Non-shivering thermogenesis is a physiological process carried out by brown adipose tissue (BAT). In mammals the enhanced production of heat is thought to be important during cold stress and as a homeostatic mechanism to burn off excess calories rather than convert them to lipid deposits. In the obese and diabetic mutants of the mouse it has been demonstrated that the ability of BAT to thermoregulate is defective. It has also been postulated that a similar defect in BAT thermoregulation exists among obese human beings. In order to carry out their heat generating function, upon receiving a signal from the hypothalamus through catecholamine-acting sympathetic neurons during an energy stress, the BAT cells respond within minutes to produce heat by uncoupling respiration from oxidative phosphorylation. This uncoupling step requires a protein, located in the inner mitochondrial membrane, called the uncoupling protein (UCP). Recently the cDNA for UCP mRNA has been cloned and used to map the Ucp gene to Chromosome 8 of the mouse and to demonstrate that UCP mRNA is highly induced within hours of cold stress. Experiments are now proposed to investigate the molecular genetics of thermoregulation in BAT in mice by analyzing the cold-induced expression of two genes, Gdc-1, the structural gene for glycerol-3-phosphate dehydrogenase, an enzyme important in lipid metabolism, and Ucp, the gene for the mitochondrial uncoupling.
The specific aims of this proposal are: (1) To determine the molecular genetic mechanisms controlling Gdc-1 expression in BAT; (2) to clone the Ucp gene and characterize regulatory sequences which promote expression during cold induction; (3) to quantify the parameters of mRNA transcription from the Gdc-1 and Ucp genes during cold and dietary stress and development; and (4) to investigate the genetics of the thermogenic response. Hence by comparing the mechanisms by which two cold-inducible gemes are regulated, it is expected that fundamental insights into the control of thermogenesis will be obtained.
|Anunciado-Koza, Rea P; Zhang, Jingying; Ukropec, Jozef et al. (2011) Inactivation of the mitochondrial carrier SLC25A25 (ATP-Mg2+/Pi transporter) reduces physical endurance and metabolic efficiency in mice. J Biol Chem 286:11659-71|
|Kozak, Leslie P (2010) Brown fat and the myth of diet-induced thermogenesis. Cell Metab 11:263-7|
|Anunciado-Koza, Rea; Ukropec, Jozef; Koza, Robert A et al. (2008) Inactivation of UCP1 and the glycerol phosphate cycle synergistically increases energy expenditure to resist diet-induced obesity. J Biol Chem 283:27688-97|
|Kozak, L P; Anunciado-Koza, R (2008) UCP1: its involvement and utility in obesity. Int J Obes (Lond) 32 Suppl 7:S32-8|
|Ukropec, Jozef; Anunciado, Rea P; Ravussin, Yann et al. (2006) UCP1-independent thermogenesis in white adipose tissue of cold-acclimated Ucp1-/- mice. J Biol Chem 281:31894-908|
|Ukropec, Jozef; Anunciado, Rea V P; Ravussin, Yann et al. (2006) Leptin is required for uncoupling protein-1-independent thermogenesis during cold stress. Endocrinology 147:2468-80|
|Guerra, C; Koza, R A; Walsh, K et al. (1998) Abnormal nonshivering thermogenesis in mice with inherited defects of fatty acid oxidation. J Clin Invest 102:1724-31|