In animal models of diet-induced obesity, the activation of an inflammatory response in the hypothalamus produces molecular and functional resistance to the anorexigenic hormones insulin and leptin. The primary events triggered by dietary fats that ultimately lead to hypothalamic cytokine expression and inflammatory signaling are unknown. Here, we test the hypothesis that dietary fats act through the activation of toll-like receptors 2/4 and endoplasmic reticulum stress to induce cytokine expression in the hypothalamus of rodents. According to our results, long-chain saturated fatty acids activate predominantly toll-like receptor 4 signaling, which determines not only the induction of local cytokine expression but also promotes endoplasmic reticulum stress. Rats fed on a monounsaturated fat-rich diet do not develop hypothalamic leptin resistance, whereas toll-like receptor 4 loss-of-function mutation and immunopharmacological inhibition of toll-like receptor 4 protects mice from diet-induced obesity. Thus, toll-like receptor 4 acts as a predominant molecular target for saturated fatty acids in the hypothalamus, triggering the intracellular signaling network that induces an inflammatory response, and determines the resistance to anorexigenic signals.

Consumption of dietary fats is amongst the most important environmental factors leading to obesity. In rodents, the consumption of fat-rich diets blunts leptin and insulin anorexigenic signaling in the hypothalamus by a mechanism dependent on the in situ activation of inflammation. Since inflammatory signal transduction can lead to the activation of apoptotic signaling pathways, we evaluated the effect of high-fat feeding on the induction of apoptosis of hypothalamic cells. Here, we show that consumption of dietary fats induce apoptosis of neurons and a reduction of synaptic inputs in the arcuate nucleus and lateral hypothalamus. This effect is dependent upon diet composition, and not on caloric intake, since pair-feeding is not sufficient to reduce the expression of apoptotic markers. The presence of an intact TLR4 receptor, protects cells from further apoptotic signals. In diet-induced inflammation of the hypothalamus, TLR4 exerts a dual function, on one side activating pro-inflammatory pathways that play a central role in the development of resistance to leptin and insulin, and on the other side restraining further damage by controlling the apoptotic activity.

Defective liver gluconeogenesis is the main mechanism leading to fasting hyperglycemia in type 2 diabetes, and, in concert with steatosis, it is the hallmark of hepatic insulin resistance. Experimental obesity results, at least in part, from hypothalamic inflammation, which leads to leptin resistance and defective regulation of energy homeostasis. Pharmacological or genetic disruption of hypothalamic inflammation restores leptin sensitivity and reduces adiposity. Here, we evaluate the effect of a hypothalamic anti-inflammatory approach to regulating hepatic responsiveness to insulin. Obese rodents were treated by intracerebroventricular injections, with immunoneutralizing antibodies against Toll-like receptor (TLR)4 or tumor necrosis factor (TNF)α, and insulin signal transduction, hepatic steatosis, and gluconeogenesis were evaluated. The inhibition of either TLR4 or TNFα reduced hypothalamic inflammation, which was accompanied by the reduction of hypothalamic resistance to leptin and improved insulin signal transduction in the liver. This was accompanied by reduced liver steatosis and reduced hepatic expression of markers of steatosis. Furthermore, the inhibition of hypothalamic inflammation restored defective liver glucose production. All these beneficial effects were abrogated by vagotomy. Thus, the inhibition of hypothalamic inflammation in obesity results in improved hepatic insulin signal transduction, leading to reduced steatosis and reduced gluconeogenesis. All these effects are mediated by parasympathetic signals delivered by the vagus nerve.

Hypothalamic inflammation is present in animal models of obesity, and the intracerebroventricular injection of TNFα can reproduce a number of features of the hypothalamus of obese animals. Because obesity is a risk factor for type 2 diabetes (DM2) we hypothesized that, by inducing hypothalamic inflammation, we could reproduce some clinical features of DM2. Lean Wistar rats and TNF receptor 1-knockout mice were employed to determine the effects of hypothalamic actions of TNFα on thermogenesis and metabolic parameters. Signal transduction and protein expression were evaluated by immunoblot and real-time PCR. Thermogenesis was evaluated in living rats, and respirometry was determined in isolated muscle fiber. In Wistar rats, hypothalamic TNFα blunts the anorexigenic effect of leptin, which is accompanied by reduced leptin signaling and increased expression of suppressor of cytokine signaling 3. In addition, hypothalamic TNFα reduces O(2) consumption and the expression of thermogenic proteins in brown adipose tissue and skeletal muscle. Furthermore, hypothalamic inflammation increases base-line plasma insulin and insulin secretion by isolated pancreatic islets, which is accompanied by an impaired insulin signal transduction in liver and skeletal muscle. Hypothalamic inflammation induced by stearic acid also reduces O(2) consumption and blunts peripheral insulin signal transduction. The use of intracerebroventricular infliximab restores O(2) consumption in obese rats, whereas TNF receptor 1-knockout mice are protected from diet-induced reduced thermogenesis and defective insulin signal transduction. Thus, low-grade inflammation of the hypothalamus is sufficient to induce changes in a number of parameters commonly impaired in obesity and DM2, and TNFα is an important mediator of this process.

Adiponectin exerts an insulin-sensitizing effect, improving insulin action in peripheral tissues and restraining insulin resistance. Here, we explore the hypothesis that adiponectin can reproduce some of the actions of insulin/leptin in the hypothalamus. The presence of AdipoR1 and AdipoR2 was mapped to the arcuate and lateral hypothalamic nuclei. Icv adiponectin reduced food intake, which was accompanied by activation/engagement of IRS1/2, ERK, Akt, FOXO1, JAK2 and STAT3. All these actions were dependent on AdipoR1, since inhibition of this receptor, and not of AdipoR2, completely reversed the effects described above. Thus, adiponectin acts in the hypothalamus, activating elements of the canonical insulin and leptin signaling pathways and promoting reduction of food intake.