Neuroendocrine Regulation of Metabolism

Glucocorticoids increase liver glycogen levels, but the mechanism and relevance of this process are unknown. By unbiased analyses of multiple transcriptomes using the NURSA platform we have identified PTG, a glycogen-associated protein phosphatase targeting subunit as a novel, glucocorticoid-induced protein. The objective of this proposal is to characterize the nature and relevance of GR/glucocorticoid-dependent induction of PTG expression. To do this we propose to first identify the mechanism by which glucocorticoids result in increased PTG expression, including identification of regulatory elements in the PTG promoter. Second, using PTG knockout mice, we propose to evaluate the relevance of glucocorticoid-dependent induction of PTG on glucose homeostasis. Together these aims will validate a novel nuclear hormone receptor target and establish its relevance in the endocrine control of glucose metabolism.

Our objective is to determine the specific roles of white adipose tissue, brown adipose tissue and muscle in diet-induced thermogenesis. We will test the hypothesis that adrenergic signaling in muscle is required for thermogenic adaptations to high fat diet. While our hypothesis focuses on muscle as the central thermogenic organ in response to increased calories, this application will test the roles of white, brown adipose tissue and muscle in mediating the thermogenic/adrenergic response to overnutrition. To do this we will utilize new technologies where adrenergic signaling can be specifically and acutely ablated in a cell specific manner. We will utilize transgenic, tissue-specific expression of DREADD receptors, coupled to the inhibitory heterotrimeric G protein Gi.

Glucocorticoids result in adverse metabolic effects including diabetes, NAFLD and weight gain. We have generated preliminary data suggesting that while these risks are present in lean individuals, the consequences are dramatically worse in obese individuals. This proposal aims to identify the molecular and physiological mechanisms that cause these effects by testing effects of obesity on chromatin availability and the role of adipocytes in these effects. Our goal is to identify why and in what tissues obesity causes increased metabolic risk to glucocorticoids.

Peripheral tissues communicate their status to the brain in ways that can modify behavior by engaging higher order processes. Diet and exercise can have potent effects on behaviors, changing appetite, reducing stress, and activating other aspects of the central and peripheral nervous system. There are likely multiple signals that mediate this, but this project will focus on an emerging hormone called GDF15. In particular, we are interested in the impact of moderate to vigorous physical activity and low-carbohydrate diets on the production of this hormone using a combination of mouse and human studies. Long term, this project will study how this hormone responds to changes in diet and exercise to modify behaviors such as food intake, food preference and anxiety.