Endocrine Abstracts

Abstract: Obesity results from an imbalance between caloric intake and energy expenditure. Specialized neurons of the hypothalamus coordinately control the integration between feeding and thermogenesis and a defective regulation of these parameters contribute to the progressive accumulation of body fat. Recent studies have revealed that at least part of hypothalamic dysfunction contributing to the development of obesity results from the activation of a local inflammatory response. TNF-α is one of the main players in this context. Inhibition of TNF-α signaling by both genetic and pharmacological approaches can, at least partially, rescue the obese phenotype. In the present study we evaluate the role played by hypothalamic TNFR-1 (TNF-α receptor type 1) in the transduction of the TNF-α signals that contribute to the development of obesity. For that, TNFR1 knockout mice (TNFR1KO) were fed a high-fat diet for eight weeks and a number of metabolic and molecular parameters were evaluated by respirometry, real-time PCR, immunoblot, immunohistochemistry and mitochondria respiration assay. The TNFR1KO were protected from diet-induced obesity, after 8-w high-fat diet consumption KO mice gained 15% less body mass than high-fat diet fed control mice. This was due to increased energy expenditure, as evaluated by in vivo respirometry and by isolated mitochondrial respiration assay, and by reduced cumulative food intake. At least part of the differences in food intake and energy expenditure were due to increased responsiveness to hypothalamic leptin and insulin. Thus, ip leptin injection led to an increase in 12 h suppression of feeding and increased STAT3 activation and SOCS-3 expression. Therefore, we conclude that TNFR1 is at least partially, implicated in the transduction of the TNF-α inflammatory signals that contributes to diet-induced hypothalamic dysfunction in obesity.