IL-6 and IL-10 anti-inflammatory activity links exercise to hypothalamic insulin and leptin sensitivity through IKKbeta and ER stress inhibition.

Overnutrition caused by overeating is associated with insulin and leptin resistance through IKKbeta activation and endoplasmic reticulum (ER) stress in the hypothalamus. Here we show that physical exercise suppresses hyperphagia and associated hypothalamic IKKbeta/NF-kappaB activation by a mechanism dependent upon the pro-inflammatory cytokine interleukin (IL)-6. The disruption of hypothalamic-specific IL-6 action blocked the beneficial effects of exercise on the re-balance of food intake and insulin and leptin resistance. This molecular mechanism, mediated by physical activity, involves the anti-inflammatory protein IL-10, a core inhibitor of IKKbeta/NF-kappaB signaling and ER stress. We report that exercise and recombinant IL-6 requires IL-10 expression to suppress hyperphagia-related obesity. Moreover, in contrast to control mice, exercise failed to reverse the pharmacological activation of IKKbeta and ER stress in C3H/HeJ mice deficient in hypothalamic IL-6 and IL-10 signaling. Hence, inflammatory signaling in the hypothalamus links beneficial physiological effects of exercise to the central action of insulin and leptin.

A central role for neuronal AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) in high-protein diet-induced weight loss.

OBJECTIVE: A high-protein diet (HPD) is known to promote the reduction of body fat, but the mechanisms underlying this change are unclear. AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) function as majors regulators of cellular metabolism that respond to changes in energy status, and recent data demonstrated that they also play a critical role in systemic energy balance. Here, we sought to determine whether the response of the AMPK and mTOR pathways could contribute to the molecular effects of an HPD. RESEARCH DESIGN AND METHODS: Western blotting, confocal microscopy, chromatography, light microscopy, and RT-PCR assays were combined to explore the anorexigenic effects of an HPD. RESULTS: An HPD reduced food intake and induced weight loss in both normal rats and ob/ob mice. The intracerebroventricular administration of leucine reduced food intake, and the magnitude of weight loss and reduction of food intake in a leucine-supplemented diet are similar to that achieved by HPD in normal rats and in ob/ob mice, suggesting that leucine is a major component of the effects of an HPD. Leucine and HPD decrease AMPK and increase mTOR activity in the hypothalamus, leading to inhibition of neuropeptide Y and stimulation of pro-opiomelanocortin expression. Consistent with a cross-regulation between AMPK and mTOR to control food intake, our data show that the activation of these enzymes occurs in the same specific neuronal subtypes. CONCLUSIONS: These findings provide support for the hypothesis that AMPK and mTOR interact in the hypothalamus to regulate feeding during HPD in a leucine-dependent manner.