Obesity and Type 2 diabetes represent global health threats that predispose millions of individuals to reduced life expectancy and incur $117 billion in annual health care costs in the U.S. alone. Leptin acts via the long isoform of the leptin receptor (LepRb) to regulate energy balance, metabolism, and neuroendocrine function. It is crucial to understand the molecular basis of LepRb action in order to understand the mechanisms governing metabolic regulation. The long-term goals of our previous and proposed studies under this award, entitled, "Molecular Mechanisms of Leptin Receptor/Jak2 Action," are to understand mechanisms of LepRb signaling and how these signals regulate neural function to control energy balance, glucose homeostasis, and endocrine function. Our findings have revealed two LepRb signals important for metabolic regulation: Tyr1138nSTAT3 and a second LepRb metabolic signaling pathway independent of LepRb tyrosine phosphorylation (the "pY-independent" pathway). To understand how LepRb controls metabolism and energy balance, we must determine how LepRb mediates the pY-independent second metabolic signal and understand how STATS and this pY-independent second signal modulate neuronal physiology to mediate downstream leptin action. Importantly, understanding how LepRb signals control physiology necessitates defining their long-term effects (as well as their acute actions). Our goals during this second period of MERIT funding are to resolve these issues. Since cultured cells do not permit the analysis of neural and physiologic leptin action, we will continue to generate and utilize LepRb mutant "knock-in" mouse lines, complemented by mouse models in which LepRb signaling molecules are disrupted in a cell- specific manner, with which to study the roles and mechanisms of action for defined LepRb signals in vivo. We propose to;
Specific Aim 1 : Identify the pY-independent LepRb moiety responsible for metabolic signaling in vivo.
Specific Aim 2 : Define the cell-autonomous roles for LepRb signals in the control of neuronal gene expression.
Specific Aim 3 : Determine the acute and chronic mechanisms by which LepRb signals modulate neural activity in vivo.

Public Health Relevance

Obesity and Type 2 diabetes represent global health threats that predispose millions of individuals to reduced life expectancy and incur $117 billion in annual health care costs in the U.S. alone. These studies will delineate the roles for specific LepRb signals in the regulation of neural and organismal physiology to define pathways that may be dysregulated in metabolic disease and that may represent potential targets for therapeutic intervention.

Agency
National Institute of Health (NIH)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37DK056731-16
Application #
8688221
Study Section
No Study Section (in-house review) (NSS)
Program Officer
Hyde, James F
Project Start
Project End
Budget Start
Budget End
Support Year
16
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Sadagurski, Marianna; Dong, X Charlie; Myers Jr, Martin G et al. (2014) Irs2 and Irs4 synergize in non-LepRb neurons to control energy balance and glucose homeostasis. Mol Metab 3:55-63
Allison, Margaret B; Myers Jr, Martin G (2014) 20 years of leptin: connecting leptin signaling to biological function. J Endocrinol 223:T25-35
Rajala, Michael W; Patterson, Christa M; Opp, Judith S et al. (2014) Leptin acts independently of food intake to modulate gut microbial composition in male mice. Endocrinology 155:748-57
Myers Jr, Martin G (2013) How is the hungry brain like a sieve? Cell Metab 17:467-8
Myers Jr, Martin G; Heymsfield, Steven B; Haft, Carol et al. (2012) Challenges and opportunities of defining clinical leptin resistance. Cell Metab 15:150-6
Mancuso, Peter; Peters-Golden, Marc; Goel, Deepti et al. (2011) Disruption of leptin receptor-STAT3 signaling enhances leukotriene production and pulmonary host defense against pneumococcal pneumonia. J Immunol 186:1081-90
Luo, Wei; Bodary, Peter F; Shen, Yuechun et al. (2011) Leptin receptor-induced STAT3-independent signaling pathways are protective against atherosclerosis in a murine model of obesity and hyperlipidemia. Atherosclerosis 214:81-5
Myers Jr, Martin G; Simerly, Richard B (2010) The neuroendocrinology and neuroscience of energy balance. Front Neuroendocrinol 31:1-3
Heinrich, Garrett; Ghosh, Sumona; Deangelis, Anthony M et al. (2010) Carcinoembryonic antigen-related cell adhesion molecule 2 controls energy balance and peripheral insulin action in mice. Gastroenterology 139:644-52, 652.e1
Argetsinger, Lawrence S; Stuckey, Jeanne A; Robertson, Scott A et al. (2010) Tyrosines 868, 966, and 972 in the kinase domain of JAK2 are autophosphorylated and required for maximal JAK2 kinase activity. Mol Endocrinol 24:1062-76

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