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1 Center for Integrative Metabolic and Endocrine Research, Departments of Pathology and Psychiatry, Wayne State University School of Medicine, Detroit, MI, USA
* To whom correspondence should be addressed. E-mail: jgranne{at}med.wayne.edu.
3-adrenergic receptors (AR) are nearly exclusively expressed in brown and white adipose tissues, and chronic activation of these receptors by selective agonists has profound anti-diabetes and anti-obesity effects. This study examined metabolic responses to acute and chronic 3-AR activation in wild type C57Bl/6 mice and congenic mice lacking functional UCP1, the molecular effector of brown adipose tissue (BAT) thermogenesis. Acute activation of 3-AR doubled metabolic rate in wild type mice and sharply elevated body temperature and BAT blood flow, as determined by laser Doppler flowmetry. In contrast, 3-AR activation did not increase BAT blood flow in mice lacking UCP1 (UCP1 KO). Nonetheless, 3-AR activation significantly increased metabolic rate and body temperature in UCP1 KO mice, demonstrating the presence of UCP1-independent thermogenesis. Daily treatment with the 3-AR agonist CL 316,243 (CL) for 6 days increased basal and CL-induced thermogenesis compared to naive mice. This expansion of basal and CL-induced metabolic rate did not require UCP1 expression. Chronic CL treatment of UCP1 KO mice increased basal and CL-stimulated metabolic rate of epididymal white adipose tissue (EWAT) by 4-fold, but did not alter BAT thermogenesis. Following chronic CL treatment, CL- stimulated thermogenesis of EWAT equaled that of IBAT per tissue mass. The elevation of EWAT metabolism was accompanied by mitochondrial biogenesis and the induction of genes involved in lipid oxidation. These observations indicate that chronic 3-AR activation induces metabolic adaptation in WAT that contributes to 3-AR-mediated thermogenesis. This adaptation involves lipid oxidation in situ and does not require UCP1 expression.
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