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AgRP neurons trigger one of the most potent orexigenic responses and are both necessary and sufficient for feeding. Recent technical advances for monitoring in vivo neuronal activity have revisited a previously well-established model of AgRP neurons' feeding regulatory effects. Our current understanding of AgRP neurons has increased in complexity and revealed a fine-tuned regulation of their activity dynamics across the whole sequence of feeding-related behaviours. This review focuses on recent studies that refined and re-evaluated our understanding of the regulatory principles and behavioural effects of AgRP circuits. We aim to cover major discoveries on the dynamic regulation of AgRP neuronal activity by exteroceptive and interoceptive food-related cues, their pleiotropic effects in feeding and whole-body homeostasis, and the associated AgRP circuits. The function and regulation of AgRP neuron will be sequentially discussed across the temporal series of behavioural and physiological changes occurring during the appetitive (food craving and foraging), the anticipatory (discovery of food-predicting cues), and the consummatory/post-ingestive phase of feeding (calorie ingestion).

International audience; Hereditary spastic paraplegias are heterogeneous neurodegenerative disorders. Understanding of their pathogenicmechanisms remains sparse, and therapeutic options are lacking. We characterized a mouse model lacking the Cyp2u1 gene, lossof which is known to be involved in a complex form of these diseases in humans. We showed that this model partially recapitulated the clinical and biochemical phenotypes of patients. Using electron microscopy, lipidomic, and proteomicstudies, we identified vitamin B2 as a substrate of the CYP2U1 enzyme, as well as coenzyme Q, neopterin, and IFN-α levels asputative biomarkers in mice and fluids obtained from the largest series of CYP2U1-mutated patients reported so far. We alsoconfirmed brain calcifications as a potential biomarker in patients. Our results suggest that CYP2U1 deficiency disruptsmitochondrial function and impacts proper neurodevelopment, which could be prevented by folate supplementation in ourmouse model, followed by a neurodegenerative process altering multiple neuronal and extraneuronal tissues.

The central nervous system (CNS) has an important role in the regulation of peripheral insulin sensitivity and glucose homeostasis. Research in this dynamically developing field has progressed rapidly due to techniques allowing targeted transgenesis and neurocircuitry mapping, which have defined the primary responsive neurons, associated molecular mechanisms and downstream neurocircuitries and processes involved. Here we review the brain regions, neurons and molecular mechanisms by which the CNS controls peripheral glucose metabolism, particularly via regulation of liver, brown adipose tissue and pancreatic function, and highlight the potential implications of these regulatory pathways in type 2 diabetes and obesity., The brain controls peripheral glucose metabolism, for example by modulating hepatic gluconeogenesis or by regulating glucose uptake into brown adipose tissue. Here, the authors review the brain regions, neurons and molecular mechanisms involved in these processes, and discuss their relevance to disease.

Summary: Interleukin (IL)-6 engages similar signaling mechanisms to leptin. Here, we find that central application of IL-6 in mice suppresses feeding and improves glucose tolerance. In contrast to leptin, whose action is attenuated in obesity, the ability of IL-6 to suppress feeding is enhanced in obese mice. IL-6 suppresses feeding in the absence of neuronal IL-6-receptor (IL-6R) expression in hypothalamic or all forebrain neurons of mice. Conversely, obese mice exhibit increased soluble IL-6R levels in the cerebrospinal fluid. Blocking IL-6 trans-signaling in the CNS abrogates the ability of IL-6 to suppress feeding. Furthermore, gp130 expression is enhanced in the paraventricular nucleus of the hypothalamus (PVH) of obese mice, and deletion of gp130 in the PVH attenuates the beneficial central IL-6 effects on metabolism. Collectively, these experiments indicate that IL-6 trans-signaling is enhanced in the CNS of obese mice, allowing IL-6 to exert its beneficial metabolic effects even under conditions of leptin resistance. : Timper et al. find that central IL-6 improves energy and glucose homeostasis via IL-6 trans-signaling. IL-6 trans-signaling is enhanced in the CNS of obese mice, allowing IL-6 to exert its beneficial metabolic effects even under conditions of leptin resistance. Keywords: interleukin-6, CNS, obesity, interleukin-6 trans-signaling, energy homeostasis, glucose homeostasis

High-fat diet (HFD) feeding induces rapid reprogramming of systemic metabolism. Here, we demonstrate that HFD feeding of mice downregulates glucose transporter (GLUT)-1 expression in blood-brain barrier (BBB) vascular endothelial cells (BECs) and reduces brain glucose uptake. Upon prolonged HFD feeding, GLUT1 expression is restored, which is paralleled by increased expression of vascular endothelial growth factor (VEGF) in macrophages at the BBB. In turn, inducible reduction of GLUT1 expression specifically in BECs reduces brain glucose uptake and increases VEGF serum concentrations in lean mice. Conversely, myeloid-cell-specific deletion of VEGF in VEGF(Δmyel) mice impairs BBB-GLUT1 expression, brain glucose uptake, and memory formation in obese, but not inlean mice. Moreover, obese VEGF(Δmyel) mice exhibit exaggerated progression of cognitive decline and neuroinflammation on an Alzheimer's disease background. These experiments reveal that transient, HFD-elicited reduction of brain glucose uptake initiates a compensatory increase of VEGF production and assign obesity-associatedmacrophage activation a homeostatic role torestore cerebral glucose metabolism, preserve cognitive function, and limit neurodegeneration in obesity.

Activation of Agouti-related peptide (AgRP) neurons potently promotes feeding, and chronically altering their activity also affects peripheral glucose homeostasis. We demonstrate that acute activation of AgRP neurons causes insulin resistance through impairment of insulin-stimulated glucose uptake into brown adipose tissue (BAT). AgRP neuron activation acutely reprograms gene expression in BAT toward a myogenic signature, including increased expression of myostatin. Interference with myostatin activity improves insulin sensitivity that was impaired by AgRP neurons activation. Optogenetic circuitry mapping reveals that feeding and insulin sensitivity are controlled by both distinct and overlapping projections. Stimulation of AgRP → LHA projections impairs insulin sensitivity and promotes feeding while activation of AgRP → anterior bed nucleus of the stria terminalis (aBNST)vl projections, distinct from AgRP → aBNSTdm projections controlling feeding, mediate the effect of AgRP neuron activation on BAT-myostatin expression and insulin sensitivity. Collectively, our results suggest that AgRP neurons in mice induce not only eating, but also insulin resistance by stimulating expression of muscle-related genes in BAT, revealing a mechanism by which these neurons rapidly coordinate hunger states with glucose homeostasis.

SummaryActivation of orexigenic AgRP-expressing neurons in the arcuate nucleus of the hypothalamus potently promotes feeding, thus defining new regulators of AgRP neuron activity could uncover potential novel targets for obesity treatment. Here, we demonstrate that AgRP neurons express the purinergic receptor 6 (P2Y6), which is activated by uridine-diphosphate (UDP). In vivo, UDP induces ERK phosphorylation and cFos expression in AgRP neurons and promotes action potential firing of these neurons in brain slice recordings. Consequently, central application of UDP promotes feeding, and this response is abrogated upon pharmacologic or genetic inhibition of P2Y6 as well as upon pharmacogenetic inhibition of AgRP neuron activity. In obese animals, hypothalamic UDP content is elevated as a consequence of increased circulating uridine concentrations. Collectively, these experiments reveal a potential regulatory pathway in obesity, where peripheral uridine increases hypothalamic UDP concentrations, which in turn can promote feeding via PY6-dependent activation of AgRP neurons.

The ventromedial nucleus of the hypothalamus (VMH) plays a critical role in regulating systemic glucose homeostasis. How neurons in this brain area adapt to the changing metabolic environment to regulate circulating glucose levels is ill-defined. Here we show that glucose load results in mitochondrial fission and reduced reactive oxygen species in VMH neurons mediated by dynamin-related peptide 1 (DRP1) under the control of uncoupling protein 2 (UCP2). Probed by genetic manipulations and chemical-genetic control of VMH neuronal circuitry, we unmasked that this mitochondrial adaptation determines the size of the pool of glucose-excited neurons in the VMH, and, that this process regulates systemic glucose homoeostasis. Thus, our data unmasked a critical cellular biological process controlled by mitochondrial dynamics in VMH regulation of systemic glucose homeostasis.

International audience; Leptin secreted by adipocytes acts on the brain to reduce food intake by regulating neuronal activity in the mediobasal hypothalamus (MBH). Obesity is associated with resistance to high circulating leptin levels. Here, we demonstrate that peripherally administered leptin activates its receptor (LepR) in median eminence tanycytes followed by MBH neurons, a process requiring tanycytic ERK signaling and the passage of leptin through the cerebrospinal fluid. In mice lacking the signal-transducing LepRb isoform or with diet-induced obesity, leptin taken up by tanycytes accumulates in the median eminence and fails to reach the MBH. Triggering ERK signaling in tanycytes with EGF reestablishes leptin transport, elicits MBH neuron activation and energy expenditure in obese animals, and accelerates the restoration of leptin sensitivity upon the return to a normal-fat diet. ERK-dependent leptin transport by tanycytes could thus play a critical role in the pathophysiology of leptin resistance, and holds therapeutic potential for treating obesity.

Uridine-diphosphate (UDP) and its receptor P2Y6 have recently been identified as regulators of AgRP neurons. UDP promotes feeding via activation of P2Y6 receptors on AgRP neurons, and hypothalamic UDP concentrations are increased in obesity. However, it remained unresolved whether inhibition of P2Y6 signaling pharmacologically, globally, or restricted to AgRP neurons can improve obesity-associated metabolic dysfunctions. Here, we demonstrate that central injection of UDP acutely promotes feeding in diet-induced obese mice and that acute pharmacological blocking of CNS P2Y6 receptors reduces food intake. Importantly, mice with AgRP-neuron-restricted inactivation of P2Y6 exhibit reduced food intake and fat mass as well as improved systemic insulin sensitivity with improved insulin action in liver. Our results reveal that P2Y6 signaling in AgRP neurons is involved in the onset of obesity-associated hyperphagia and systemic insulin resistance. Collectively, these experiments define P2Y6 as a potential target to pharmacologically restrict both feeding and systemic insulin resistance in obesity.

SummaryMaternal metabolic homeostasis exerts long-term effects on the offspring’s health outcomes. Here, we demonstrate that maternal high-fat diet (HFD) feeding during lactation predisposes the offspring for obesity and impaired glucose homeostasis in mice, which is associated with an impairment of the hypothalamic melanocortin circuitry. Whereas the number and neuropeptide expression of anorexigenic proopiomelanocortin (POMC) and orexigenic agouti-related peptide (AgRP) neurons, electrophysiological properties of POMC neurons, and posttranslational processing of POMC remain unaffected in response to maternal HFD feeding during lactation, the formation of POMC and AgRP projections to hypothalamic target sites is severely impaired. Abrogating insulin action in POMC neurons of the offspring prevents altered POMC projections to the preautonomic paraventricular nucleus of the hypothalamus (PVH), pancreatic parasympathetic innervation, and impaired glucose-stimulated insulin secretion in response to maternal overnutrition. These experiments reveal a critical timing, when altered maternal metabolism disrupts metabolic homeostasis in the offspring via impairing neuronal projections, and show that abnormal insulin signaling contributes to this effect.

Maternal diabetes is a common complication of pregnancy, and the offspring of diabetic mothers have a higher risk of developing obesity and type 2 diabetes later in life. Despite these observations, the precise biological processes mediating this metabolic programming are not well understood. Here, we explored the consequences of maternal diabetes on the organization of hypothalamic neural circuits involved in the regulation of energy balance. To accomplish this aim, we used a mouse model of maternal insulin deficiency induced by streptozotocin injections. Maternal diabetes was found to be associated with changes in offspring growth as revealed by a significantly higher pre- and postweaning body weight in the offspring of insulin-deficient dams relative to those of control mice. Mice born to diabetic dams also showed increased fasting glucose levels, increased insulin levels, and increased food intake during their adult lives. These impairments in metabolic regulation were associated with leptin resistance during adulthood. Importantly, the ability of leptin to activate intracellular signaling in arcuate neurons was also significantly reduced in neonates born to diabetic dams. Furthermore, neural projections from the arcuate nucleus to the paraventricular nucleus were markedly reduced in the offspring of insulin-deficient dams. Together, these data show that insulin deficiency during gestation has long-term consequences for metabolic regulation. They also indicate that animals born to diabetic dams display abnormally organized hypothalamic feeding pathways that could result from the attenuated responsiveness of hypothalamic neurons to the neurotrophic actions of leptin during neonatal development.

Ghrelin is a pleiotropic hormone that was originally described as promoting feeding and stimulating growth hormone release in adults. A growing body of evidence suggests that ghrelin may also exert developmental and organizational effects during perinatal life. The perinatal actions of ghrelin include the regulation of early developmental events such as blastocyst development and perinatal growth. Moreover, alterations in perinatal ghrelin levels result in structural differences in various peripheral organs, such as the pancreas and gastrointestinal tract. Recent data have also suggested that ghrelin acts on appetite-related brain centers in early life. Together, these observations indicate that exposure to factors that alter how ghrelin impacts development may induce lasting effects on physiological regulation.

International audience; Estrogens and nitric oxide (NO) exert wide-ranging effects on brain function. Recent evidence suggested that one important mechanism for the regulation of NO production may reside in the differential coupling of the calcium-activated neuronal NO synthase (nNOS) to glutamate NMDA receptor channels harboring NR2B subunits by the scaffolding protein post-synaptic density-95 (PSD-95), and that estrogens promote the formation of this ternary complex. Here, we demonstrate that 30-min estradiol-treatment triggers the production of NO by physically and functionally coupling NMDA receptors to nNOS in primary neurons of the rat preoptic region in vitro. The ability of estradiol to activate neuronal NO signaling in preoptic neurons and to promote changes in protein-protein interactions is blocked by ICI 182,780, an estrogen receptor antagonist. In addition, blockade of NMDA receptor NR2B subunit activity with ifenprodil or disruption of PSD-95 synthesis in preoptic neurons by treatment with an anti-sense oligodeoxynucleotide inhibited the estradiol-promoted stimulation of NO release in cultured preoptic neurons. Thus, estrogen receptor-mediated stimulation of the nNOS/PSD-95/NMDA receptor complex assembly is likely to be a critical component of the signaling process by which estradiol facilitates coupling of glutamatergic fluxes for NO production in neurons.