Low-Grade Hypothalamic Inflammation Leads to Defective Thermogenesis, Insulin Resistance, and Impaired Insulin Secretion

Abstract

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.

Central IKKβ inhibition prevents air pollution mediated peripheral inflammation and exaggeration of type II diabetes

“…However, TNFα blockade at the dosage used in the study did not antagonize the adverse effects of PM 2.5 on glucose metabolism and energy homeostasis. Our results are however contrary to reports showing that central TNFα administration reduced the expression of thermogenic proteins in brown adipose tissue and skeletal muscle, effects that were blunted in TNFα receptor knockout mice [16,48]. Depending on its local concentrations, TNFα can exert dual functions in the hypothalamus, being catabolic at high and anabolic at low concentrations.…”

“…In time course studies, peripheral inflammation takes weeks to develop following initiation of a high fat diet, whereas hypothalamic inflammation occurs rapidly within 24 hrs and prior to substantial weight gain and peripheral inflammation [13,14]. Targeting inflammation in the hypothalamus by the inactivation of IκB kinase or TNFα blockade protects against defective thermogenesis, obesity and IR [15,16], suggesting that hypothalamic dysfunction may precede and mechanistically contribute to obesity-associated IR and Type II diabetes (Type II DM). We hypothesized that inhalation of concentrated PM 2.5 would result in hypothalamic inflammation and exert effects on peripheral inflammation and IR and tested this hypothesis in a genetically susceptible mouse model of Type II DM.…”

Hypothalamic PGC-1α Protects Against High-Fat Diet Exposure by Regulating ERα

“…To determine if these results were specific to PA, we tested the inflammatory response to stearic and linoleic acid. Consistent with the literature (Arruda et al, 2011), stearic acid induced inflammation, while linoleic acid did not (Fig. S3 c).…”

Inactivation of TNF/LT locus alters mouse metabolic response to concentrated ambient PM2.5

“…In contrast, the role of TNFα in BAT activity regulation remains controversial (Cawthorn and Sethi, 2008). It has been shown that TNFα treatment increases BAT whitening and knockout of its receptor decrease BAT whitening (Arruda et al, 2011; Romanatto et al, 2009). This is consistent with our results in FA-exposed animals.…”