Maria F. Fernandes

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.

Prolonged exercise of medium to high intensity is known to promote a substantial effect on the energy balance of rats. In male rats, moderately to severely intense programs lead to a reduction in food intake. However, the exact causes for the appetite-suppressive effects of exercise are not known. Here, we show that intracerebroventricular insulin or leptin infusion reduced food intake in exercised rats to a greater extent than that observed in control animals. Exercise was associated with a markedly increased phosphorylation/activity of several proteins involved in leptin and insulin signal transduction in the hypothalamus. The regulatory role of interleukin (IL)-6 in mediating the increase in leptin and insulin sensitivity in hypothalamus was also investigated. Treatment with insulin or leptin markedly reduced food intake in exercised rats that were pretreated with vehicle, although no increase in sensitivity to leptin- and insulin-induced anorexia after pretreatment with anti-IL-6 antibody was detected. The current study provides direct measurements of leptin and insulin signaling in the hypothalamus and documents increased sensitivity to these hormones in the hypothalamus of exercised rats in an IL-6-dependent manner. These findings provide support for the hypothesis that the appetite-suppressive actions of exercise may be mediated by the hypothalamus.

Depression is a complex disorder influenced by a variety of biological and environmental factors. Due to significant heterogeneity, there are remarkable differences in how patients respond to treatment. A primary objective of psychiatric research is to identify biological markers that could be used to better predict and enhance responses to antidepressant treatments. Diet impacts various aspects of health, including depression. The fatty acid composition of the Western diet, which has a high ratio of n-6:n-3 polyunsaturated fatty acids, is associated with increased incidence of depression. The brain is rich in lipids, and dietary fatty acids act within specific brain regions to regulate processes that impact emotional behavior. This manuscript reviews existing evidence demonstrating brain region-specific fatty acid profiles, and posits that specific fatty acids may serve as predictive biomarkers of response to antidepressants. Furthermore, increasing blood levels of certain fats, such as n-3s, via dietary intervention may serve as an adjunct to improve the efficacy of antidepressants. Notably, most of the existing research regarding fats and depression-related brain regions has focused on n-3s, as compared to n-6s, monounsaturated, and saturated fats. This review article will help guide future work investigating the relationships between fatty acids, brain regions, and antidepressant efficacy.