phenotype. Rothhammer and colleagues showed that tryptophan-derived metabolites produced by the commensal flora limits microglial inflammatory activation in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. Specific removal of aryl hydrocarbon receptor (AHR) receptor from microglia, a receptor for tryptophan metabolites, worsened microglial inflammation and subsequent outcomes of EAE 148 . These 3 pioneering studies lay the foundations for a new field of research on the microbiota-microglia axis 141,149 . Yet, previous studies had already shown that microbiota-derived molecules (SCFA, AHR ligands) modulate neuroinflammation and microglia function. SCFA levels are altered in obese subjects, among which butyrate can counteract most of the side-effects of HFD including lipogenesis and inflammation 150,151 .

Butyrate also decreases LPS-mediated microglial activation in vitro, by blocking NFκB pathway and by promoting apoptosis in these cells [152][153][154][155] . In vivo, butyrate and high-fiber diet (which increases SCFA levels) dampen neuroinflammation in mice models of aging, stroke and acute LPS injection [155][156][157] . The microbiota can also generate conjugated fatty acids from dietary fatty acids. A recent study showed that 10-oxo-trans-11-octadecenoic acid and 10hydroxy-cis-12-octadecenoic acid, two LA derivatives produced by lactobacillus plantarum, exert anti-inflammatory effects in BV2 cells 158 . Beyond these studies, only little is known about the mechanisms involved. Yet, it was shown that brain concentration of gut-derived tryptophan metabolites, such as the indole family, increases following systemic administration of these compounds, suggesting that they can reach the CNS after production by the microbiota 159 . Moreover, butyrate is likely to exert its effect by binding to several types of receptors: the above-mentioned FFARs but also GPR109a (or HCAR2) and GPR164 (or Olfr558) 160 .

Bile acid. Bile acid (BA) synthesis and recycling depends on the tight collaboration between the liver and the gut 161,162 , BA being released by the liver and controlling lipid absorption in the intestine. The microbiota control liver-derived BA pool size. Moreover, reduced BA levels in the gut are associated with bacterial overgrowth and inflammation 163 . Two main receptors are thought to mediate their effects, namely the nuclear farnesoid X receptor (FXR) and the Takeda G protein-coupled receptor 5 (TGR5). BA-mediated activation of these receptors modulates metabolism (lipid and carbohydrate metabolism, energy expenditure) and inflammatory processes 161,162,164 . Their role in the control of microglia function has been highlighted by recent studies showing that BA per se or targets of BA receptors control microglial activation in animal models of neuroinflammation (hepatic encephalopathy, retinal degeneration, LPS or Aβ injection, HFD) [165][166][167][168][169][170][171][172] . BA is likely to indirectly act on the brain by activating TGR5 in enteroendocrine cells that in turn release GLP-1, a known modulator of brain function 173 .

Overall, all these studies suggest that the microbiota communicates with the brain using various, direct and indirect, pathways. If most of above-mentioned gut-derived metabolites can theoretically reach the brain, it remains unclear how they modulate microglia function in return. Moreover, most of these molecules may act peripherally, by modulating neurotransmitter release in the gut, by stimulating vagus nerve terminals or by acting on peripheral organs that would lead to the release of secondary messengers (e.g. hormones, cytokines or chemokines).

Hormones and microglia

Both the quantity and quality (SFA, MUFA, PUFA, short-or long-chain, etc.) of lipids can modulate metabolic outcomes including insulin resistance, adiposity, inflammation and hormones levels [START_REF] Valdearcos | Microglia Dictate the Impact of Saturated Fat Consumption on Hypothalamic Inflammation and Neuronal Function[END_REF]174,175 . PUFA for instance, especially from the n-3 series, decrease triglyceridemia, insulin resistance or inflammation [176][177][178][179][180] . A recent study showed that the transplantation of microbiota from Fat-1 mice (genetically enriched in n-3 PUFA) prevents metabolic disorders triggered by HFD exposure in WT littermates 181 . This suggests that the beneficial effects of n-3 PUFA on metabolic deficits are mediated by the microbiota, at least partially. Moreover, dietary lipids modulate hormone release by peripheral organs such as the gut, liver, stomach and pancreas 178,182 . In this part, we will discuss the link between circulating hormones, metabolic status and microglia function as a potential indirect mechanism by which lipids may regulate neuroinflammation.

Insulin. Obesity and SFA intake induce insulin resistance and hyperinsulinemia [START_REF] Maldonado-Ruiz | Microglia activation due to obesity programs metabolic failure leading to type two diabetes[END_REF] . If the effects of insulin on neurons have been extensively studied, how this hormone might regulate microglia remains largely unknown. One in vitro study revealed that insulin application on microglial cells decreases LPS-induced NO and TNF-α production, and potentiates their phagocytic activity, in a dose-dependent manner 212 . Overall, insulin might exert antiinflammatory and pro-repair effects, yet this needs to further studies.

Insulin like growth factor 1 (IGF-1). IGF-1 is a growth factor that shares structural similarities with insulin. Its blood concentration is decreased in metabolic syndrome and obese subjects, while PUFA (both n-6 and n-3 series) can increase it 185,186 . Specific microglial populations can synthesize and release IGF-1 [187][188][189][190] . These cells usually support neurodevelopmental processes such as neuron survival and myelination among others.

Glucagon-like peptide-1. The peptide GLP-1 is mainly synthesized by enteroendocrine L cells. It promotes insulin sensitivity and reduces food intake, plasma glucose levels and body weight 191 . Both the type and amount of lipids modulate GLP-1 release 192,193 . Moreover, microbiota can also increase GLP-1 levels through the activity of its metabolites 160 . When produced, GLP-1 has a very short lifetime as it is rapidly degraded by dipeptidyl-peptidase 4.

Hence, it is thought that peripheral GLP-1 is mainly acting on brain vagal signaling 194 .

However, neurons and microglia can also sense and release GLP-1 194,195 . Microglial GLP-1 production is blunted in LPS-treated microglia or in the context of obesity 195,196 . Moreover, administration of GLP-1 receptor agonists (e.g. liraglutide, lixisenatide, exendin-4 or NLY01) prevents microglial activation 197,198 . Yun and colleagues recently showed that NLY01 displays neuroprotective properties in a model of α-synucleinopathy by preventing microgliamediated conversion of astrocytes into an A1 (inflammatory) phenotype 198 . The same neuroprotective effect of GLP-1 receptor activation has been observed in a wide variety of neuroinflammation models 195,[199][200][201][202][203] .

Leptin. Leptin originates from the adipose tissue. It is an anorexigenic hormone whose production is increased in obese patients (combined to leptin resistance), while a supplementation with n-3 PUFA can decrease it [START_REF] Maldonado-Ruiz | Microglia activation due to obesity programs metabolic failure leading to type two diabetes[END_REF]204 . Leptin is structurally close to interleukins and influences neuroinflammatory processes 205,206 . Under SFA-enriched diet, microglia decreases leptin signaling in the hypothalamus as shown by depleting these cells with the CSF1R inhibitor PLX5622 [START_REF] Valdearcos | Microglia Dictate the Impact of Saturated Fat Consumption on Hypothalamic Inflammation and Neuronal Function[END_REF] . Microglia express the leptin receptor and respond to the hormone by mounting a proinflammatory response [205][206][207][208] . Deletion of microglial leptin receptor recapitulates many symptoms observed in mice lacking leptin receptor (db/db mice) especially in the context of obesity 209 . Moreover, this specific deletion alters microglia morphology and decreases its phagocytic activity 209 .

Amylin. Amylin is a pancreatic peptide that shares several biological effects with GLP-1 and exerts neuroimmunomodulatory activity 191 . Amylin treatment regulates microglia inflammatory response, as its application stimulates IL-6 production by microglia which in turn increases the sensitivity to leptin, giving amylin the role of "leptin sensitizer" 210,211 .

Adiponectin. Adiponectin originates from adipocytes. Its production is decreased in obese patients and increased by n-3 PUFA intake 204,212 . This hormone exerts anti-inflammatory effects on microglial cells through its receptor AdipoR1 [212][213][214] . Song and colleagues also suggested that adiponectin promotes neuroprotective phenotype of microglia by activating PPAR-γ 214 .

Ghrelin. Ghrelin is an orexigenic hormone produced by the stomach and the duodenum 212 .

Obesity is known to decrease the overall ghrelin levels while it increases its active form, namely acyl-ghrelin 212,215 . Ghrelin exerts anti-inflammatory and anti-oxidative effects on LPS-stimulated microglia 216 . Moreover, its neuroprotective action has been observed in many models of neuroinflammation 205,[217][218][219] . The mechanisms through which ghrelin decreases microglial activation remain elusive since these cells do not express the ghrelin receptor.

Some studies indicate that inhibition of endothelial cells-derived MMP-3 release could represent one mechanisms 219,220 .

Conclusion

All these data demonstrate that dietary lipids affect microglia function, either directly or through indirect mechanisms. Yet, many questions remain:

1-Considering other factors (genetic and environmental) that can influence lipid transport and metabolism, including the production of bioactive metabolites.

2 - 3 -

 23 Using large-scale analyses of microglia, such as lipidomics and transcriptomics, to help understanding how lipids regulate microglial function in a wide range of pathophysiological situations. Addressing if and how the peripheral alteration of lipid homeostasis (inflammation, metabolic disturbances and gut microbiota alterations) could either alleviate or reinforce the effects of fatty acids on microglial cells. 4-Exploring further whether circulating hormones and gut microbiota composition/function represent interesting targets to understand the co-morbidities between metabolic diseases (obesity, diabetes) and neuroinflammation. 5-Defining the impact of other nutrients such as carbohydrates and proteins on microglia function especially regarding its role in neuroinflammation.

Acknowledgement

AN and SL are supported by the Institut National pour la Recherche Agronomique (INRA), the Bordeaux University, the Foundation for Medical research (FRM), the French Foundation (FDF), the Excellence Initiative Labex Brain and the Nouvelle Région Aquitaine. QL was supported by the region Ile de France (PICRI, the Ceberal Palsy Foundation) and by the FRM.