Hypothalamic gliosis as a potential mediator of improved glucose tolerance induced by time-restricted feeding in obese mice.

Time-restricted feeding (TRF) has been shown to improve glycemic control, reduce liver fat, and decrease cardiovascular risk in humans and diet-induced obese (DIO) mice. However, the mechanisms associated with this improvement are not completely understood. High-fat diet (HFD)-associated hypothalamic inflammation and glial activation promote obesity and metabolic dysfunction, raising the possibility that TRF mitigates these factors.

Obesity-associated microglial inflammatory activation paradoxically improves glucose tolerance.

Hypothalamic gliosis associated with high-fat diet (HFD) feeding increases susceptibility to hyperphagia and weight gain. However, the body-weight-independent contribution of microglia to glucose regulation has not been determined. Here, we show that reducing microglial nuclear factor κB (NF-κB) signaling via cell-specific IKKβ deletion exacerbates HFD-induced glucose intolerance despite reducing body weight and adiposity.

Central androgen action reverses hypothalamic astrogliosis and atherogenic risk factors induced by orchiectomy and high-fat diet feeding in male mice.

Hypogonadism in males confers elevated cardiovascular disease (CVD) risk by unknown mechanisms. Recent radiological evidence suggests that low testosterone (T) is associated with mediobasal hypothalamic (MBH) gliosis, a central nervous system (CNS) cellular response linked to metabolic dysfunction. To address mechanisms linking CNS androgen action to CVD risk, we generated a hypogonadal, hyperlipidemic mouse model with orchiectomy (ORX) combined with hepatic PCSK9 overexpression.

Prostaglandin PGE2 Receptor EP4 Regulates Microglial Phagocytosis and Increases Susceptibility to Diet-Induced Obesity.

In rodents, susceptibility to diet-induced obesity requires microglial activation, but the molecular components of this pathway remain incompletely defined. Prostaglandin PGE2 levels increase in the mediobasal hypothalamus during high-fat-diet (HFD) feeding, and the PGE2 receptor EP4 regulates microglial activation state and phagocytic activity, suggesting a potential role for microglial EP4 signaling in obesity pathogenesis. To test the role of microglial EP4 in energy balance regulation, we analyzed the metabolic phenotype in a microglia-specific EP4 knockout (MG-EP4 KO) mouse model.

CX3CL1 Action on Microglia Protects from Diet-Induced Obesity by Restoring POMC Neuronal Excitability and Melanocortin System Activity Impaired by High-Fat Diet Feeding.

Both hypothalamic microglial inflammation and melanocortin pathway dysfunction contribute to diet-induced obesity (DIO) pathogenesis. Previous studies involving models of altered microglial signaling demonstrate altered DIO susceptibility with corresponding POMC neuron cytological changes, suggesting a link between microglia and the melanocortin system. We addressed this hypothesis using the specific microglial silencing molecule, CX3CL1 (fractalkine), to determine whether reducing hypothalamic microglial activation can restore POMC/melanocortin signaling to protect against DIO.

Microglial Inflammatory Signaling Orchestrates the Hypothalamic Immune Response to Dietary Excess and Mediates Obesity Susceptibility.

Dietary excess triggers accumulation of pro-inflammatory microglia in the mediobasal hypothalamus (MBH), but the components of this microgliosis and its metabolic consequences remain uncertain. Here, we show that microglial inflammatory signaling determines the immunologic response of the MBH to dietary excess and regulates hypothalamic control of energy homeostasis in mice. Either pharmacologically depleting microglia or selectively restraining microglial NF-κB-dependent signaling sharply reduced microgliosis, an effect that includes prevention of MBH entry by bone-marrow-derived myeloid cells, and greatly limited diet-induced hyperphagia and weight gain.

Sex differences in microglial CX3CR1 signalling determine obesity susceptibility in mice.

Female mice are less susceptible to the negative metabolic consequences of high-fat diet feeding than male mice, for reasons that are incompletely understood. Here we identify sex-specific differences in hypothalamic microglial activation via the CX3CL1-CX3CR1 pathway that mediate the resistance of female mice to diet-induced obesity. Female mice fed a high-fat diet maintain CX3CL1-CX3CR1 levels while male mice show reductions in both ligand and receptor expression.

Central injection of fibroblast growth factor 1 induces sustained remission of diabetic hyperglycemia in rodents.

Type 2 diabetes (T2D) is among the most common and costly disorders worldwide. The goal of current medical management for T2D is to transiently ameliorate hyperglycemia through daily dosing of one or more antidiabetic drugs. Hypoglycemia and weight gain are common side effects of therapy, and sustained disease remission is not obtainable with nonsurgical approaches.

Functional identification of a neurocircuit regulating blood glucose.

Previous studies implicate the hypothalamic ventromedial nucleus (VMN) in glycemic control. Here, we report that selective inhibition of the subset of VMN neurons that express the transcription factor steroidogenic-factor 1 (VMN(SF1) neurons) blocks recovery from insulin-induced hypoglycemia whereas, conversely, activation of VMN(SF1) neurons causes diabetes-range hyperglycemia. Moreover, this hyperglycemic response is reproduced by selective activation of VMN(SF1) fibers projecting to the anterior bed nucleus of the stria terminalis (aBNST), but not to other brain areas innervated by VMN(SF1) neurons.

Hypothalamic inflammation and gliosis in obesity.

Purpose Of Review: Hypothalamic inflammation and gliosis are recently discovered mechanisms that may contribute to obesity pathogenesis. Current research in this area suggests that investigation of these central nervous system responses may provide opportunities to develop new weight loss treatments.

Recent Findings: In rodents, hypothalamic inflammation and gliosis occur rapidly with high-fat diet consumption prior to significant weight gain.

Evidence That in Uncontrolled Diabetes, Hyperglucagonemia Is Required for Ketosis but Not for Increased Hepatic Glucose Production or Hyperglycemia.

Several lines of evidence implicate excess glucagon secretion in the elevated rates of hepatic glucose production (HGP), hyperglycemia, and ketosis characteristic of uncontrolled insulin-deficient diabetes (uDM), but whether hyperglucagonemia is required for hyperglycemia in this setting is unknown. To address this question, adult male Wistar rats received either streptozotocin (STZ) to induce uDM (STZ-DM) or vehicle and remained nondiabetic. Four days later, animals received daily subcutaneous injections of either the synthetic GLP-1 receptor agonist liraglutide in a dose-escalating regimen to reverse hyperglucagonemia or its vehicle for 10 days.

Kisspeptin receptor haplo-insufficiency causes premature ovarian failure despite preserved gonadotropin secretion.

Premature ovarian failure (POF) affects 1% of women in reproductive age, but its etiology remains uncertain. Whereas kisspeptins, the products of Kiss1 that act via Kiss1r (aka, Gpr54), are known to operate at the hypothalamus to control GnRH/gonadotropin secretion, additional actions at other reproductive organs, including the ovary, have been proposed. Yet, their physiological relevance is still unclear.

Loss of Ntrk2/Kiss1r signaling in oocytes causes premature ovarian failure.

Neurotrophins (NTs), once believed to be neural-specific trophic factors, are now known to also provide developmental cues to non-neural cells. In the ovary, NTs contribute to both the formation and development of follicles. Here we show that oocyte-specific deletion of the Ntrk2 gene that encodes the NTRK2 receptor (NTRK2) for neurotrophin-4/5 and brain-derived neurotrophic factor (BDNF) results in post-pubertal oocyte death, loss of follicular organization, and early adulthood infertility.

Leptin action in the ventromedial hypothalamic nucleus is sufficient, but not necessary, to normalize diabetic hyperglycemia.

In rodent models of type 1 diabetes, leptin administration into brain ventricles normalizes blood glucose at doses that have no effect when given peripherally. The ventromedial nucleus of the hypothalamus (VMN) is a potential target for leptin's antidiabetic effects because leptin-sensitive neurons in this brain area are implicated in glucose homeostasis. To test this hypothesis, we injected leptin directly into the bilateral VMN of rats with streptozotocin-induced uncontrolled diabetes mellitus.

Neurotrophins acting via TRKB receptors activate the JAGGED1-NOTCH2 cell-cell communication pathway to facilitate early ovarian development.

Tropomyosin-related kinase (TRK) receptor B (TRKB) mediates the supportive actions of neurotrophin 4/5 and brain-derived neurotrophic factor on early ovarian follicle development. Absence of TRKB receptors reduces granulosa cell (GC) proliferation and delays follicle growth. In the present study, we offer mechanistic insights into this phenomenon.