Deletion of Tumor Necrosis Factor-alpha-receptor 1 (tnfr1) Protects against Diet-induced Obesity by Means of Increased Thermogenesis

In diet-induced obesity, hypothalamic and systemic inflammatory factors trigger intracellular mechanisms that lead to resistance to the main adipostatic hormones, leptin and insulin. Tumor necrosis factor-alpha (TNF-) is one of the main inflammatory factors produced during this process and its mechanistic role as an inducer of leptin and insulin resistance has been widely investigated. Most of TNF- inflammatory signals are delivered by TNFR1; however, the role played by this receptor in the context of obesity-associated inflammation is not completely known. Here, we show that TNFR1 knockout (TNFR1 KO) mice are protected from diet-induced obesity due to increased thermogenesis. Under standard rodent chow or high-fat diet, TNFR1 KO gain significantly less body mass in spite of increased caloric intake. Visceral adiposity and mean adipocyte diameter are reduced and blood concentrations of insulin and leptin are lower. Protection from hypothalamic leptin resistance is evidenced by increased leptininduced suppression of food intake and preserved activation of leptin signal transduction through JAK2, STAT3 and FOXO1. Under high fat diet, TNFR1 KO mice present a significantly increased expression of the thermogenesis-related neurotransmitter, TRH. Further evidence of increased thermogenesis includes the increased O2 consumption in respirometry measurements, increased expressions of UCP1 and UCP3 in brown adipose tissue and skeletal muscle, respectively, and increased O2 consumption by isolated skeletal muscle fiber mitochondria. This demonstrates that TNF- signaling through TNFR1 is an important mechanism involved in obesity-associated defective thermogenesis.