The long-term objective is to understand the physiologic and developmental regulation of brown adipose tissue (BAT). The thermogenic activity of brown adipose tissue (BAT) is regulated in response to a number of physiologic signals including cold- exposure, arousal from hibernation and overfeeding. The unique thermogenic properties of BAT derive from the uncoupling of mitochondrial respiration and oxidative phosphorylation through the action of the BAT-specific uncoupling protein (UCPI). Because heat production is equivalent to energy expenditure, BAT can play a dual role in the organism of ensuring homeothermy and energy balance. Ablation of BAT in transgenic mice causes obesity in the absence of hyperphagia confirming the important role of BAT in energy balance. Obesity is a major risk factor for the development of diabetes, hypertension and coronary artery disease. A deeper understanding of the mechanisms controlling BAT growth and development may lead to the development of novel therapeutic approaches to the problem of obesity. UCP1 controls the thermogenic activity of BAT and is the defining gene product of the brown adipocyte. Thus, the regulatory factors controlling UCP1 expression are likely to be fundamental determinants of brown adipocyte differentiation and physiologic regulation. The HIB-1B cell line derived from a brown fat cell tumor differentiates into brown adipocytes that appropriately express the UCP1 gene. The UCP1 enhancer located at -2.5 to -2.3 kb is capable of directing high level gene expression to BAT of transgenic mice and expression is regulated by physiological stimuli such as cold exposure and fasting/refeeding.
Specific aim 1 will utilize the HIB-1B cells to systematically identify the cis-acting elements within this enhancer.
Specific aim 2 will examine the regulation of a novel BAT coactivator PGC1.
Specific aim 3 examines the role of cAMP and retinoic acid response elements in mediating the response to cold exposure and fasting/feeding.