Consumption of a Fat-Rich Diet Activates a Proinflammatory Response and Induces Insulin Resistance in the Hypothalamus

TLDR

Obesity is an epidemic driven by lifestyle changes, especially fat‑rich diets, and is regulated by hypothalamic neurons that respond to leptin and insulin signals. High‑fat feeding triggers hypothalamic inflammation via cytokine expression and JNK/NF‑κB activation, impairs insulin signaling, and inhibition of JNK restores insulin action and reduces food intake and body weight.

Abstract

Obesity has reached epidemic proportions in several regions of the world. General changes in lifestyle, including consumption of fat-rich food, are among the most important factors leading to an unprecedented increase in the prevalence of this disease. Weight gain results from an imbalance between caloric intake and energy expenditure. Both of these parameters are under the tight control of specialized neurons of the hypothalamus that respond to peripheral anorexigenic and adipostatic signals carried by leptin and insulin. Here we show, by macroarray analysis, that high-fat feeding [hyperlipidic diet (HL)] induces the expression of several proinflammatory cytokines and inflammatory responsive proteins in hypothalamus. This phenomenon is accompanied by increased activation of c-Jun N-terminal kinase and nuclear factor-κB. In addition, HL feeding leads to impaired functional and molecular activation of the insulin-signaling pathway, which is paralleled by increased serine phosphorylation of the insulin receptor and insulin receptor substrate-2. Intracerebroventricular treatment of HL rats with a specific inhibitor of c-Jun N-terminal kinase (SP600125) restores insulin signaling and leads to a reduced caloric intake and weight loss. We conclude that HL feeding induces a local proinflammatory status in the hypothalamus, which results in impaired anorexigenic insulin signaling.