Brain lipid sensing and the neural control of energy balance

Molecular and Cellular Endocrinology xxx (2015) 1e6

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Brain lipid sensing and the neural control of energy balance Christophe Magnan a, *, Barry E. Levin b, c, Serge Luquet a Univ Paris Diderot, Sorbonne Paris Cit
e, CNRS UMR 8251, F-75205, Paris, France Neurology Service, VA Medical Center, East Orange, NJ, USA c Department of Neurology, Rutgers, NJ Medical School, Newark, NJ, USA a

b

a r t i c l e i n f o

a b s t r a c t

Article history: Received 26 December 2014 Received in revised form 14 September 2015 Accepted 22 September 2015 Available online xxx

Fatty acid (FA) -sensitive neurons are present in the brain, especially the hypothalamus, and play a key role in the neural control of energy and glucose homeostasis including feeding behavior, secretion insulin and action. Subpopulations of neurons in the arcuate and ventromedial hypothalamic nuclei are selectively either activated or inhibited by FA. Molecular effectors of these FA effects include ion channels such as chloride, potassium or calcium. In addition, at least half of the responses in the hypothalamic ventromedial FA neurons are mediated through interaction with the FA translocator/receptor, FAT/CD36, that does not require metabolism to activate intracellular signaling downstream. Recently, an important role of lipoprotein lipase in FA detection has also been demonstrated not only in the hypothalamus, but also in the hippocampus and striatum. Finally, FA could overload energy homeostasis via increased hypothalamic ceramide synthesis which could, in turn, contribute to the pathogenesis of diabetes of obesity and/or type 2 in predisposed individuals by disrupting the endocrine signaling pathways of insulin and/or leptin. © 2015 Elsevier Ireland Ltd. All rights reserved.

Keywords: Hypothalamus FAT/CD36 Lipoprotein lipase Ion channels Energy balance Ceramides

1. Introduction The central nervous system (CNS) plays a key role in the regulation of energy balance in mammals (Luquet and Magnan, 2009). Indeed signals conveyed from the periphery via hormones (leptin, insulin, ghrelin etc.) and nutrients (glucose and fatty acids) are detected by specialized neurons in areas like the hypothalamus and brainstem (Blouet and Schwartz, 2010; Lam et al., 2005a,b; Levin et al., 2011). Among these informative molecules there is increasing evidence highlighting hypothalamic fatty acid (FA) sensing as an important contributor to the regulation of energy balance. Oomura et al. were among the first to show that some neurons in lateral hypothalamus were sensitive to FA (Oomura et al., 1975). Since then, others have confirmed a role for central FA sensing in the regulation of facets of energy and glucose homeostasis such as food intake, insulin secretion and action, hepatic glucose production, linear growth, and adipose deposition (Cruciani-Guglielmacci et al., 2004; Lam et al., 2005a,b; Le Foll et al., 2013, 2014; Obici et al., 2002). The molecular mechanisms

^timent Buffon, * Corresponding author. Univ Paris Diderot, Case Courrier 7126, Ba me e
tage, 4 rue Marie-Andre
e Lagroua Weill-Halle 75205 Paris Cedex 13, France. 5e E-mail address: [email protected] (C. Magnan).

involved in this neuronal FA sensing are still under active investigation. Some documented mechanisms include intracellular events including acylCoA synthase and FA oxidation (Migrenne et al., 2011) and the plasma membrane translocator/receptor FAT/CD36 (CD36) (Le Foll et al., 2013, 2014; Moulle et al., 2013). Recent studies have highlighted a role for neuronal lipoprotein lipase (LPL)-mediated hydrolysis of triglycerides (TG)-enriched particles in the regulation energy balance (Wang et al., 2011) in the hippocampus (Picard et al., 2013) and mesolimbic structures (Cansell et al., 2014). Here we will review the molecular, cellular and systemic mechanisms of lipid actions on CNS areas controlling the physiological regulation of energy homeostasis, with a focus on the hypothalamus. In addition, we will review the evidence that dysregulation of brain FA sensing may contribute to the deterioration of energy balance and development of obesity, with or without type 2 diabetes (Velloso and Schwartz, 2011; Yue and Lam, 2012) through ceramide-dependent effects (Contreras et al., 2014). A better understanding of these mechanisms, as well as further characterization of FA sensitive neurons and their role in physiological and pathological processes, may lead to identification of novel pharmacological targets for the prevention and treatment of obesity and diabetes.

http://dx.doi.org/10.1016/j.mce.2015.09.019 0303-7207/© 2015 Elsevier Ireland Ltd. All rights reserved.

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1.1. Transport of FA into the brain and evidence for hypothalamic FA sensitive neurons Brain has the highest lipid content of any organ except for adipose tissue and cerebral lipids are essential components of both membranes and intracellular signaling pathways (Edmond, 2001; Watkins et al., 2001). Cerebral lipids are derived both from local synthesis and uptake from the bloodstream. Several studies show that some polyunsaturated FA (PUFA) are able to cross the bloodebrain barrier (BBB) (Rapoport et al., 2001; Smith and Nagura, 2001). While still poorly understood, some mechanisms for the transport of FA from the bloodstream into the CNS have been identified. For example, a role for Mfsd2a (major facilitator superfamily domain-containing 2a) has recently been identified as a major carrier absorption of DHA in the brain (Nguyen et al., 2014). Also, FA binding proteins (FABPs) 3, 4 and 5 mRNA and protein are expressed in immortalized human brain endothelial cells (hCMEC/ D3) (Lee et al., 2015). Once they have crossed the BBB, FA are avidly taken up and oxidized, mainly by astrocytes (Escartin et al., 2007). Many other FA such as arachidonate are largely incorporated into phospholipids in both neurons and astrocytes (Rapoport et al., 2001). Ventromedial hypothalamic nucleus (VMN) neurons and astrocytes can also presumably take up FA since they express mRNA for FA transport proteins (FATP)-1 and 4 and CD36 (Le Foll et al., 2013, 2014; Le Foll et al., 2009). Genes for the intracellular metabolism of FA, such as long chain acyl-CoA synthase (ACS), carnitine palmitoyltransferase-1a and 1c (CPT1a and 1C) and uncoupling protein-2 (UCP2), are also expressed in VMN neurons, although it is unlikely that neurons derive much of their energy supply from FA (Le Foll et al., 2009). In addition, VMN neurons also express enzymes for de novo FA synthesis such as FA synthase (FAS) (Le Foll et al., 2009). Finally, lipase (LPL), which is highly expressed in the brain (Ben-Zeev et al., 1990), could provide a signal of the metabolic state to FA sensitive neurons by converting locally triglyceride (TG)rich lipoproteins into FA (Wang and Eckel, 2012). Interestingly, neuronal specific deletion of LPL has been demonstrated to play a role in the regulation of energy balance (Picard et al., 2013; Wang et al., 2011). Several decades ago Oomura et al. demonstrated that FA activated lateral hypothalamic neurons (Oomura et al., 1975). In FA sensitive neurons, exposure to long chain FA can alter the activity of a wide variety of ion channels including Cl
, GABAA (Tewari et al., 2000), potassium, KþeCa2þ (Honen et al., 2003) or Ca2þ channels (Oishi et al., 1990). Oleic acid (OA) sensitive-neurons have been characterized using whole cell patch clamp records in arcuate nucleus (ARC) slices from 14 to 21 day old rats as well as in vivo recording using implanted microelectrode (Wang et al., 2006). Of all ARC neurons sampled, 13% were excited and 30% were inhibited by OA (Wang et al., 2006). The excitatory effects of OA appeared to be due to closure of chloride channels leading to membrane depolarization and increased action potential frequency (Wang et al., 2006). On the other hand, the inhibitory effect of OA may involve KATP channels since this inhibition was reversed by the KATP channel blocker tolbutamide (Wang et al., 2006). Using fura-2 calcium imaging in dissociated VMN neurons, OA excited up to 43% and inhibited up to 29% of all VMN neurons independently of glucose concentrations (Le Foll et al., 2009). However, in these neurons, inhibition of the KATP channel mediated FA sensing in only a small percentage of FA sensing neurons. The differences between the findings in vivo and in vitro using electrophysiological methods and individual dissociated neurons using calcium imaging are likely due to the additional presynaptic inputs to the neurons assessed by electrophysiological methods and the fact that the drugs used affect both neurons and astrocytes in slice preparations in vivo. In addition, although a relatively large percentage of hypothalamic

neurons are FA sensors, a select population also sense glucose and their responses to FA are highly dependent upon ambient glucose concentration (Le Foll et al., 2013, 2014; Le Foll et al., 2009; Migrenne et al., 2006). Such data suggest that the responses of hypothalamic FA sensitive neurons are dependent upon the metabolic state of the animal and thus might be expected to respond differently during fasting (when FA levels rise and glucose levels fall) vs. the overfed state when glucose levels rise while free FA levels remain relatively unchanged (Le Foll et al., 2013, 2014; Le Foll et al., 2009; Migrenne et al., 2006). 1.2. FA fate in sensitive neurons While intracellular FA metabolism may be responsible for altering neuronal activity in some FA sensitive neurons, such as ARC POMC neurons (Jo et al., 2009), it accounts for a relatively small percent of the excitatory or inhibitory effects of OA on dissociated VMN neurons (Le Foll et al., 2013, 2014; Le Foll et al., 2009). In those neurons, inhibition of CPT1, reactive oxygen species formation, long-chain acylCoA synthetase and KATP channel activity or activation of uncoupling protein 2 (UCP2) account for no more than 20% of the excitatory or approximately 40% of the inhibitory effects of OA (Le Foll et al., 2009). On the other hand, inhibition of CD36 which can alter cell function independently of intracellular FA metabolism, reduced the excitatory and inhibitory effects of OA on FA-glucose sensitive neurons by up to 77% in FA-excited and completely abolished OA effects on FA inhibited neurons (Le Foll et al., 2013, 2014; Le Foll et al., 2009). Thus, in most VMN FA sensing neurons, CD36 may act primarily as receptor for long chain FA as it does on taste cells on the tongue where it activates storeoperated calcium channels to alter membrane potential and release of serotonin (Gaillard et al., 2008). These effects all occur in the presence of nanomolar concentrations of OA in dissociated neurons (Le Foll et al., 2009), whereas micromolar concentrations are generally required to effect similar changes in neuronal activity in brain slice preparations (Jo et al., 2009; Migrenne et al., 2006; Wang et al., 2006). Thus, in the absence of astrocytes and presynaptic inputs, OA can directly affect VMN neuronal activity through both metabolic and non-metabolic pathways. Alternatively, FA might act as signaling molecules by covalent attachment to proteins (N-terminal acylation) to alter the function of membrane and intracellular signaling molecules. For example, palmitoylation facilitates the targeting and plasma membrane binding of proteins which otherwise would remain in the cytosolic compartment (Resh, 1999). Some membrane proteins (TGFa, a 25 kDa synaptosomal-associated protein which is required for exocytosis) and plasma membrane receptors (seven transmembrane G-protein-coupled receptors such as a2a- and b2-adrenoceptors) are typically palmitoylated on one or several cysteine residues located adjacent to or just within the transmembrane domain (Resh, 1999). Such mechanisms might also modulate neuronal FA sensing. It may also be possible that certain fatty acids might alter neuronal activity by binding to GPR120 receptors. However, although these receptors are expressed in the rHypoE-7 hypothalamic cell line (Wellhauser and Belsham, 2014), mRNA for GRP120 is not expressed in VMN neurons (LeFoll et al.). 1.3. Which neurotransmitters or neuropeptides? The final consequence of the activation or inactivation of a neuron is the release of neurotransmitters and neuropeptides. Since FA decrease food intake, they might be expected to alter the activity of neurons specifically involved in the regulation of feeding. For example, OA activates ARC POMC neurons in mice by inhibiting ATP-sensitive Kþ (KATP) channel activity and the effect of OA on HGP

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is abolished by icv administration of a KATP channel inhibitor (Jo et al., 2009). In vivo, Obici et al. (Obici et al., 2002) reported that prolonged (3 day) icv administration of OA markedly inhibited glucose production and food intake, accompanied by a decrease in the hypothalamic expression of the anabolic peptide, neuropeptide Y. Similarly, reduction of VMH CD36 expression decreases expression of both AgRP and POMC in association with a redistribution of fat from visceral to subcutaneous depots and a marked impairment in insulin sensitivity (Le Foll et al., 2013, 2014; Le Foll et al., 2009; Migrenne et al., 2006). On the other hand, an n-3 FA-enriched diet increases food intake in anorexic tumor-bearing rats in association with reduced tumor appearance and growth and the onset of anorexia (Ramos et al., 2005). In these rats, neuropeptide Y immunoreactivity increased by 38% in the ARC and 50% in the paraventricular nucleus, whereas a-melanocyte stimulating hormone (a catabolic peptide cleavage product of POMC) decreased by 64% in the ARC and by 29% in the paraventricular nucleus (Ramos et al., 2005). Finally, intracellular metabolism FA is required to obtain the maximum orexigenic effect of ghrelin (Lage et al., 2010; Lopez et al., 2008). 1.4. Physiological effects of brain FA sensing As mentioned above, there is increasing evidence demonstrating that hypothalamic FA sensing is critical for the regulation of energy balance involving effects on ingestive behavior, energy storage and utilization. For example, Obici et al. demonstrated that a 3 days intracerebroventricular (icv) infusion of OA reduced food intake, as well as hepatic glucose production (HGP) (Obici et al., 2002). These effects were mimicked by inhibition of CPT1 suggesting a role for malonylCOA and/or acylCoA (Obici et al., 2003). In another study, HGP was decreased by direct bilateral infusion of OA into the mediobasal hypothalamus (MBH) (Ross et al., 2010). Similarly, central inhibition of CPT1 was associated with an increase in the acylCoA intracellular pool which was postulated to be the “final” satiety signal rather than FA themselves (Lam et al., 2005a,b). Another way to link brain FA metabolism and regulation of food intake is to centrally administrate C75, an inhibitor of FAS. This also increases malonyl-CoA concentration in the hypothalamus, suppresses food intake and leads to profound weight loss (Proulx et al., 2008). It has been proposed that centrally, C75 and cerulenin (another inhibitor of FAS) alter the expression profiles of feeding-related neuropeptides, often inhibiting the expression of orexigenic peptides such as neuropeptide Y (Proulx and Seeley, 2005). Whether through centrally mediated or peripheral mechanisms, C75 also increases energy expenditure, which contributes to weight loss (Clegg et al., 2002; Tu et al., 2005). In vitro and in vivo studies demonstrate that at least part of C75's effects are mediated by the modulation of AMP-activated kinase (AMPK), a known energy-sensing kinase (Ronnett et al., 2005). Besides these effects of brain FA sensing on the regulation of food intake or hepatic glucose production it must also be mentioned their role in regulation of hepatic lipoprotein very low density lipoprotein enriched in triglycerides (VLDL-TG). Indeed Yue et al. have recently shown that the infusion of OA in the mediobasal hypothalamus (MBH) activates a PKC-d and that it was involved via a relay in the dorsal vagal complex (DVC) in the regulation of production VLDL-TG in the liver (Yue et al., 2015). Hypothalamic FA sensing also mediates physiological effects of several hormones. For example, the physiological effect of ghrelin on food intake involves specific inhibition of FA biosynthesis and activation of CPT1 through an AMPK-dependent mechanism, as previously mentioned (Lopez et al., 2008; Theander-Carrillo et al., 2006). Indeed, the orexigenic effect of ghrelin was lost when AMPK was inhibited (Lopez et al., 2008). Such lipid sensing is also involved

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in thyroid regulation of energy balance where inhibition of lipogenic pathway in the VMH impairs brown adipose tissue activation induced by thyroid hormones (Lopez et al., 2010). A role for hypothalamic AMPK as a FA-mediated regulator of hormone actions such as estradiol (Martinez de Morentin et al., 2014) and melanocortin (Nogueiras et al., 2007) regulation of energy balance. A major caveat of all of these in vivo studies is that, because the majority of brain FA metabolism (oxidation) occurs in astrocytes, rather than neurons (Edmond, 2001; Escartin et al., 2007)there is no way to directly implicate the physiological effects measured after such pharmacological manipulations to alterations in the activity of FA sensitive neurons. In fact, AMPK activation increases astrocyte production of ketone bodies (Blazquez et al., 1999) and local VMH astrocyte production of ketones rats fed a high fat diet decreases food intake (Le Foll et al., 2013, 2014; Le Foll, et al., 2015)Thus, many of the physiological effects observed after altering hypothalamic FA metabolism might primarily be due to effects on ketone production which might then be utilized by neurons to alter their FA and glucose sensing (Escartin et al., 2007; Le Foll et al., 2013, 2014). Indeed, while a select group of neurons in the hypothalamus clearly responds directly to changes in ambient FA levels by altering their activity (Le Foll et al., 2013, 2014; Le Foll et al., 2009; Oomura et al., 1975), only a relatively small percentage of these responses depend upon neuronal FA metabolism (Le Foll et al., 2009). Also, ketone bodies have a predominant effect on stimulating VMH FA sensitive neurons, whether they are either excited or inhibited by FA. Thus, local ketone production by astrocytes can override the direct effects of FA on these VMN neurons (Le Foll et al., 2013, 2014)Furthermore, although b-oxidation and formation of malonyl-CoA and FA metabolites such as acyl-CoA may be mediators of the in vivo effects produced by FA infusions (Dowell et al., 2005), it is likely that most of these occur within astrocytes. If so, then there must be a mechanism by which alterations in astrocyte FA metabolism can provide a signal to those neurons which regulate HGP and food intake. We suggest that this communication between astrocyte FA metabolism and neuronal FA sensing involves the production and export of ketone bodies from astrocytes and subsequent uptake by neurons (Escartin et al., 2007; Le Foll et al., 2013, 2014). Finally, the idea that increases in brain FA levels act as a satiety signal to inhibit feeding (Obici et al., 2003) is counterintuitive given the fact that plasma FA levels do not rise substantially after food ingestion, but do rise significantly during fasting, a situation in which food intake would be expected to increase (Ruge et al., 2009). On the contrary, plasma TG-enriched particles increase following a meal and such particles could be locally hydrolyzed providing FA to sensitive neurons. Accordingly, studies highlighting a role for cerebral LPL in the control of energy balance strongly this hypothesis (Cansell et al., 2014; Picard et al., 2013; Wang et al., 2011). First, deficiency of LPL in neurons leads to obesity in rodents (Wang et al., 2011). Secondly specific deletion of LPL in the hippocampus also leads to body weight gain and decreased locomotor activity through a ceramide-dependent pathway (Picard et al., 2013). Finally role for dietary TG has been also demonstrated in mesolimbic structures as a regulator of rewarding and motivated feeding behavior through a LPL dependent mechanism (Cansell et al., 2014). In this study 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 foodseeking behavior (Cansell et al., 2014). Conversely, targeted disruption of the TG-hydrolyzing enzyme lipoprotein lipase specifically in the nucleus accumbens increased palatable food preference and food-seeking behavior (Cansell et al., 2014). Altogether these data suggest a role for lipoproteins in regulation of brain lipid sensing (Wang and Eckel, 2014).

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1.5. Pathological implications of excess FA

2. Conclusion

It is now well established that alterations of hypothalamic function occur in preclinical models of diet-induced obesity (Velloso and Schwartz, 2011) and neuronal FA sensing is abnormal in rats bred to be obesity-prone before they actually become obese (Le Foll et al., 2009). In addition, enhanced brain FA uptake occurs in humans with metabolic syndrome and is reversed by weight reduction (Karmi et al., 2010). Thus, besides the physiological regulation of energy balance by hypothalamic neuronal FA sensing, impaired regulation of such sensing might contribute to the development of metabolic diseases such as obesity and type 2 diabetes in predisposed subjects exposed to a chronic lipid overload (Migrenne et al., 2011) such has been described in skeletal muscles, liver or pancreatic b cell (Delarue and Magnan, 2007). First, excessive brain lipid levels might alter control of glucose and lipid homeostasis through changes of autonomic nervous system activity. For example, a two-fold increase in plasma TG produced by a two day systemic infusion of triglyceride emulsion was associated with decreased sympathetic activity (Magnan et al., 1999). This reduced sympathetic tone is also produced by central FA infusions (Magnan et al., 1999) and might contribute to the associated FA-induced exaggeration of glucose-induced insulin secretion (GIIS), a condition which is similar to what occurs in the prediabetic state (Magnan et al., 1999). Finally, this exaggerated GIIS and a reduction in HGP were mimicked by infusing TG together with heparin into the carotid artery (Cruciani-Guglielmacci et al., 2004) and were reversed by central inhibition of CPT1 (CrucianiGuglielmacci et al., 2004). Also, a lipid overload due to high-fat diet intake alters both hypothalamic monoamine turnover (Levin et al., 1983) and peripheral sympathetic activity in rats (Young and Walgren, 1994). Molecular mechanisms underlying hypothalamic lipotoxicity may include inflammation and ceramide overproduction. Indeed, dysregulation of hypothalamic control of energy balance following lipid overload might involve increased inflammation (Cintra et al., 2012). Contreras et al. demonstrated that ceramide-induced lipotoxicity was a key mechanism modulating thermogenesis by brown adipose tissue (BAT) and energy balance (Contreras et al., 2014). Interestingly, this lipotoxic effect was related to ER stress induced by ceramides (Contreras et al., 2014) as has also been described in pancreatic b cell. Furthermore, Wellhauser et al. demonstrated that GPR120 was functionally active in the hypothalamic neuronal line, rHypoE-7 where it mediated the actions of DHA to reduce the inflammatory response to TNFa (Wellhauser and Belsham, 2014). It has been also demonstrated that increased de novo synthesis ceramides in the hippocampus was responsible for decreased parasympathetic nervous activity and locomotor activity leading to increased body weight gain in rodents (Picard et al., 2013). Finally, while FA such as OA and linoleic acid can depolarize neurons, other FA may actually impede signaling and neuronal function. For example, the atypical protein kinase C, PKCQ, is expressed in discrete neuronal populations of the ARC and the dorsal medial hypothalamic nucleus (Benoit et al., 2009). CNS exposure to palmitic acid (PA) via direct infusion or by oral gavage increased the localization of PKCQ to hypothalamic cell membranes in association with impaired hypothalamic insulin and leptin signaling (Benoit et al., 2009). This finding was specific for PA, as the monounsaturated FA, OA, neither increased membrane localization of PKCQ nor reduced insulin signaling. Finally, ARC-specific knockdown of PKCQ attenuated diet-induced obesity and improved hypothalamic insulin signaling (Benoit et al., 2009). These results suggest that many of the deleterious effects of high fat diets, specifically those enriched with PA, are CNS mediated via PKCQ activation, resulting in reduced insulin activity.

There is increasing evidence that specialized neurons within hypothalamus are able to sense FA (Lam et al., 2005a,b; Levin et al., 2011). Other brain areas such as the hippocampus (Picard et al., 2013) and striatum may also sense lipids (Cansell and Luquet, 2015). The neuronal networks of these FA sensitive neurons are likely very complex given the fact that FA can either inhibit or excite specific neurons. In addition, many of these neurons also utilize glucose as a signaling molecule and there is often an inverse responsiveness of such “metabolic sensing” neurons to FA vs. glucose. Thus, these neurons are ideally suited to respond differentially under a variety of metabolic conditions such as fasting, feeding, hypo- or hyperglycemia. However, while it is clear that specific neurons can respond to changes in ambient FA levels, many questions remain. We still do not know for certain how FA are transported into the brain, astrocytes or neurons and whether those FA that are transported are derived from circulating free FA or triglycerides. Since most studies suggest that rising FA levels reduce food intake, then we must explain why plasma FA levels are most elevated during fasting when the drive to seek and ingest food should be at its strongest. Another major issue relates to the interaction between astrocytes and neurons with regard to the metabolism and signaling of FA. Also, we still know little about the basic mechanisms utilized by neurons to sense FA, where such FA sensitive neurons reside throughout the brain and what neurotransmitters and peptides they release when responding to FA. Finally, it has been postulated that diabetes may be a disorder of the brain (Elmquist and Marcus, 2003). If so, dysfunction of these FA sensitive neurons could be, at least in part, one of the early mechanisms underlying impairment of neural control of energy and glucose homeostasis and the development of obesity and type 2 diabetes in predisposed individuals (Le Stunff et al., 2013). Recent evidence highlights that the deleterious effects of FA in the hypothalamus are related to increased ceramide synthesis which could, in turn, lead to inflammation and ER stress and thence impaired neuronal function. A better understanding of this central nutrient sensing, including both FA and glucose, could provide clues for the identification of new therapeutic targets for the prevention and treatment of both diabetes and obesity. Conflict of interest Authors declare no conflict of interest. Acknowledgment This work was supported by grant from the ANR (French National Agency for Research): Lipobrain, Grant number: 11-BSV1-021 01; and other grant sponsors: CORDDIM Ile-de-France, EFSD/Lilly
te
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