Acting Locally

The limited success of life-style modifications like diet and exercise in controlling weight is apparent in the ever-expanding epidemic of obesity. An alternative approach might be to manipulate metabolic rate. For instance, thyroid hormone increases basal metabolism and stimulates weight loss; however, excess thyroid hormone can lead to dangerous systemic effects, such as atrial fibrillation and bone loss (see Baxter and Webb). Watanabe et al . found that supplementing a high-fat diet (HF) with the bile acid cholic acid (CA) limited weight gain in C57BL/6J mice. Indeed, obese mice fed HF supplemented with CA lost weight and adipose mass. Mice fed HF supplemented with CA showed increased oxygen consumption and CO 2 production relative to mice fed chow or HF without CA, indicating increased energy expenditure. Expression of the gene that encodes the adenosine 3′,5′-monophosphate (cAMP)-dependent thyroid hormone activating enzyme type 2 iodothyronine deiodinase (D2, which converts thyroxine into the more active triiodothyronine) was increased in brown adipose tissue (BAT) of mice fed HF supplemented with CA, and HF supplemented with CA failed to prevent weight gain in mice lacking D2. D2 mRNA was coexpressed in BAT with the mRNA for TGR5, a G protein-coupled receptor stimulated by bile acids, and bile acids activated a gene reporter sensitive to cAMP signaling in CHO (Chinese hamster ovary) cells transfected with TGR5. Bile acids increased cAMP concentration, D2 mRNA abundance, and D2 activity in isolated brown adipocytes. Although humans have little BAT, bile acids increased cAMP concentration, D2 activity, and oxygen consumption in human skeletal muscle myoblasts (which express TGR5 and D2 ). Thus, bile acids appear to selectively stimulate conversion of thyroxine into triiodothyronine in thermogenic tissues (and thereby increase metabolic rate) through a TGR5-cAMP-mediated pathway. Baxter and Webb note that bile acids may have toxic side effects but that an increased understanding of this pathway could lead to therapeutic interventions against obesity. M. Watanabe, S. M. Houten, C. Mataki, M. A. Christoffolete, B. W. Kim, H. Sato, N. Messaddeq, J. W. Harney, O. Ezaki, T. Kodama, K. Schoonjans, A. C. Bianco, J. Auwerx, Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature 439 , 484-489 (2006). [PubMed] J. D. Baxter, P. Webb, Bile acids heat things up. Nature 439 , 402-403 (2006). [PubMed]