Obesity and Type 2 diabetes occurs with an alarming incidence in the United States, altogether affecting more than 120 million people, many of which are children. Currently, more people are obese and have diabetes in the world as compared to the number of humans who are undernourished. These diseases are associated with billions of dollars in health costs each year. The cause of common obesity/diabetes is unknown and effective treatments do not exist. Leptin is a hormone that is normally produced in fat tissue, released into circulation, and acts in the brain to reduce caloric intake and bodyweight, and to improve glucose balance. Among many leptin-responsive cells in the brain are two neuronal populations, the hypothalamic proopiomelanocortin (POMC) and agouti-related peptide (AgRP) neurons. POMC produce peptides that act via specific melanocortin receptors in the brain to reduce food intake and body weight, and their expression is stimulated by leptin. In parallel, leptin inhibits expression and release of AgRP, a peptide that increases caloric intake by inhibiting POMC-peptide signaling. Humans and mice lacking leptin or leptin receptors, or have mutations in the POMC or the melanocortin receptor genes, suffer from severe hyperphagia, obesity, and insulin resistance. We will in this proposal use transgenic mice to investigate how leptin decreases caloric intake and reduces body weight, and vastly improves glucose balance, by acting via POMC and AgRP neurons. Altogether, the proposed studies will increase our understanding of how leptin acts to decrease body weight and food intake, and to improve glucose balance. The findings may help identification of novel anti-obesity/diabetes drug-targets.

Public Health Relevance

This project aims to identify mechanisms whereby the hormone leptin acts in the brain to reduce body weight and fat mass, reduce caloric intake, and improve glucose metabolism. Specifically, we will identify pathways by which leptin influences these processes, via signaling in hypothalamic POMC and AGRP neurons. The grant will also determine regulation of leptin receptor localization within these specific neurons as this pertains to mechanisms of leptin-resistant obesity. Obtained data will therefore be relevant for future identification of novel anti-obesity/diabetes drug pathways/targets.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK060673-07
Application #
7896441
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Hyde, James F
Project Start
2002-02-01
Project End
2011-06-30
Budget Start
2010-07-01
Budget End
2011-06-30
Support Year
7
Fiscal Year
2010
Total Cost
$434,688
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Gonçalves, Gabriel H M; Li, Wenjing; Garcia, Adriana V C-G et al. (2014) Hypothalamic agouti-related peptide neurons and the central melanocortin system are crucial mediators of leptin's antidiabetic actions. Cell Rep 7:1093-103
Ha, Sangdeuk; Baver, Scott; Huo, Lihong et al. (2013) Somato-dendritic localization and signaling by leptin receptors in hypothalamic POMC and AgRP neurons. PLoS One 8:e77622
Coppari, Roberto; Bjørbæk, Christian (2012) Leptin revisited: its mechanism of action and potential for treating diabetes. Nat Rev Drug Discov 11:692-708
Gamber, Kevin M; Huo, Lihong; Ha, Sangdeuk et al. (2012) Over-expression of leptin receptors in hypothalamic POMC neurons increases susceptibility to diet-induced obesity. PLoS One 7:e30485
Backholer, Kathryn; Bowden, Marissa; Gamber, Kevin et al. (2010) Melanocortins mimic the effects of leptin to restore reproductive function in lean hypogonadotropic ewes. Neuroendocrinology 91:27-40
Bjørbaek, Christian (2009) Central leptin receptor action and resistance in obesity. J Investig Med 57:789-94
Huo, Lihong; Gamber, Kevin; Greeley, Sarah et al. (2009) Leptin-dependent control of glucose balance and locomotor activity by POMC neurons. Cell Metab 9:537-47
Huo, Lihong; Maeng, Lisa; Bjorbaek, Christian et al. (2007) Leptin and the control of food intake: neurons in the nucleus of the solitary tract are activated by both gastric distension and leptin. Endocrinology 148:2189-97
Huo, Lihong; Grill, Harvey J; Bjorbaek, Christian (2006) Divergent regulation of proopiomelanocortin neurons by leptin in the nucleus of the solitary tract and in the arcuate hypothalamic nucleus. Diabetes 55:567-73
Huo, Lihong; Munzberg, Heike; Nillni, Eduardo A et al. (2004) Role of signal transducer and activator of transcription 3 in regulation of hypothalamic trh gene expression by leptin. Endocrinology 145:2516-23

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