Neuroendocrine Regulation of Metabolism

Project Summary

Obesity, NAFLD Insulin resistance can be caused by several factors including obesity and inflammation. One of the more fascinating aspects of this physiology is how these phenotypes involve substantial communication between tissues, and the brain. We are working on how several hormones, including insulin and GDF15 communicate from the body the brain, and how other hormones under neuronal control (BDNF, cortisol and growth hormone) affect the periphery.

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., 2015 in PLOS One) or Cushing's disease (see Hochberg et al. 2015 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.

Obesity as a Modifier of Glucocorticoid Signaling

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.

While evaluating transcriptional and physiological changes in glucocorticoid responses in adipose lysates from patients with Cushing's disease, we were surprised to find that obesity strongly promoted insulin resistance, NAFLD and the adipose transcriptome (see Hochberg et al. 2015).

To understand this further, we did several experiments where we generated lean and diet-induced obese mice and then gave them glucocorticoids, to ask whether the response was stronger in the obese mice. As we describe in Harvey et al., 2018 the mice with pre-existing obesity had dramatically worsened insulin sensitivity, fatty liver disease and lipolysis. We identified that in adipose tissue there was a strong up-regulation by obesity and glucocorticoids of the lipolytic enzyme ATGL, and elevated lipolysis. This suggested to us that adipose tissue is critical for these worsened metabolic responses. We are currently working to understand how obesity affects stress hormone signaling, and whether other effects of stress hormone signaling are affected by obesity. In terms of muscle function, we identified that obesity also increases dexamethasone-induced muscle atrophy and weakness, with a pronounced effect in type II muscle fibers (Gunder et al., 2020).

Who is Working on This?

Dave Bridges
Associate Professor, Department of Nutritional Sciences, University of Michigan since 2022-09-01
Cody Cousineau
Doctoral Candidate, Rackham Graduate School, University of Michigan since 2019-09-01
Jiayin Liu
MS Student, Department of Nutritional Sciences, University of Michigan since 2023-01-01

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.

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.


What have we published on this topic?

  1. Scott Ochsner, David Abraham, Kirt Martin, Wei Ding, Apollo McOwiti, Wasula Kankanamge, Zichen Wang, Kaitlyn Andreano, Ross Hamilton, Yue Chen, Angelica Hamilton, Marin Gantner, Michael Dehart, Shijing Qu, Susan Hilsenbeck, Lauren Becnel, Dave Bridges, Avi Ma'ayan, Janice Huss, Fabio Stossi, Charles Foulds, Anastasia Kralli, Donald McDonnell and Neil McKenna. The Signaling Pathways Project, an integrated 'omics knowledgebase for mammalian cellular signaling pathways 2019. Scientific Data 6(1):252 Full Text Details.
  2. Liam McAllan, Kristen Maynard, Alisha Kardian, Amanda Stayton, Shelby Fox, Erin Stephenson, Clint Kinney, Noor Alshibli, Charles Gomes, Joseph Pierre, Michelle Puchowicz, Dave Bridges, Keri Martinowich and Joan Han. Disruption of brain-derived neurotrophic factor production from individual promoters generates distinct body composition phenotypes in mice 2018. American Journal of Physiology - Endocrinology and Metabolism 315(6):E1168-E1184 Full Text Details.
  3. Michael Keufner, Kevin Pham, JeAnna Redd, Erin Stephenson, Innocence Harvey, Xiong Deng, Dave Bridges, Eric Boilard, Marshal Elam and Edwards Park. Secretory phospholipase A2 group IIA (PLA2G2A) modulates insulin sensitivity and metabolism. 2017. Journal of Lipid Research Full Text Details.
  4. 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.
  5. 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.
  6. 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.
  7. 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.
  8. 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.


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