Obesity is one of the most important risk factors for the development of cardiovascular disease, diabetes and other conditions associated with metabolic syndrome. As the primary organ involved in the storage of excess lipids, white adipose tissue (WAT) is essential for maintaining metabolic function and has recently been shown to be an important mediator of whole body metabolism by regulating appetite and insulin sensitivity through the release of signaling molecules such as adiponectin and leptin. The sterol-regulatory element-binding proteins, SREBP-1 and SREBP-2, are important regulators of cholesterol homeostasis and the metabolism of glucose and fatty acids1-3. Recent work by our lab and others has established that, in humans, the intronic microRNAs miR-33a and miR-33b, located within the genes encoding SREBP-2 and SREBP-1 respectively, are transcribed in concert with their host genes and function alongside them in their regulation of cholesterol, fatty acid, and glucose metabolism4-9. SREBP-1 is highly expressed in mature WAT and plays a critical role in promoting adipocyte differentiation10. While the role of miR-33 in helping to mediate the metabolic functions of SREBP-1 and 2 in the liver and macrophages has been well established, it is not known whether miR-33 is induced upon or involved in the regulation of adipogenesis. Our preliminary findings show that miR-33b is highly induced upon differentiation of human WAT in concert with its host gene, SREBP-1. Therefore, we hypothesize that miR-33b may also function alongside SREBP-1 in WAT, as has been previously demonstrated in other tissues. The primary focus of this application is to explore the role of miR-33b in regulating adipocyte differentiation and function. Initial studies will utilize lentiviral constructs to overexpress and inhibit miR-33b in human pre-adipocytes and assess how this impacts differentiation into mature adipocytes in vitro. Since an alteration in the region of the murine SREBP1 gene encoding mir- 33b precludes analysis of mir-33b function in wild type mice, we have generated mouse strain harboring the human SREBP1 gene, including the region encoding miR-33b. We will use this model to elucidate the role of mir-33b in fat mass accumulation and regulation of metabolic function during diet-induced obesity. This research will help improve our understanding of how adipocyte differentiation is regulated in humans with important implications for the development of obesity and metabolic syndrome.

Public Health Relevance

The aim of this work is to explore the role of miR-33b in regulating the differentiation of human pre-adipocytes into mature adipocytes in vitro, and to determine how this impacts the accumulation of fat mass and regulation of metabolic function during diet-induced obesity using a newly generated mouse strain harboring the human SREBP1 gene, including the region encoding miR-33b. This research will help improve our understanding of how adipocyte differentiation is regulated in humans, with important implications for the development of obesity and metabolic syndrome.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32DK103489-01A1
Application #
8836267
Study Section
Special Emphasis Panel (ZDK1-GRB-R (O1))
Program Officer
Castle, Arthur
Project Start
2014-09-05
Project End
2017-09-04
Budget Start
2014-09-05
Budget End
2015-09-04
Support Year
1
Fiscal Year
2014
Total Cost
$55,982
Indirect Cost
Name
Yale University
Department
Veterinary Sciences
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520