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International audience; AIMS: Although prebiotics, probiotics, and fecal transplantation can alter the sensation of hunger and/or feeding behavior, the role of the constitutive gut microbiota in the short-term regulation of food intake during normal physiology is still unclear. RESULTS: An antibiotic-induced microbiota depletion study was designed to compare feeding behavior in conventional and microbiota-depleted mice. Tissues were sampled to characterize the time profile of microbiota-derived signals in mice during consumption of either standard or high-fat food for 1 hour. Pharmacological and genetic tools were used to evaluate the contribution of postprandial endotoxemia and inflammatory responses in the short-term regulation of food intake. We observed constitutive microbial and macronutrient-dependent control of food intake at the time scale of a meal, i.e., within 1 hour of food introduction. Specifically, microbiota depletion increased food intake and the microbiota-derived anorectic effect became significant during the consumption of high-fat but not standard food. This anorectic effect correlated with a specific postprandial microbial metabolic signature and did not require postprandial endotoxemia or an NLRP3 (NOD-, LRR- and Pyrin domain-containing protein 3)-inflammasome mediated inflammatory response. Innovation and Conclusion: These findings show that the gut microbiota controls host appetite at the time scale of a meal under normal physiology. Interestingly, a microbiota-derived anorectic effect develops specifically with a high-fat meal, indicating that gut microbiota activity is involved in the satietogenic properties of foods.

Ageing is characterised at the molecular level by six transcriptional ‘hallmarks of ageing’, that are commonly described as progressively affected as time passes. By contrast, the ‘Smurf’ assay separates high-and-constant-mortality risk individuals from healthy, zero-mortality risk individuals, based on increased intestinal permeability. Performing whole body total RNA sequencing, we found that Smurfness distinguishes transcriptional changes associated with chronological age from those associated with biological age. We show that transcriptional heterogeneity increases with chronological age in non-Smurf individuals preceding the other five hallmarks of ageing, that are specifically associated with the Smurf state. Using this approach, we also devise targeted pro-longevity genetic interventions delaying entry in the Smurf state. We anticipate that increased attention to the evolutionary conserved Smurf phenotype will bring about significant advances in our understanding of the mechanisms of ageing.Graphical abstractThe two-phase model of ageing allows to study separately the effect of chronological and physiological age.(A)Classic approaches for studying ageing tend to consider it as a black box affecting all individuals progressively from birth to death. Instead, the Smurf phenotype shows that life can be divided into two consecutive phases separated by an abrupt transition.(B)All individuals undergo this transition at a different moment in their life, prior to death. This allows us to switch from population based approaches, comparing bulks of age-matched individuals through time, to individuals-centred approaches relying on direct access to their transition status.(C)Such paradigm shift shows that hallmarks of ageing long thought to progressively change with age are actually mostly affected in a growing proportion of Smurfs, allowing for the identification of the chain of events accompanying ageing and death from natural causes.(D)By studying the behaviour of the ageing transcriptome as a function of chronological age and Smurfness separately, we demonstrate that the progressively changing transcriptional ageing signature, as described in Frenk & Houseley (2018), is in fact the convolution changes accompanying chronological age signature (increased transcriptional noise) and changes associated with Smurfness (or biological age) signature (increased stress response and inflammation, decreased expression of ribosomal and mitochondrial genes). We also identified a hallmark partially associated with only old Smurfs (ATH5), suggesting that chronological age can affect, late in life, the Smurf response.

Summary: Mechanistic studies in rodents evidenced synaptic remodeling in neuronal circuits that control food intake. However, the physiological relevance of this process is not well defined. Here, we show that the firing activity of anorexigenic POMC neurons located in the hypothalamus is increased after a standard meal. Postprandial hyperactivity of POMC neurons relies on synaptic plasticity that engages pre-synaptic mechanisms, which does not involve structural remodeling of synapses but retraction of glial coverage. These functional and morphological neuroglial changes are triggered by postprandial hyperglycemia. Chemogenetically induced glial retraction on POMC neurons is sufficient to increase POMC activity and modify meal patterns. These findings indicate that synaptic plasticity within the melanocortin system happens at the timescale of meals and likely contributes to short-term control of food intake. Interestingly, these effects are lost with a high-fat meal, suggesting that neuroglial plasticity of POMC neurons is involved in the satietogenic properties of foods. : State-dependent plasticity in neuronal circuits controlling hunger is well established. Nuzzaci et al. show that this process is recapitulated after a meal. Postprandial hyperglycemia induces glial retraction around hypothalamic POMC neurons, which increases the activity of these anorectic neurons. This macronutrient-dependent plasticity provides a neurobiological basis for satiety. Keywords: hypothalamus, plasticity, energy homeostasis, obesity, melanocortin system, pro-opiomelanocortin neurons, astrocytes, food intake, satiety

Resume Le surpoids et l’obesite representent le cinquieme facteur de risque mondial de deces (estimation de 2008, Organisation mondiale de la sante [OMS]). Dans la plupart des cas, l’obesite est due a une deregulation de la balance energetique qui est l’equilibre entre les entrees et les sorties d’energie. Un des elements majeurs dans la regulation de cette balance est le cerveau. En effet, celui-ci integre les signaux provenant de la peripherie et va en retour adapter la prise alimentaire et la depense energetique afin de maintenir un poids constant tout au long de la vie adulte d’un individu. Depuis les annees 2000, le role de la detection cerebrale des lipides nutritionnels dans la regulation de la balance energetique par le cerveau est de plus en plus etudie. Il existe differentes classes de lipides nutritionnels dont les acides gras (AG) et les triglycerides (TG). Recemment il a ete mis en evidence que la lipoproteine lipase (LPL) qui est l’enzyme responsable de l’hydrolyse des TG en AG est active dans les neurones, regule l’assimilation des lipides par le cerveau et participe a la regulation de la balance energetique. Cette revue vise donc a faire un point bibliographique sur la lipoproteine lipase dans le cerveau et sur son impact dans la detection cerebrale des lipides et la regulation centrale de la balance energetique.

In humans, obesity was associated with brain inflammation and glial cell proliferation. Studies in rodents showed that glial cell proliferation occurs within 24 hours of high-fat diet (HFD) consumption, before obesity development. This proliferation was mainly observed in the hypothalamus (HT), a crucial brain structure for controlling body weight. Therefore, we sought to characterize the post-prandial HT inflammatory response to 1-3-6 hours exposure to a standard diet and HFD. HFD exposure increased gene expression of astrocyte and microglial marker (GFAP and Iba1) compare to standard treated mice and induced morphological modifications of microglial cells in HT. This remodeling was associated with higher expression of inflammatory genes and differential activation of hypothalamic neuropeptides involved in energy balance regulation. DREADD and PLX5622 technologies, used to modulate GFAP-positive or microglial cells activity respectively, showed that both glial cell types are involved in hypothalamic post-prandial inflammation, but in a different time frame and with a diet specificity Thus, an exacerbated post-prandial inflammation in brain might predispose individuals to obesity and needs to be characterized to address this worldwide crisis.

Il existe, dans l’hypothalamus et dans d’autres structures cerebrales comme l’hippocampe ou le striatum, des neurones specialises capables de detecter les variations quotidiennes des acides gras circulants. Ces neurones participent au maintien a l’equilibre de la balance energetique en controlant la prise alimentaire, la secretion d’insuline ou la production hepatique de glucose. Les mecanismes moleculaires relayant l’effet des acides gras impliquent des recepteurs d’acides gras comme FAT (fatty acid transporter )/CD36. Toute deregulation de cette detection centrale des acides gras peut contribuer a la mise en place des maladies metaboliques, telles que l’obesite ou le diabete de type 2.

Energy homoeostasis is maintained through a complex interplay of nutrient intake and energy expenditure. The central nervous system is an essential component of this regulation, as it integrates circulating signals of hunger and satiety to develop adaptive responses at the behavioural and metabolic levels, while the hypothalamus is regarded as a particularly crucial structure in the brain in terms of energy homoeostasis. The arcuate nucleus (ARC) of the hypothalamus contains at least two intermingled neuronal populations: the neurons that produce neuropeptide Y (NPY); and the Agouti-related protein (AgRP) produced by AgRP/NPY neurons situated below the third ventricle in close proximity to proopiomelanocortin (POMC)-producing neurons. POMC neurons exert their catabolic and anorectic actions by releasing α-melanocyte-stimulating hormone (α-MSH), while AgRP neurons oppose this action by exerting tonic GABAergic inhibition of POMC neurons and releasing the melanocortin receptor inverse agonist AgRP. The release of neurotransmitters and neuropeptides by second-order AgRP neurons appears to take place on a multiple time scale, thereby allowing neuromodulation of preganglionic neuronal activity and subsequent control of nutrient partitioning – in other words, the coordinated regulation of conversion, storage and utilization of carbohydrates vs. lipids. This suggests that the function of AgRP neurons extends beyond the strict regulation of feeding to the regulation of efferent organ activity, such that AgRP neurons may now be viewed as an important bridge between central detection of nutrient availability and peripheral nutrient partitioning, thus providing a mechanistic link between obesity and obesity-related disorders.

Resume Dans nos societes modernes, l’abondance de nourriture riche en energie et le mode vie sedentaire entraine un desequilibre de la balance energetique a l’origine du developpement de l’obesite qui se traduit par une consommation excessive de calories et une diminution des depenses energetiques. En particulier, l’exposition a des nourritures riches en lipides est supposee promouvoir les alterations metaboliques dans les tissus peripheriques associes a l’obesite comme l’inflammation et la resistance a l’insuline. La regulation de la balance energetique repose sur la capacite du cerveau a fournir une reponse adaptee aux variations des facteurs circulants de satiete et de faim refletant le statut energetique de l’organisme. L’hypothalamus et le tronc cerebral sont des structures fondamentales dans le controle energetique de la prise alimentaire. Cependant les comportements alimentaires sont egalement modules par des facteurs sensoriels comme le gout et l’odeur de la nourriture, ainsi que par des facteurs emotionnels, qui vont reguler l’aspect hedonique de la prise alimentaire. Cet aspect de la prise alimentaire est en relation etroite avec la liberation de dopamine au niveau du systeme de la recompense, qui est stimulee par les nourritures riches en calories ainsi que par differents objets de desir. De maniere interessante, les structures impliquees dans la regulation de la prise alimentaire expriment differentes enzymes impliquees dans la prise en charge des lipides et de plus en plus de donnees de la litterature montrent que les lipides nutritionnels peuvent agir, dans des regions specifiques du cerveau, comme des signaux refletant la disponibilite en nutriments et controler ainsi directement l’aspect energetique et hedonique de la prise alimentaire.

Resume Plusieurs millions d’annees d’evolution ont permis de forger un systeme adaptatif permettant d’assurer l’apport d’energie necessaire a la survie de tout organisme. Une multitude de signaux hormonaux et nerveux sont integres au niveau de l’hypothalamus et du tronc cerebral, et participent en permanence a la maintenance de l’homeostasie energetique. A cette regulation, s’ajoute la composante hedonique et motivationnelle de la prise alimentaire dont l’encodage est assure par des circuits neuronaux du systeme mesolimbique dopaminergique (SMD). La prise de nourriture est l’aboutissement d’une sequence comportementale complexe qui resulte de l’integration au niveau central des signaux metaboliques de faim et de satiete, mais egalement des proprietes organoleptiques de la nourriture, tel le gout et l’odeur, ainsi que des facteurs emotionnels, tels que le stress ou l’anxiete, au niveau du SMD. Ainsi, certains parametres du comportement alimentaire de type compulsif presentent des similitudes avec les conduites addictives associees a l’utilisation de drogues d’abus.

International audience; Sickness behavior defines the endocrine, autonomic, behavioral, and metabolic responses associated with infection. While inflammatory responses were suggested to be instrumental in the loss of appetite and body weight, the molecular underpinning remains unknown. Here, we show that systemic or central lipopolysaccharide (LPS) injection results in specific hypothalamic changes characterized by a precocious increase in the chemokine ligand 2 (CCL2) followed by an increase in pro-inflammatory cytokines and a decrease in the orexigenic neuropeptide melanin-concentrating hormone (MCH). We therefore hypothesized that CCL2 could be the central relay for the loss in body weight induced by the inflammatory signal LPS. We find that central delivery of CCL2 promotes neuroinflammation and the decrease in MCH and body weight. MCH neurons express CCL2 receptor and respond to CCL2 by decreasing both electrical activity and MCH release. Pharmacological or genetic inhibition of CCL2 signaling opposes the response to LPS at both molecular and physiologic levels. We conclude that CCL2 signaling onto MCH neurons represents a core mechanism that relays peripheral inflammation to sickness behavior.

International audience; The reinforcing and motivational aspects of food are tied to the release of the dopamine in the mesolimbic system (ML). Free fatty acids from triglyceride (TG)-rich particles are released upon action of TG-lipases found at high levels in peripheral oxidative tissue (muscle, heart), but also in the ML. This suggests that local TG-hydrolysis in the ML might regulate food seeking and reward. Indeed, evidence now suggests that dietary TG directly target the ML to regulate amphetamine-induced locomotion and reward seeking behavior. Though the cellular mechanisms of TG action are unresolved, TG act in part through ML lipoprotein lipase, upstream of dopamine 2 receptor (D2R), and show desensitization in conditions of chronically elevated plasma TG as occur in obesity. TG sensing in the ML therefore represents a new mechanism by which chronic consumption of dietary fat might lead to adaptations in the ML and dysregulated feeding behaviors.

Objective Obesity is one of the primary healthcare challenges of the 21st century. Signals relaying information regarding energy needs are integrated within the brain to influence body weight. Central among these integration nodes are the brain pro-opiomelanocortin (POMC) peptides, perturbations of which disrupt energy balance and promote severe obesity. However, POMC neurons are neurochemically diverse and the crucial source of POMC peptides that regulate energy homeostasis and body weight remains to be fully clarified. Methods Given that a 5-hydroxytryptamine 2c receptor (5-HT2CR) agonist is a current obesity medication and 5-HT2CR agonist's effects on appetite are primarily mediated via POMC neurons, we hypothesized that a critical source of POMC regulating food intake and body weight is specifically synthesized in cells containing 5-HT2CRs. To exclusively manipulate Pomc synthesis only within 5-HT2CR containing cells, we generated a novel 5-HT2CRCRE mouse line and intercrossed it with Cre recombinase-dependent and hypothalamic specific reactivatable PomcNEO mice to restrict Pomc synthesis to the subset of hypothalamic cells containing 5-HT2CRs. This provided a means to clarify the specific contribution of a defined subgroup of POMC peptides in energy balance and body weight. Results Here we transform genetically programed obese and hyperinsulinemic male mice lacking hypothalamic Pomc with increased appetite, reduced physical activity and compromised brown adipose tissue (BAT) into lean, healthy mice via targeted restoration of Pomc function only within 5-HT2CR expressing cells. Remarkably, the same metabolic transformation does not occur in females, who despite corrected feeding behavior and normalized insulin levels remain physically inactive, have lower energy expenditure, compromised BAT and develop obesity. Conclusions These data provide support for the functional heterogeneity of hypothalamic POMC neurons, revealing that Pomc expression within 5-HT2CR expressing neurons is sufficient to regulate energy intake and insulin sensitivity in male and female mice. However, an unexpected sex difference in the function of this subset of POMC neurons was identified with regard to energy expenditure. We reveal that a large sex difference in physical activity, energy expenditure and the development of obesity is driven by this subpopulation, which constitutes approximately 40% of all POMC neurons in the hypothalamic arcuate nucleus. This may have broad implications for strategies utilized to combat obesity, which at present largely ignore the sex of the obese individual., Graphical abstract, Highlights • Generation of 5-HT2CRYFP mouse line revealed 40% of hypothalamic POMC neurons co-express 5-HT2CRs in male and female mice. • Pomc expressed exclusively within 5-HT2CR cells modulates energy intake and insulin sensitivity in male and female mice. • An unexpected sex difference in physical activity and energy expenditure is modulated by hypothalamic Pomc. • Pomc expressed exclusively within 5-HT2CR cells differentially impacts body weight accumulation in male and female mice.

Obesity-related diseases such as diabetes and dyslipidemia result from metabolic alterations including the defective conversion, storage and utilization of nutrients, but the central mechanisms that regulate this process of nutrient partitioning remain elusive. As positive regulators of feeding behaviour, agouti-related protein (AgRP) producing neurons are indispensible for the hypothalamic integration of energy balance. Here, we demonstrate a role for AgRP-neurons in the control of nutrient partitioning. We report that ablation of AgRP-neurons leads to a change in autonomic output onto liver, muscle and pancreas affecting the relative balance between lipids and carbohydrates metabolism. As a consequence, mice lacking AgRP-neurons become obese and hyperinsulinemic on regular chow but display reduced body weight gain and paradoxical improvement in glucose tolerance on high-fat diet. These results provide a direct demonstration of a role for AgRP-neurons in the coordination of efferent organ activity and nutrient partitioning, providing a mechanistic link between obesity and obesity-related disorders.

International audience; Feeding behavior is exquisitely regulated by homeostatic and hedonic neural substrates that integrate energy demand as well as the reinforcing and rewarding aspects of food. Understanding the net contribution of homeostatic and reward-driven feeding has become critical because of the ubiquitous source of energy-dense foods and the consequent obesity epidemic. Hypothalamic agouti-related peptide-secreting neurons (AgRP neurons) provide the primary orexigenic drive of homeostatic feeding. Using models of neuronal inhibition or ablation, we demonstrate that the feeding response to a fast ghrelin or serotonin receptor agonist relies on AgRP neurons. However, when palatable food is provided, AgRP neurons are dispensable for an appropriate feeding response. In addition, AgRP-ablated mice present exacerbated stress-induced anorexia and palatable food intake--a hallmark of comfort feeding. These results suggest that, when AgRP neuron activity is impaired, neural circuits sensitive to emotion and stress are engaged and modulated by food palatability and dopamine signaling.

Fatty acid sensitive neurons located in hypothalamus, hippocampus or striatum are able to detect daily variations of plasma fatty acid levels. Thus, these neurons play a role to regulate energy balance by controling food intake, insulin secretion or hepatic glucose production. Molecular mechanisms that mediate fatty acid effects include receptor FAT (fatty acid transporter)/CD36. Deregulation of this brain lipid sensing may be an early event leading to further dysfunction of energy balance leading to obesity and type 2 diabetes.

In both developed and emerging countries, sedentary life style and over exposition to high energy dense foods has led to a thermodynamic imbalance and consequently obesity. Obesity often involves a behavioural component in which, similar to drugs abuse, compulsive consumption of palatable food rich in lipids and sugar drives energy intake far beyond metabolic demands. The hypothalamus is one of the primary integration sites of circulating energy-related signals like leptin or ghrelin and is therefore considered as one of the main central regulators of energy balance. However, food intake is also modulated by sensory inputs, such as tastes and odours, as well as by affective or emotional states. The mesolimbic pathway is well established as a key actor of the rewarding aspect of feeding. Particularly, the hedonic and motivational aspects of food are closely tied to the release of the neurotransmitter dopamine (DA) in striatal structure such as the Nucleus Accumbens (Nacc). In both rodent and humans several studies shows an attenuated activity of dopaminergic signal associated with obesity and there is evidence that consumption of palatable food per se leads to DA signalling alterations. Furthermore impaired cognition in obese mice is improved by selectively lowering triglycerides (TG) and intracerebroventricular administration of TG induces by itself acquisition impairment in several cognitive paradigms in normal body weight mice. Together, these observations raise the possibility that nutritional lipids, particularly TG, directly affect cognitive and reward processes by modulating the mesolimbic pathway and might contribute to the downward spiral of compulsive consumption of palatable food and obesity. This review is an attempt to capture recent evolution in the field that might point toward a direct action of nutritional lipid in the reward circuitry.

International audience; Circulating triglycerides (TGs) normally increase after a meal but are altered in pathophysiological conditions, such as obesity. Although TG metabolism in the brain remains poorly understood, several brain structures express enzymes that process TG-enriched particles, including mesolimbic structures. For this reason, and because consumption of high-fat diet alters dopamine signaling, we tested the hypothesis that TG might directly target mesolimbic reward circuits to control reward-seeking behaviors. We found that the delivery of small amounts of TG to the brain through the carotid artery rapidly reduced both spontaneous and amphetamine-induced locomotion, abolished preference for palatable food and reduced the motivation to engage in food-seeking behavior. Conversely, targeted disruption of the TG-hydrolyzing enzyme lipoprotein lipase specifically in the nucleus accumbens increased palatable food preference and food-seeking behavior. Finally, prolonged TG perfusion resulted in a return to normal palatable food preference despite continued locomotor suppression, suggesting that adaptive mechanisms occur. These findings reveal new mechanisms by which dietary fat may alter mesolimbic circuit function and reward seeking.

The arcuate nucleus (ARC) of the hypothalamus is particularly regarded as a critical platform that integrates circulating signals of hunger and satiety reflecting energy stores and nutrient availability. Among ARC neurons, pro-opiomelanocortin (POMC) and agouti-related protein and neuropeptide Y (NPY/AgRP neurons) are considered as two opposing branches of the melanocortin signaling pathway. Integration of circulating signals of hunger and satiety results in the release of the melanocortin receptor ligand α-melanocyte-stimulating hormone (αMSH) by the POMC neurons system and decreases feeding and increases energy expenditure. The orexigenic/anabolic action of NPY/AgRP neurons is believed to rely essentially on their inhibitory input onto POMC neurons and second-orders targets. Recent updates in the field have casted a new light on the role of the ARC neurons in the coordinated regulation of peripheral organs involved in the control of nutrient storage, transformation and substrate utilization independent of food intake.

International audience; Fatty acid (FA)-sensitive neurons are present in the brain, especially the hypothalamus, and play a key role in the neural control of energy homeostasis. Through neuronal output, FA may modulate feeding behaviour as well as insulin secretion and action. Subpopulations of neurons in the ventromedial and arcuate hypothalamic nuclei are selectively either inhibited or activated by FA. Molecular effectors of these FA effects probably include chloride or potassium ion channels. While intracellular metabolism and activation of the ATP-sensitive K⁺ channel appear to be necessary for some of the signalling effects of FA, at least half of the FA responses in ventromedial hypothalamic neurons are mediated by interaction with FAT/CD36, an FA transporter/receptor that does not require intracellular metabolism to activate downstream signalling. Thus, FA or their metabolites can modulate neuronal activity as a means of directly monitoring ongoing fuel availability by brain nutrient-sensing neurons involved in the regulation of energy and glucose homeostasis. Recently, the role of lipoprotein lipase in FA sensing has also been shown in animal models not only in hypothalamus, but also in hippocampus and striatum. Finally, FA overload might impair neural control of energy homeostasis through enhanced ceramide synthesis and may contribute to obesity and/or type 2 diabetes pathogenesis in predisposed subjects.

During the last several decades, the world has witnessed a pandemic expansion of pathologies related to high-fat and high-carbohydrate diets including obesity, diabetes, dyslipidemia, and cardiovascular diseases—collectively referred to as metabolic syndrome. Obesity is now considered by the World Health Organization (WHO) to be a worldwide epidemic, having more than doubled since 1980. In 2008, there were 1.5 billion overweight adults in both developed and developing countries (http://www.who.int/mediacentre/factsheets/fs311/en/). The WHO believes the fundamental cause of obesity and being overweight is an energy imbalance between calories consumed and calories expended. Appropriate energy balance is reached when energy intake and energy expenditure are adapted to meet energy demands and nutrient availability. In the central nervous system (CNS), the hypothalamus was identified as a key integrator of nutrients-induced signals of hunger and satiety directing information regarding energy stores and food availability. The arcuate nucleus (ARC) subdivision of the hypothalamus lies at the bottom of the third ventricle close to a circumventricular organ called median eminence (ME). In this region, the blood–brain barrier is fenestrated and allows for facilitated blood–brain exchange. Neurons that reside there are referred to as “first order neurons” because they would be the first to respond to the circulating signals of hunger and satiety such as leptin, insulin or ghrelin. The ARC contains at least two crucial populations of neurons that continuously monitor signals reflecting energy status and promote the appropriate behavioral and metabolic responses to changes in nutritional availability and demand [1]. Neurons in the ARC that make both pro-opiomelanocortin (POMC) and cocaine- and amphetamine-related transcript secrete the melanocortin peptides adrenocorticotropic hormone (ACTH) and α, β and γ-melanocyte-stimulating hormone (MSH), which are derived from posttranslational processing of POMC. POMC neurons decrease food intake and increase energy expenditure through activation of melanocortin receptors (MCR) via the release of α-MSH (Fig. 1). Conversely, activity of neighboring neurons expressing the orexigenic neuropeptides, agouti-related protein (AgRP) and neuropeptide Y (NPY) (AgRP neurons), increase feeding by opposing the anorexigenic actions of the neighboring POMC neurons, in part through the release of AgRP, a competitive inhibitor of MCRs. The two populations project to several nuclei within and outside of the hypothalamus [2] and are an integral part of the so called “melanocortin system” which represent a canonical neurocircuitry involved in the regulation of energy balance. Any mutation in the melanocortin signaling pathway results in hyperphagia, hypometabolism, hyperinsulinemia, and hyperglycemia in both rodents and humans. Figure 1 MiRNAs processing in POMC neurons is critical for central regulation of energy balance. Arcuate(ARC) POMC and AgRP neurons define the two antagonistic branch of the melanocortin system that lies at the bottom of the 3rd ventricules. POMC and AgRP neurons ... In recent years, several processes were described to link high fat feeding and obesity to aberrant development and function of POMC neurocircuitry, such as defective leptin signaling [3,4], inflammation [5] or autopaghy processes [6]. Moreover, high fat feeding was found to alter not only POMC neuron activity but also the ability of this network to renew and rewire during adulthood [7,8]. In this issue of Molecular Metabolism, a study from Schneeberger et al. provides an important molecular clue to understand the molecular mechanisms that could relay peripheral nutrient excess and/or obesity to the function and maintenance of hunger-related neurocircuitry. The authors applied a variety of elegant techniques combined with integrated approaches to tackle the role of microRNA (miRNA) processing enzyme Dicer to the development, activity and survival of POMC neurons [9]. miRNAs are small non-coding RNAs that are processed through primary transcript (pri-miRNA) maturation into pre-miRNA and subsequently exported from the nucleus to be transformed from double stranded RNA into small 20–25 bp long interfering single strand RNA (siRNA) through the specific action of the endoribonuclease Dicer [10]. In turn, Dicer promotes the formation of the RNA-induced silencing complex (RISC) in which siRNA association with target mRNA leads to either translational repression or degradation of the transcript (Fig. 1). miRNAs biogenesis recently emerged as a fundamental regulatory process involved in a wide variety of biological functions including metabolism, cancer and neurological disorders. The authors demonstrate first the expression of Dicer in both AgRP and POMC neurons, they went on showing that hypothalamic but not hindbrain Dicer mRNA expression is regulated by nutritional manipulation and genetic obesity. Fasting induces Dicer mRNA while in animals fed high fat diets or lack leptin (ob/ob) showed reduced Dicer mRNA levels, consistent with an integral role of Dicer in energy sensing. Using sophisticated approaches in which deletion of Dicer1 was restricted to POMC-expressing cells (Pomc-Cre; Dicer1flox/flox), the authors described increased body weight gain, adiposity, hyperglycemia, hyperinsulinemia and glucose intolerance. This phenotype was observed at 12 weeks of age while 6-week old mice remained asymptomatic. Lack of Dicer expression is associated with a sharp reduction of POMC and CART peptide abundance in the hypothalamus at 3 weeks and became undetectable at 6 weeks. This defect paralleled a progressive loss of arcuate POMC neurons. Importantly, the authors provide evidence that POMC survival and maintenance in adulthood critically requires the integrity of miRNA biogenesis while POMC neurons neurogenesis remained unaffected. Since POMC is expressed in the pituitary, the authors also explored thoroughly the consequence of Dicer1 inactivation in these cells. They found that POMC-specific deletion of Dicer1 leads to the absence of pituitary intermediary lobe, a reduction of adrenocorticotropic hormone (ACTH) together with specific deletion of melanotroph and corticotroph genes and altered adrenal morphology. Finally, the authors also provided DNA array data supporting that defective MAPK signaling, proteasome, and ribosomal function are likely involved in the neurodegenerative processes that results from Dicer1 inactivation. This elegant work firmly establishes that DICER-dependent processing of miRNA biogenesis in POMC expressing cells is critically required to sustain survival and activity of POMC cells in both hypothalamus and the pituitary. Importantly, the metabolic syndrome described here is presumably attributable to hypothalamic cell loss since reduced corticosterone level and adrenal corticotropic function is often associated with reduced obesity. In conclusion, this works provides fundamental clues to understand how energy surplus may impact on feeding-related neurocircuitry. The progressive degeneration of POMC neurons observed in POMCDicerKO mice somewhat hampers the conclusion that can be drawn regarding the role of DICER in POMC neurons activity in adult animals. Therefore additional genetic approaches allowing for temporal deletion of Dicer1 will be needed in the future to explore several aspect miRNA-mediated post-transcriptional regulation of POMC neuron electrophysiological activity, neuropeptide processing, neurotransmitter release, synaptic remodeling, or receptor expression. There is no doubt that the breakthrough achieved by such discovery will complement the arsenal of strategies that could be mobilized to curtail the obesity epidemic.

International audience; The modern abundance of energy-rich foods combined with a shift to more sedentary lifestyles has led to a thermodynamic imbalance in which excessive caloric intake and reduced energy expenditure account for the prevalence of obesity. In particular, exposure to lipid-rich diet is thought to promote metabolic alteration in peripheral tissue associated with obesity-related diseases. The regulation of energy balance depends on the ability of the brain to provide an adaptive response to change in circulating factors of hunger and satiety. The hypothalamus is particularly regarded as key integrative structure but, aside from hypothalamic-mediated homeostatic control, feeding behavior is also modulated by sensory inputs, such as tastes and odors, as well as by affective or emotional states. The reinforcing and motivational aspects of food are closely tied to the release of the neurotransmitter dopamine by the mesolimbic system, which is stimulated by calorie-dense foods as well as by most other objects of desire. Therefore feeding behavior is regulated by homeostatic as well as non-homeostatic inputs from the hypothalamus and the mesolimbic region. Interestingly, these structures expresses several enzymes involved in the processing of triglyceride and fatty acid and the recent literature provide growing evidence that fatty acid metabolism within discrete brain regions can function as sensor of nutrient availability directly control the hedonic and the homeostatic aspect of feeding.

The arcuate nucleus of the hypothalamus contains at least two crucial populations of neurons that continuously monitor signals reflecting energy status and promote the appropriate behavioral and metabolic responses to changes in energy demand. Neurons making pro-opiomelanocortin (POMC) decrease food intake and increase energy expenditure through activation of G protein-coupled receptors melanocortin receptors (MCR) via the release of a-melanocyte stimulating hormone. A prevailing idea until recently was that the neighboring neurons expressing the orexigenic neuropeptides, agouti-related protein (AgRP) and neuropeptide Y (NPY) (AgRP neurons) increased feeding by opposing the anorexigenic actions of the POMC neurons. AgRP neurons activation but not POMC neurons inhibition was recently demonstrated to be necessary and sufficient to promote feeding. AgRP expressing axons were identified in mesolimbic, midbrain and pontine structure where they regulate feeding but also feeding-independent functions such as reward or peripheral nutrient partitioning. Post-synaptic Gamma aminobutyric acid (GABA), lasting in a timeline similar to neuromodulation, was identified as the core mechanism by which hunger-activated neurons regulate feeding and non-food related processes in a melanocortin independent manner.

International audience; Lipids are essential components of a living organism as energy source but also as constituent of the membrane lipid bilayer. In addition fatty acid (FA) derivatives interact with many signaling pathways. FAs have amphipathic properties and therefore require being associated to protein for both transport and intracellular trafficking. Here we will focus on several FA handling proteins, among which the fatty acid translocase/CD36 (FAT/CD36), members of fatty acid transport proteins (FATPs), and lipid chaperones fatty acid-binding proteins (FABPs). A decade of extensive studies has helped decipher the mechanism of action of these proteins in peripheral tissue with high lipid metabolism. However, considerably less information is available regarding their role in the brain, despite the high lipid content of this tissue. This review will primarily focus on the recent studies that have highlighted the crucial role of lipid handling proteins in brain FA transport, neuronal differentiation and development, cognitive processes and brain diseases. Finally a special focus will be made on the recent studies that have revealed the role of FAT/CD36 in brain lipid sensing and nervous control of energy balance.

Santiago Vernia et alt., Laforin is a dual specificity protein phosphatase involved in Lafora disease (LD), a fatal form of progressive myoclonus epilepsy characterized by neurodegeneration and the presence of intracellular polyglucosan inclusions (Lafora bodies) in different tissues. In this work, we describe that mice lacking laforin (epm2a−/−) have enhanced insulin response leading to altered whole-body energy balance. This enhanced insulin response overactivates the Akt pathway which increases glucose uptake in the heart, resulting in increased glycogen levels and the formation of polyglucosan inclusions. In addition, enhanced insulin response resulted in increased liver lipid biosynthesis, resulting in hepatic steatosis. On the contrary, overexpression in rat hepatoma FTO2B cells of native laforin but not of a form lacking phosphatase activity (C266S) resulted in attenuation of insulin signaling. These results define laforin as a new regulator of insulin sensitivity, which provides novel insights into LD pathogenesis and identifies this phosphatase as a potential novel component of the insulin signaling cascade, This work was supported by a grant from the Spanish Ministry of Education and Science (SAF2008-01907) and by EXGENESIS, an Integrated Project (LSHM-CT-2004-005272) of the European Commission to P.S.

International audience; In both developed and emerging countries, sedentary life style and over exposition to high energy dense foods has led to a thermodynamic imbalance and consequently obesity. Despite genetic predisposition, obesity often involves a behavioral component in which, similar to drugs of abuse, compulsive consumption of palatable food rich in lipids and sugar drives energy intake far beyond metabolic demands. Food intake is modulated by sensory inputs, such as tastes and odours, as well as by affective or emotional states. The mesolimbic pathway is well established as a main actor of the rewarding aspect of feeding. Particularly, the hedonic and motivational aspects of food are closely tied to the release of the neurotransmitter dopamine (DA) in striatal structure such as the Nucleus Accumbens (Nacc). In both rodent and humans several studies shows an attenuated activity of dopaminergic signal associated with obesity and there is evidence that consumption of palatable food per se leads to DA signalling alterations. Furthermore impaired cognition in obese mice is improved by selectively lowering triglycerides (TG) and intracerebroventricular administration of TG induces by itself acquisition impairment in several cognitive paradigms in normal body weight mice. Together, these observations raise the possibility that nutritional lipids, particularly TG, directly affect cognitive and reward processes by modulating the mesolimbic pathway and might contribute to the downward spiral of compulsive consumption of palatable and obesity. This review is an attempt to capture recent evolution in the field that might point toward a direct action of nutritional lipid in the mesolimbic pathway.

Introduction L’integration de signaux peripheriques de faim et de satiete au niveau du systeme nerveux central permet de developper une reponse adaptee aux modifications de la disponibilite en nutriments. Les neurones orexigenes a Neuropeptide Y et agouti-related protein (NPY/AgRP) et les neurones anorexigenes a pro-opiomelanocortine (POMC) sont consideres comme de « premier ordre » dans ce processus. Nous disposons d’un modele animal dans lequel les neurones NPY/AgRP peuvent etre selectivement elimines au stade perinatal et le but de cette etude est de caracteriser plus avant l’implication de ces neurones dans la regulation de la balance energetique. Materiels et methodes Resultats Les animaux deficients en neurones NPY/AgRP sont legerement hypophagiques sur un regime standard et ne sont plus sensibles a l’action orexigene de la ghreline. Cependant ces animaux developpent paradoxalement une obesite massive. De plus sous regime riche en graisses, les souris controles developpent une intolerance au glucose accompagnee d’une hyperglycemie a jeun, alors que les animaux depourvus en neurones NPY/AgRP semblent resistants a l’action diabesitogene du regime. L’analyse des parametres metaboliques et de l’activite locomotrice indique une activite nocturne diminuee mais une consommation d’O2 et une depense energetique plus elevee que les controles au stade symptomatique comme asymptomatique. Cette obesite n’est pas due a une augmentation de la prise alimentaire ni a une diminution de l’efficacite metabolique et semble paradoxalement associee a une relative protection contre les effets diabesitogenes d’un regime hyperlipidique. Cette obesite est associee a une augmentation de la production et de l’export hepatique des lipides ainsi qu’a un metabolisme accru des lipides. Enfin la perte des neurones NPY/AgRP se traduit par une hyperinsulinemie precoce et nous demontrons qu’une intervention sur le tonus sympathique permet de resorber ce phenotype. Conclusion Ces resultats suggerent que la perte des neurones NPY/AgRP conduit a une obesite qui peut s’expliquer par une modification de la balance autonome et de la partition des flux energetiques en peripherie, independamment de la prise alimentaire. Cette etude indique que les circuits centraux impliques dans le developpement de l’obesite d’une part, et du diabete d’autre part, pourraient etre distincts et confere aux neurones NPY/AgRP un role cle dans la regulation fine de la partition des flux energetiques en peripherie.

Introduction Le role des nutriments en tant que molecules informatives, ou « nutrient sensing », est fondamental pour le controle de l’homeostasie energetique, et toute modification des concentrations circulantes en nutriment est detectee au niveau du systeme nerveux central (SNC) par des neurones sensibles aux nutriments. Au cours d’un jeune de 24 h, la lipolyse est stimulee et la concentration plasmatique en acides gras libres (AGL) triple, on observe egalement une resistance a l’insuline. Dans cette etude nous avons teste si l’effet des AGL sur le cerveau module la sensibilite a l’insuline et la prise alimentaire suite a la renutrition des animaux apres 24 h de jeune. Materiels et methodes Nous avons constitue un groupe de rats temoins nourris et trois groupes de rats a jeun 24 h : un groupe controle, un groupe perfuse d’acide nicotinique (AN), un inhibiteur de la lipolyse, dans la veine jugulaire, et enfin un groupe ayant 2 perfusions, AN dans la veine jugulaire plus Intralipid/ heparine (IL) dans l’artere carotide en direction du cerveau. Ce dernier groupe permet d’obtenir un modele de rats a jeun ayant une augmentation des AGL au niveau du cerveau uniquement. Les concentrations plasmatiques en AGL et en corps cetoniques ont ete mesurees tout au long de l’etude, et nous avons pratiques des tests de tolerance a l’insuline. Chez d’autres animaux nous avons mesure la prise alimentaire 3 heures apres la renutrition. Resultats La perfusion d’AN, seule ou associe a la perfusion intracarotidienne d’IL, diminue les AGL et les corps cetoniques circulants jusqu’a atteindre les valeurs des temoins nourris. La sensibilite a l’insuline est augmentee dans le groupe AN, qui ne presente pas d’augmentation de l’activite lipolytique, comparee aux temoins a jeun. En revanche le groupe AN + IL presente une sensibilite a l’insuline plus faible, similaire a celle des temoins a jeun. De meme, lors de la renutrition, les rats AN presentent une prise alimentaire plus elevee, tandis que les rats AN + IL ont une prise alimentaire similaire aux temoins a jeun. Conclusion Ces resultats suggerent que les AGL sont des molecules informatives capables de moduler la sensibilite a l’insuline pendant le jeune et la prise alimentaire au moment de la renutrition.