Obesity has reached epidemic proportions, affecting 30% of Americans, with a projected prevalence of 50% by 2030. The increasing prevalence of obesity has been associated with adverse health outcomes including diabetes, cardiovascular disease and cancer. Despite successful weight loss that could, if sustained, improve risk of negative health outcomes, the majority of weight reduced persons return to baseline body weight over a period of time following successful dietary and pharmacotherapy intervention. The mechanisms responsible for this return to baseline bodyweight remain unknown. Leptin is a protein secreted by adipocytes which acts to reduce appetite and increase energy expenditure. Leptin levels are increased in proportion to the degree of adiposity and circulating leptin levels decrease with weight loss. Our group has shown that decreasing leptin levels mediate the neuroendocrine response to food deprivation in both animals and humans. Thus, reduced leptin levels associated with weight loss could be responsible for defending baseline body weight by reducing thyroid hormone levels, reducing sympathetic nervous system activity and reducing metabolic rate. Although we have demonstrated that leptin regulates neuroendocrine function in lean subjects, the above hypothesis has never been studied in the setting of a randomized, controlled trial involving obese subjects who are apparently """"""""tolerant"""""""" or """"""""resistant"""""""" to leptin. Also, although animal studies indicate that leptin sensitivity is associated with changes in the expression of leptin receptor and second messengers of leptin signaling in leptin sensitive tissues, any changes that occur in these proteins with weight loss have never been studied in humans. We propose to study the role of leptin in defending baseline body weight by performing a placebo-controlled, randomized study of leptin administration to weight reduced obese subjects. By careful study of body weight, body composition, neuroendocrine function and metabolic rate, we plan to study the mechanisms involved in return to baseline body weight and the effect of leptin administration in preventing this. We also plan to study the changes in leptin signaling and leptin receptor expression. This novel and clinically relevant role for leptin is an area that urgently requires further study. Understanding the biology of the defense against weight loss will help to plan appropriate long-term weight maintenance therapies and ensure that obese patients derive long-term benefit from their efforts to reduce weight.

Public Health Relevance

Obesity has reached epidemic proportions, affecting 30% of Americans, with a projected prevalence of 50% by 2030. Several effective therapies, including lifestyle interventions, are available however the majority of individuals who manage to lose a clinically significant amount of weight, generally regain that weight over a period of months and years. Understanding the mechanisms and developing effective therapies to combat this phenomenon is of huge public health importance.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK079929-02
Application #
7653727
Study Section
Clinical and Integrative Diabetes and Obesity Study Section (CIDO)
Program Officer
Miles, Carolyn
Project Start
2008-07-15
Project End
2013-06-30
Budget Start
2009-07-01
Budget End
2010-06-30
Support Year
2
Fiscal Year
2009
Total Cost
$361,250
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Hamnvik, Ole-Petter Riksfjord; Thakkar, Bindiya; Chamberland, John et al. (2015) Omentin-1 levels are reduced by pharmacologic doses of leptin, but remain unaffected by energy deprivation and display no day-night variation. Int J Obes (Lond) 39:260-264
Liu, Xiaowen; Hamnvik, Ole-Petter R; Chamberland, John P et al. (2014) Circulating alanine transaminase (ALT) and ?-glutamyl transferase (GGT), but not fetuin-A, are associated with metabolic risk factors, at baseline and at two-year follow-up: the prospective Cyprus Metabolism Study. Metabolism 63:773-82
Matarese, Giuseppe; La Rocca, Claudia; Moon, Hyun-Seuk et al. (2013) Selective capacity of metreleptin administration to reconstitute CD4+ T-cell number in females with acquired hypoleptinemia. Proc Natl Acad Sci U S A 110:E818-27
Foo, Joo-Pin; Aronis, Konstantinos N; Chamberland, John P et al. (2013) Gender dimorphism and lack of day/night variation or effects of energy deprivation on undercarboxylated osteocalcin levels in humans. Obesity (Silver Spring) 21:E527-32
Moon, Hyun-Seuk; Mantzoros, Christos S (2013) Adiponectin and metformin additively attenuate IL1?-induced malignant potential of colon cancer. Endocr Relat Cancer 20:849-59
Vamvini, Maria T; Aronis, Konstantinos N; Panagiotou, Grigorios et al. (2013) Irisin mRNA and circulating levels in relation to other myokines in healthy and morbidly obese humans. Eur J Endocrinol 169:829-34
Thakkar, Bindiya; Aronis, Konstantinos N; Vamvini, Maria T et al. (2013) Metformin and sulfonylureas in relation to cancer risk in type II diabetes patients: a meta-analysis using primary data of published studies. Metabolism 62:922-34
Aronis, Konstantinos N; Chamberland, John P; Mantzoros, Christos S (2013) GLP-1 promotes angiogenesis in human endothelial cells in a dose-dependent manner, through the Akt, Src and PKC pathways. Metabolism 62:1279-86
Huffman, Derek M; Augenlicht, Leonard H; Zhang, Xueying et al. (2013) Abdominal obesity, independent from caloric intake, accounts for the development of intestinal tumors in Apc(1638N/+) female mice. Cancer Prev Res (Phila) 6:177-87
Moon, Hyun-Seuk; Dincer, Fadime; Mantzoros, Christos S (2013) Pharmacological concentrations of irisin increase cell proliferation without influencing markers of neurite outgrowth and synaptogenesis in mouse H19-7 hippocampal cell lines. Metabolism 62:1131-6

Showing the most recent 10 out of 64 publications