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)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
4R37DK056731-15
Application #
8636205
Study Section
Special Emphasis Panel (NSS)
Program Officer
Hyde, James F
Project Start
1999-03-15
Project End
2018-05-31
Budget Start
2013-06-25
Budget End
2014-05-31
Support Year
15
Fiscal Year
2013
Total Cost
$377,884
Indirect Cost
$127,020
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Flak, Jonathan N; Myers Jr, Martin G (2016) Minireview: CNS Mechanisms of Leptin Action. Mol Endocrinol 30:3-12
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Greenwald-Yarnell, Megan L; Marsh, Courtney; Allison, Margaret B et al. (2016) ERα in Tac2 Neurons Regulates Puberty Onset in Female Mice. Endocrinology 157:1555-65
Lam, Daniel D; Attard, Courtney A; Mercer, Aaron J et al. (2015) Conditional expression of Pomc in the Lepr-positive subpopulation of POMC neurons is sufficient for normal energy homeostasis and metabolism. Endocrinology 156:1292-302
Allison, Margaret B; Patterson, Christa M; Krashes, Michael J et al. (2015) TRAP-seq defines markers for novel populations of hypothalamic and brainstem LepRb neurons. Mol Metab 4:299-309
Dodd, Garron T; Worth, Amy A; Nunn, Nicolas et al. (2014) The thermogenic effect of leptin is dependent on a distinct population of prolactin-releasing peptide neurons in the dorsomedial hypothalamus. Cell Metab 20:639-49
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
Sutton, Amy K; Pei, Hongjuan; Burnett, Korri H et al. (2014) Control of food intake and energy expenditure by Nos1 neurons of the paraventricular hypothalamus. J Neurosci 34:15306-18

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