Peripheral and Central Interactions in Energy Balance (Barbara B. Kahn, MD, Principal Investigator, Beth Israel Deaconess Medical Center). Obesity and related disorders such as Type 2 diabetes mellitus are major healthcare issues in the United States, and decreasing their incidence in adults and children would have profound social and economic ramifications. For this to occur, an increased understanding of the mechanisms controlling food intake and body weight is essential. There has been tremendous recent progress in elucidating critical metabolic signals and the oathways in the brain and in peripheral tissues in which these signals act. In the past grant period the projects in this orogram investigated the central and peripheral actions of leptin. This included the neural pathways activated by leptin and the cellular pathways engaged by leptin in the CMS and skeletal muscle. We also examined the effects of manipulation of leptin receptors in specific neuronal cell groups on energy homeostasis. We offer 5 individual proposals that utilize state of the art genetic, physiological, biochemical, and neuroanatomic techniques to investigate the actions of critical metabolic cues including leptin, ghrelin, and nutrient sensing in the regulation of food intake, energy expenditure, and body weight. These studies will extend from molecular mechanisms of action to systems based studies to understand the physiological importance of these hormones through specific neural circuits. Our proposal consists of 5 individual projects and 3 cores. Project 1 will use functional neuroanatomy to assess the hypothesis that the recently identified hormone ghrelin acts through similar pathways as leptin. Studies will critically test the role of AGRP/NPY neurons in mediating the important actions of ghrelin by generating and evaluating mice that express ghrelin receptors exclusively on AGRP/NPY neurons. Project 2 will assess the role of melanin concentrating hormone (MCH) in regulating energy expenditure through effects on sympathetic activity and resting energy expenditure and through effects on the dopamine system locomotor activity. Project 3 focuses exclusively on the arcuate nucleus (AGRP/NPY neurons and POMC neurons) and uses genetically engineered mice to test specific hypotheses regarding the role of two afferent signals, leptin (new Aim #1) and """"""""lipid sensing"""""""" (new Aim #2), and two efferent signals, glutamate and GABA (new Aim #3) in regulating energy homeostasis. Project 4 will assess the biologic significance of the AMP-activated protein kinase (AMPK) pathway in mediating the central and peripheral effects of leptin on energy homeostasis. This will include determining if impaired leptin action on AMPK contributes to """"""""leptin resistance"""""""" in obesity; how the AMPK pathway integrates with other leptin signaling pathways; and which neuronal circuits mediate the effects of AMPK on food intake and energy homeostasis. Project 5 will examine the role of suppressor of cytokine signaling 3 (SOCS3) in the neuronal actions of both leptin and insulin. This will involve studies of leptin and insulin signaling and physiologic actions in mice with generalized neuronal deletion of SOCS3, and deletion or overexpression of SOCS3 in AgRP and POMC neurons. Core A will be an administrative core. Core B will be a Neuroanatomy Core and Core C will be a Physiology Core. Together, these projects will continue to leverage the collaborative efforts and expertise of investigators in Boston and will greatly increase the understanding of the central circuits regulating body weight.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
5P01DK056116-08
Application #
7215693
Study Section
Special Emphasis Panel (ZDK1-GRB-C (J1))
Program Officer
Sato, Sheryl M
Project Start
1999-08-01
Project End
2010-03-31
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
8
Fiscal Year
2007
Total Cost
$1,880,178
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Sohn, Jong-Woo; Elmquist, Joel K; Williams, Kevin W (2013) Neuronal circuits that regulate feeding behavior and metabolism. Trends Neurosci 36:504-12
Robins, S C; Stewart, I; McNay, D E et al. (2013) ?-Tanycytes of the adult hypothalamic third ventricle include distinct populations of FGF-responsive neural progenitors. Nat Commun 4:2049
Kawashima, Junji; Alquier, Thierry; Tsuji, Youki et al. (2012) Ca2+/calmodulin-dependent protein kinase kinase is not involved in hypothalamic AMP-activated protein kinase activation by neuroglucopenia. PLoS One 7:e36335
Dagon, Yossi; Hur, Elizabeth; Zheng, Bin et al. (2012) p70S6 kinase phosphorylates AMPK on serine 491 to mediate leptin's effect on food intake. Cell Metab 16:104-12
McNay, David E G; Briançon, Nadege; Kokoeva, Maia V et al. (2012) Remodeling of the arcuate nucleus energy-balance circuit is inhibited in obese mice. J Clin Invest 122:142-52
Chiappini, Franck; Cunha, Lucas L; Harris, Jamie C et al. (2011) Lack of cAMP-response element-binding protein 1 in the hypothalamus causes obesity. J Biol Chem 286:8094-105
Pulinilkunnil, Thomas; He, Huamei; Kong, Dong et al. (2011) Adrenergic regulation of AMP-activated protein kinase in brown adipose tissue in vivo. J Biol Chem 286:8798-809
Vella, Kristen R; Ramadoss, Preeti; Lam, Francis S et al. (2011) NPY and MC4R signaling regulate thyroid hormone levels during fasting through both central and peripheral pathways. Cell Metab 14:780-90
Loh, Kim; Fukushima, Atsushi; Zhang, Xinmei et al. (2011) Elevated hypothalamic TCPTP in obesity contributes to cellular leptin resistance. Cell Metab 14:684-99
Xu, Yong; Jones, Juli E; Lauzon, Danielle A et al. (2010) A serotonin and melanocortin circuit mediates D-fenfluramine anorexia. J Neurosci 30:14630-4

Showing the most recent 10 out of 96 publications