Interplay of peripheral circadian clocks with energy balance and body weight regulation

点击翻译按钮获取中文摘要

Circadian clocks - endogenous oscillators present in the hypothalamus as well as in peripheral tissues - and metabolic processes are intimately intertwined: a huge body of evidence demonstrates that dysregulation of one system substantially affects the other and vice versa. Little is known, however, about (i) the role of meal timing as well as (ii) the role of tissue-specific circadian clocks for body weight (BW) regulation. In the first funding period we could show that insulin directly regulates the expression of the clock gene Per2 in mouse and human adipose tissue as well as in murine hepatocytes. These findings provide a direct link to energy metabolism since Per2 was shown to regulate circadian food intake, hormonal rhythms (glucocorticoids and alphaMSH) and obesity in mice. Human monocytes were shown to display similar circadian patterns as adipose tissue. Meal tests in humans showed acute regulation of PER2 in man. Moreover, lowering the carbohydrate content of foods resulted in a pronounced shift of circadian gene expression of the clock genes PER1, PER2, PER3 and of DBP in man which was associated with an altered expression of numerous metabolic and inflammatory genes related to energy metabolism. We therefore propose to investigate the interaction of the circadian system with food intake in the management of energy imbalance such as obesity. Specifically, we will study the role of adipose tissue and liver circadian clocks in mice for body weight regulation using appropriate genetic models and feeding paradigms. In addition, the mechanisms by which insulin signaling affects clock gene expression at a cellular level and potentially contributes to feeding-induced entrainment of circadian clocks will be analyzed. Complementary a human study aims to unravel the interaction of circadian mechanisms with metabolic/hormonal responses to food intake. To this end, the daytime dependence of food-induced effects on clock gene expression as well as on insulin responses will be examined with regard to their reciprocal regulation of clock genes and hormonal / metabolic responses thereby translating the animal data into human application.