SUMMARY 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. Conversely, forcing microglial activation through cell-specific deletion of the negative NF-κB regulator A20 induced spontaneous MBH microgliosis and cellular infiltration, reduced energy expenditure, and increased both food intake and weight gain even in absence of a dietary challenge. Thus, microglial inflammatory activation, stimulated by dietary excess, orchestrates a multicellular hypothalamic response that mediates obesity susceptibility, providing a mechanistic rationale for non-neuronal approaches to treat metabolic diseases.

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. We also report that neurons in the lateral parabrachial nucleus (LPBN), a brain area that is also implicated in the response to hypoglycemia, make synaptic connections with the specific subset of glucoregulatory VMN SF1 neurons that project to the aBNST. These results collectively establish a physiological role in glucose homeostasis for VMN SF1 neurons and suggest that these neurons are part of an ascending glucoregulatory LPBN→VMN SF1 →aBNST neurocircuit.glucoregulatory circuit | counter regulation | ventromedial nucleus | bed nucleus of the stria terminalis | hyperglycemia B ecause the brain relies exclusively on glucose as a fuel source, brain function is rapidly compromised when circulating glucose levels drop below the normal range. Consequently, hypoglycemia elicits a robust, integrated, and redundant set of counterregulatory responses (CRRs) that ensure the rapid and efficient recovery of plasma glucose concentrations into the normal range (1). Components of the CRR include increased secretion of the hormones glucagon, epinephrine, and glucocorticoids, inhibition of glucoseinduced insulin secretion, increased sympathetic nervous system (SNS) outflow to the liver, and increased food intake (1-3). Owing to this redundancy, recovery from hypoglycemia is difficult to block in normal humans and animal models, even when adrenal or glucagon responses are prevented. Only when multiple responses are blocked is the ability to recover from hypoglycemia significantly compromised (4). This arrangement is perhaps unsurprising, given the threat to survival posed by hypoglycemia.Although glucose sensing can occur at peripheral (e.g., neurons innervating the hepatic portal vein) as well as central sites (3, 5), the brain is the organ responsible both for transducing this information into effective glucose counterregulation and for terminating this response once euglycemia is restored. Of the many brain areas that have been investigated, the hypothalamic ventromedial nucleus (VMN) has emerged as potentially being both necessary and sufficient to elicit this powerful response. This assertion is based on evidence that, whereas electrical stimulation of the VMN activates the CRR and thereby raises circulating glucose levels (6), glucose infusion directly into the VMN can suppress the CRR during hypoglycemia (7) and thereby impair recovery of normal blood glucose levels (8). Moreover, two recent papers identified a circuit comprise...

ObjectiveObesity and high fat diet (HFD) consumption in rodents is associated with hypothalamic inflammation and reactive gliosis. While neuronal inflammation promotes HFD-induced metabolic dysfunction, the role of astrocyte activation in susceptibility to hypothalamic inflammation and diet-induced obesity (DIO) remains uncertain.MethodsMetabolic phenotyping, immunohistochemical analyses, and biochemical analyses were performed on HFD-fed mice with a tamoxifen-inducible astrocyte-specific knockout of IKKβ (GfapCreERIkbkbfl/fl, IKKβ-AKO), an essential cofactor of NF-κB-mediated inflammation.ResultsIKKβ-AKO mice with tamoxifen-induced IKKβ deletion prior to HFD exposure showed equivalent HFD-induced weight gain and glucose intolerance as Ikbkbfl/fl littermate controls. In GfapCreERTdTomato marker mice treated using the same protocol, minimal Cre-mediated recombination was observed in the mediobasal hypothalamus (MBH). By contrast, mice pretreated with 6 weeks of HFD exposure prior to tamoxifen administration showed substantially increased recombination throughout the MBH. Remarkably, this treatment approach protected IKKβ-AKO mice from further weight gain through an immediate reduction of food intake and increase of energy expenditure. Astrocyte IKKβ deletion after HFD exposure—but not before—also reduced glucose intolerance and insulin resistance, likely as a consequence of lower adiposity. Finally, both hypothalamic inflammation and astrocytosis were reduced in HFD-fed IKKβ-AKO mice.ConclusionsThese data support a requirement for astrocytic inflammatory signaling in HFD-induced hyperphagia and DIO susceptibility that may provide a novel target for obesity therapeutics.

No abstract

Type 2 diabetes (T2D) is among the most common and costly disorders worldwide1. The goal of current medical management of T2D is to transiently ameliorate hyperglycemia through daily dosing of one or more anti-diabetic drugs. Hypoglycemia and weight are common side effects of therapy, and sustained disease remission is not obtainable with non-surgical approaches. Based on the potent glucose-lowering response elicited by activation of brain fibroblast growth factor (FGF) receptors2–4, we explored the anti-diabetic efficacy of centrally administered FGF1, which, unlike other FGF peptides, activates all FGF receptor subtypes5. We report that a single intracerebroventricular (i.c.v.) injection of FGF1 at a dose one-tenth of that needed for systemic anti-diabetic efficacy induces sustained diabetes remission in both mouse and rat models of T2D. This anti-diabetic effect is not secondary to weight loss, does not increase the risk of hypoglycemia, and involves a novel and incompletely understood mechanism for increasing glucose clearance from the bloodstream. We conclude that the brain has the inherent potential to induce diabetes remission and that brain FGF receptors are potential pharmacological targets for achieving this goal.