The adipose tissue pool in mammals comprises at least two functionally different types of fat: white and brown. Excess white adipose tissue is the defining characteristic of obesity, a pathologic state of increasing severity throughout the world. Brown adipose tissue (BAT) is specialized for energy expenditure and thermogenesis through numerous mitochondria and the expression of the unique uncoupling protein 1 (UCP-1). BAT affects whole-body metabolism, capable of altering insulin sensitivity and modifying one's susceptibility to weight gain. BAT is present in rodents throughout life and has been recently found to be avid for 18F-fluorodeoxyglucose (FDG) and therefore detectable via PET/CT. In contrast, in humans BAT is present in infants, but thought to be nonexistent in adults. Based on our recent findings, we have demonstrated that 18F-FDG PET/CT-evident adipose tissue is in fact BAT and that it substantial amounts are present in over 5% of human adults. We hypothesize that adult human BAT is (1) functional;(2) metabolically relevant;and (3) can be regulated through pharmacological and environmental interventions. The first set of studies (Aim 1) will demonstrate that human BAT generates heat, is associated with insulin sensitivity, and can be activated pharmacologically. The second phase (Aim 2) will probe the ultrastructural and gene expression profile of human BAT. Finally, the murine studies (Aim 3) will establish that BAT mass and activity can be quantified non-invasively via 18F-FDG PET/CT and infrared thermography. We will then determine if pharmacological and nutritional interventions designed to increase BAT mass and activity are effective at improving improved insulin sensitivity and body weight. The studies described in this proposal will enable us to develop a research platform utilizing PET/CT and infrared imaging in both rodents and humans to characterize BAT mass, function, and activation, and identify novel methods to treat obesity and diabetes.

Public Health Relevance

Obesity is the accumulation of too much harmful fat, and it increases the risk for heart attacks, cancers, and diabetes. Recent studies show that adults may have a heat-generating organ known as brown fat. Our research will show that brown fat burns calories and is important for weight loss. The ultimate goal is to find new ways to increase brown fat activity and help obese people lose weight and improve their overall health.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23DK081604-05
Application #
8535730
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Hyde, James F
Project Start
2009-09-01
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
5
Fiscal Year
2013
Total Cost
$152,886
Indirect Cost
$10,206
Name
Joslin Diabetes Center
Department
Type
DUNS #
071723084
City
Boston
State
MA
Country
United States
Zip Code
02215
Torriani, Martin; Zanni, Markella V; Fitch, Kathleen et al. (2013) Increased FDG uptake in association with reduced extremity fat in HIV patients. Antivir Ther 18:243-8
Cypess, Aaron M; White, Andrew P; Vernochet, Cecile et al. (2013) Anatomical localization, gene expression profiling and functional characterization of adult human neck brown fat. Nat Med 19:635-9
Chen, Yin-Ching Iris; Cypess, Aaron M; Chen, Yih-Chieh et al. (2013) Measurement of human brown adipose tissue volume and activity using anatomic MR imaging and functional MR imaging. J Nucl Med 54:1584-7
Cypess, Aaron M; Doyle, Ashley N; Sass, Christina A et al. (2013) Quantification of human and rodent brown adipose tissue function using 99mTc-methoxyisobutylisonitrile SPECT/CT and 18F-FDG PET/CT. J Nucl Med 54:1896-901
Torriani, Martin; Fitch, Kathleen; Stavrou, Eleni et al. (2012) Deiodinase 2 expression is increased in dorsocervical fat of patients with HIV-associated lipohypertrophy syndrome. J Clin Endocrinol Metab 97:E602-7
Cypess, Aaron M; Zhang, Hongbin; Schulz, Tim J et al. (2011) Insulin/IGF-I regulation of necdin and brown adipocyte differentiation via CREB- and FoxO1-associated pathways. Endocrinology 152:3680-9
Drubach, Laura A; Palmer 3rd, Edwin L; Connolly, Leonard P et al. (2011) Pediatric brown adipose tissue: detection, epidemiology, and differences from adults. J Pediatr 159:939-44
Tseng, Yu-Hua; Cypess, Aaron M; Kahn, C Ronald (2010) Cellular bioenergetics as a target for obesity therapy. Nat Rev Drug Discov 9:465-82
Cypess, Aaron M; Kahn, C Ronald (2010) Brown fat as a therapy for obesity and diabetes. Curr Opin Endocrinol Diabetes Obes 17:143-9
Cypess, Aaron M; Kahn, C Ronald (2010) The role and importance of brown adipose tissue in energy homeostasis. Curr Opin Pediatr 22:478-84