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Learning New Tricks from Old Dogs: ß-Adrenergic Receptors Teach New Lessons on Firing Up Adipose Tissue Metabolism

CIIT Centers for Health Research, Research Triangle Park, North Carolina 27709

Address all correspondence and requests for reprints to: Sheila Collins, Ph.D., CIIT Centers for Health Research, Six Davis Drive, Research Triangle Park, North Carolina 27709. E-mail: scollins{at}ciit.org.

The three ßAR (ß-adrenergic receptor) subtypes (ß₁AR, ß₂AR, and ß₃AR) are members of the large family of G protein-coupled receptors, each of which is coupled to Gs and increases in intracellular cAMP levels. In white adipose tissues, catecholamine activation of the ßARs leads to the mobilization of stored fatty acids and regulates release of several adipokines, whereas in brown adipose tissue they stimulate the specialized process of adaptive nonshivering thermogenesis. Noteworthy, in most models of obesity the ßAR system is dysfunctional, and its ability to stimulate lipolysis and thermogenesis are both impaired. Nevertheless, selective agonists for the ß₃AR, a subtype that is found predominantly in adipocytes, have been able to prevent or reverse obesity and accompanying insulin resistance in animal models. Whether this is a viable therapeutic option for human obesity is much debated with regard to the existence of brown adipocytes in humans or their ability to be recruited. Nevertheless, probing the physiological changes in adrenoceptor function in rodent obesity, as well as the process by which ß₃AR agonists promote a thermogenic shift in fuel use, have yielded unexpected new insights into ßAR signaling and adipocyte physiology. These include the recent discovery of an essential role of p38 MAPK in mediating adaptive thermogenesis, as well as the accessory role of the ERK MAPK pathway for the control of lipolysis. Because these metabolic events were traditionally ascribed solely to the cAMP/protein kinase A system, the integration of these signaling mechanisms may pose new therapeutic directions in the quest to counter the obesity epidemic in our midst.

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