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

摘要

Jose B. Carvalheira, and Licio A. Velloso Hypothalamic inflammation is present in animal models of obe- sity, and the intracerebroventricular injection of TNFa can repro- duce a number of features of the hypothalamus of obese ani- mals. 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 TNFa on thermogenesis and metabolic parameters. Signal transduction and protein ex- pression were evaluated by immunoblot and real-time PCR. Ther- mogenesis was evaluated in living rats, and respirometry was determined in isolated muscle fiber. In Wistar rats, hypothalamic TNFa blunts the anorexigenic effect of leptin, which is accom- panied by reduced leptin signaling and increased expression of suppressor of cytokine signaling 3. In addition, hypothalamic TNFa reduces O, consumption and the expression of thermo- genic proteins in brown adipose tissue and skeletal muscle. Fur- thermore, 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, consumption and blunts periph- eral insulin signal transduction. The use of intracerebroventric- ular infliximab restores O, consumption in obese rats, whereas TNF receptor 1-knockout mice are protected from diet-induced reduced thermogenesis and defective insulin signal transduc- tion. Thus, low-grade inflammation of the hypothalamus is suf- ficient to induce changes in a number of parameters commonly impaired in obesity and DM2, and TNFa is an important mediator of this process.