Obesity is a growing epidemic in the United States, and predisposes to type 2 diabetes and cardiovascular disease. Adipose tissue is a central regulator of whole body energy balance underscoring its importance in obesity. Two major types of adipose tissue exist, white and brown, and each depot is comprised of its requisite adipocyte. White adipocytes store energy as triglycerides, while brown adipocytes dissipate their fuel stores as heat (thermogenesis). The thermogenic capacity of brown fat is believed to render it anti-obesity. In the treatment of obesity, one dream of rationale therapeutics is to formulate compounds that confer the thermogenic qualities of brown fat onto their white adipocyte counterpart. Central to achieving such a goal is a basic understanding of brown adipocyte biology. Coactivators of the PGC-1 family regulate brown adipocyte determination, however, the molecular basis for this specificity is unknown. We recently found that LRP130 specifies PGC-1? function in hepatic gluconeogenesis, and have begun to explore the role of LRP130 in brown fat development. Preliminarily data indicates a crucial role for LRP130 in brown fat determination. LRP130 regulates several PGC-1 dependent brown fat markers, including uncoupling protein 1 (Ucp1), which is important for thermogenesis and is a hallmark of brown adipocyte determination. The goal of this application is to evaluate the role of LRP130 in brown adipocyte determination, and identify its underlying transcriptional mechanisms. We postulate that LRP130 regulates a subset of PGC-1 targets important for brown adipocyte determination.
Three specific aims will test the hypothesis as follows:
Aim (1) Evaluate brown adipocyte determination and mitochondrial function in adipocytes deficient for LRP130.
Aim (2) Evaluate brown adipocyte determination in adipocytes expressing ectopic LRP130.
Aim (3) Identify the regulatory regions of the Ucp1 promoter responsive to LRP130. Completion of this project will advance the current understanding of mechanisms underlying brown adipocyte determination, and may inform the search for new diagnostic and therapeutic interventions.
Obesity predisposes to heart disease and diabetes. Unique fat cells called brown fat cells, burn fat as heat, protect against obesity, and are found in human fat. This proposal will investigate the role of a gene called LRP130, in regulating this fat burning potential, and may aid the search for drugs that safely promote weight loss.
| Liu, Lijun; Sanosaka, Masato; Lei, Shi et al. (2011) LRP130 protein remodels mitochondria and stimulates fatty acid oxidation. J Biol Chem 286:41253-64 |
| Estall, Jennifer L; Kahn, Mario; Cooper, Marcus P et al. (2009) Sensitivity of lipid metabolism and insulin signaling to genetic alterations in hepatic peroxisome proliferator-activated receptor-gamma coactivator-1alpha expression. Diabetes 58:1499-508 |
