Neuroendocrine Regulation of Metabolism

Project Summary

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?

Dave Bridges
Assistant Professor, Department of Nutritional Sciences, University of Michigan since 2016-06-01
Innocence Harvey
Doctoral Candidate, Department of Nutritional Sciences, University of Michigan since 2016-09-01

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.

Publications

What have we published on this topic?

Suriyan Ponnusamy, Quynh Tran, Thirumagal Thiyagarajan, Duane Miller, Dave Bridges and Ramesh Narayanan. An Estrogen Receptor b-Selective Agonist Inhibits Non-Alcoholic Steatohepatitis (NASH) in Preclinical Models by Regulating Bile Acid and Xenobiotic Receptors 2017. Experimental Biology and Medicine 242(6):606-616 Full Text Details.
Suriyan Ponnusamy, Quynh Tran, Innocence Harvey, Heather Smallwood, Thirumagal Thiyagarajan, Souvik Banerjee, Daniel Johnson, James Dalton, Ryan Sullivan, Duane Miller, Dave Bridges and Ramesh Narayanan. Pharmacologic activation of estrogen receptor-beta; increases mitochondrial function, energy expenditure, and brown adipose tissue. 2017. FASEB Journal 31(1):266-281 Full Text Details.
Nora Urraca, R. Menon, I. El-Iyachi, Sarita Goorha, Colleen Valdez, Quynh Tran, Reese Scroggs, G. Miranda-Carboni , Martin Donaldson, Dave Bridges and Lawrence Reiter. Characterization of neurons from immortalized dental pulp stem cells for the study of neurogenetic disorders. 2015. Stem Cell Research 15(3):722-30 Full Text Details.
Irit Hochberg, Innocence Harvey, Quynh Tran, Erin Stephenson, Ariel Barkan, Alan Saltiel, William Chandler and Dave Bridges. Gene expression changes in subcutaneous adipose tissue due to Cushing's disease. 2015. Journal of Molecular Endocrinology 55(2):81-94 Full Text Details.
Irit Hochberg, Quynh Tran, Ariel Barkan, Alan Saltiel, William Chandler and Dave Bridges. Gene Expression Signature in Adipose Tissue of Acromegaly Patients. 2015. PLOS One 10(6):e0129359 Full Text Details.

What are some key papers on this topic?

Kevin Hall, Thomas Bemis, Robert Brychta, Kong Chen, Amber Courvillle, Emma Crayner, Stephanie Goodwin, Juen Guo, Lillian Howard, Nicolas Knuth, Bernard Miller, Carla Prado, Maria Siervo, Monica Skarulis, Mary Walter, Peter Walter and Laura Yannai. Calorie for Calorie, Dietary Fat Restriction Results in More Body Fat Loss than Carbohydrate Restriction in People with Obesity 2015. Cell Metabolism 22(3):427-436 Full Text Our Thoughts Details.
Rachel Perry, Joao-Paulo Camporez, Romy Kursawe, Paul Titchenell, Dongyan Zhang, Curtis Perry, Michael Jurczak, Abulizi Abudukadier, Myoung Sook Han, Xian-Man Zhang, Hai-Bin Ruan, Xiaoyong Yang, Sonia Caprio, Susan Kaech, Hei Sook Sul, Morris Birnbaum, Roger Davis, Gary Cline, Kitt Peterson and Gerald Shulman. Hepatic acetyl CoA links adipose tissue inflammation to hepatic insulin resistance and type 2 diabetes. 2015. Cell 160(4):745-758 Full Text Details.

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