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.
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.
|Xu, Yuanzhong; Chang, Jeffrey T; Myers Jr, Martin G et al. (2016) Euglycemia Restoration by Central Leptin in Type 1 Diabetes Requires STAT3 Signaling but Not Fast-Acting Neurotransmitter Release. Diabetes 65:1040-9|
|Burke, Luke K; Doslikova, Barbora; D'Agostino, Giuseppe et al. (2016) Sex difference in physical activity, energy expenditure and obesity driven by a subpopulation of hypothalamic POMC neurons. Mol Metab 5:245-52|
|Flak, Jonathan N; Myers Jr, Martin G (2016) Minireview: CNS Mechanisms of Leptin Action. Mol Endocrinol 30:3-12|
|Sutton, Amy K; Myers Jr, Martin G; Olson, David P (2016) The Role of PVH Circuits in Leptin Action and Energy Balance. Annu Rev Physiol 78:207-21|
|Greenwald-Yarnell, Megan L; Marsh, Courtney; Allison, Margaret B et al. (2016) ERÎ± 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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