Obesity is associated with major health costs for the United States and affects more than 120 million people, including an increasing number of children. The underlying cause for the development of overweight and obesity is unknown. Leptin is a fat-derived hormone that normally reduces body weight in humans and in rodents. This occurs via actions on the brain leading to inhibition of appetite and stimulation of energy expenditure. However, for unknown reasons leptin is ineffective to reduce body weight and fat mass in obese animals and humans. This proposal is aimed at increasing the understanding of this issue. Normal mice given a Western-style high fat diet develop progressive obesity and leptin resistance. A central goal of this grant is therefore to use this widely accepted mouse-model of human obesity to determine why these animals become obese and why they are resistant to leptin. We have developed a highly sensitive immunohistochemical (IHC) method to anatomically measure leptin action and we have already determined that a specific region (arcuate nucleus) of the hypothalamus, but not other brain regions, is selectively resistant to leptin in obese mice. We will in this application determine the mechanism(s) of leptin resistance in the hypothalamus. Our overall hypothesis is that defective leptin action in the arcuate nucleus plays a role in development of obesity in DIO mice. Results from these studies would greatly increase our understanding of development of leptin-resistant obesity, and may help to unravel key mechanisms involved in body-weight regulation and sensitivity to a high-fat-containing Western diet. Ultimately, findings from this proposal may help to identify novel anti-obesity drug-targets that can eventually lead to development of new treatments for obese humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK065743-04
Application #
7333309
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Sato, Sheryl M
Project Start
2005-01-01
Project End
2009-06-30
Budget Start
2008-01-01
Budget End
2009-06-30
Support Year
4
Fiscal Year
2008
Total Cost
$278,021
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
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; Gamber, Kevin M; Grill, Harvey J et al. (2008) Divergent leptin signaling in proglucagon neurons of the nucleus of the solitary tract in mice and rats. Endocrinology 149:492-7
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