Insulin resistance can be caused by several factors including obesity and inflammation. Some pituitary tumors lead to over production of either growth hormone or cortisol, resulting in acromegaly and Cushing's Disease respectively. There is an incomplete understanding of the molecular mechanisms by which growth hormone and cortisol mediate insulin resistance and aberrant lipid metabolism in vivo.
To address this, in collaboration with groups at the Ramban Medical Institute in Haifa Israel, and the University of Michigan, we have performed an unbiased transcriptomic analysis of adipose tissue from human patients with acromegaly (see Hochberg et al. in PLOS One) or Cushing's disease (see Hochberg et al. in JME). We are using these data along with cell culture and mouse models to determine the mechanisms by which these endocrine diseases lead to altered metabolism.
Cortisol and the Metabolic Effects of Stress Hormones
There are several major effects of acute stress hormones including increased lipolysis, impaired insulin sensitivity, and muscle breakdown. Over the long run, chronic elevations in glucocorticoids can lead to increased adiposity and increased non-alcoholic fatty liver disease. Our team is working to understand the molecular mechanisms that underlie these changes.
Who is Working on This?
What sources of funding support this project?
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.