Muscle

The long-term benefits of exercise for the muscular system are relatively well understood. Inmice,activemuscles turnonaprogramofgeneexpressiondrivenbythe transcription factor PGC1-a, which boosts production of mitochondria and encourages the formation of new blood vessels, increasing the muscle’s ability to respond to increasedworkload.However, exercise alsopromotes ahost of other changesacross the whole body that aremore difficult to explain. In fact, simply increasing expression of PGC1-a in mouse muscle is sufficient to induce many of these changes, including enhanced resistance to bothdiabetes and age-related obesity and extended lifespan. How is it that the musculature can exert such a powerful global influence onmetabolism? Boström et al. (2012) now identify a new hormone that is released by muscle under conditions of regular exercise. The hormone, which they named irisin after the Greekmessengergoddess Iris, actson subcutaneous fat deposits to stimulate energy consumption. It does this by causing white fat cells to take on characteristics of thermogenic brown fat. Brown adipose tissue expends energy by metabolizing lipid and glucose to generate heat rather than ATP. This presents a paradox: what is the benefit of wasting energy to generate heat in conditions inwhichATPdemanddue to exercise is increased? It is possible that themechanismoriginally evolvedas a response to the cold; muscle activity from shivering would trigger additional heat production from the adipose tissues. The effect of irisin on energy consumption may, however, have an unexpected payoff for modern humans. ‘‘Browning’’ of white adipose tissue by genetic manipulation of the differentiation program has previously been shown to improve glucose homeostasis, so the authors tested whether injecting mice with a viral vector carrying the irisin gene would have a similar effect. Remarkably, even though thesemice display relatively modest increases in circulating irisin levels, the treatment significantly improves glucose tolerance in mice fed a high-fat diet. Their results raise hopes that the hormone may provide therapeutic benefits for the treatment of type II diabetes and obesity in humans and could be particularly valuable for patients who are otherwise unable to exercise. It remains to be discovered how irisin signals to its target cells, but identification of the irisin receptor may be the next step toward identifying other target tissues for this exciting new hormone. Boström, P., et al. (2012). Nature 481, 463–468.