The secret life of fat suggests new therapeutic targets.

Not so many years ago, most considered fat a passive recipient of our indulgence. But since the discovery of leptin in 1994,1 it has become ever clearer that fat is more than a storage site for excess calories. Rather, fat plays an active, communicative role in metabolism that research is beginning to uncover. Two recent studies not only represent our rapidly changing grasp of the biology of fat but also suggest potential treatments for one of the world’s most intractable chronic health conditions: obesity. A paper in Nature2 in January 2012 from the laboratory of Bruce Spiegelman, PhD, of the Dana-Farber Cancer Institute in Boston, MA, reported the discovery of a new hormone released by muscle that converts white fat deposits into thermogenic brown fat. Whereas white fat acts as a repository for excess, mitochondria-rich brown fat cells burn ordinary fat as energy to produce heat. Once thought to only exist in rodents and infants, several groups have confirmed brown fat in humans. It is found in small patches along the spine, in the upper back, on the sides of the neck, and between the collarbone and shoulder. A few weeks after Spiegelman’s Nature paper was published, a publication3 in the Journal of Clinical Investigation from the laboratory of Shelia Collins, PhD, of the Sanford-Burnham Medical Research Institute in Orlando, FL, revealed the heart plays a role in the regulation of fat burning. Collins, first author Marica Bordicchia, and colleagues reported that cardiac natriuretic peptides increased browning of white fat, elevating uncoupling protein 1 (UCP1)–dependent energy expenditure. C. Ronald Kahn, MD, chief academic officer at the Joslin Diabetes Center in Boston, MA, says the recent discoveries are likely just the opening act in our growing knowledge about fat metabolism. “Right now we’re looking at the first things that have been discovered. They’re already very interesting,” Kahn said. “There will be more factors discovered for sure, because, once you realize there is this metabolic flexibility to this tissue, then it begins to challenge you to think, ‘I wonder what will change the metabolic potential of this tissue?’” During the last 10 years, Spiegelman’s laboratory and others demonstrated that the transcription factor that regulates mitochondrial biogenesis, peroxisome proliferator activated receptorcoactivator 1(PGC1), mediated most of the effects of endurance exercise on muscle.4 “It is induced by exercise, and, in turn, when it’s elevated in muscle, it gives muscle many of the benefits of exercise: mitochondrial biogenesis, fiber-type switching, increased angiogenesis, resistance to atrophy and dystrophy,” Spiegelman said. “So it wasn’t that big a stretch to ask, ‘Does PGC1in muscle secrete something that may affect health and function of other tissues?’” In the new study, Spiegelman, first author Pontus Bostrm̈, and colleagues found that PGC1increases expression of the membrane protein FNDC5. FNDC5 is cleaved and secreted as a previously unidentified hormone that browns white fat, turning it into energy-burning multilocular cells, rich in mitochondria and high in expression of UCP1. The researchers called the newly discovered hormone irisin (pronounced eye-risin), after Iris, the Greek messenger goddess. Certain white fat cells respond sharply to irisin, which is 100% conserved from mice to humans. Cells treated with uncleaved FNDC5 had dose-dependent increases of UCP1 mRNA from 7to 500-fold. Cells treated with bone morphogenic protein 7 (BMP7), known to induce browning of white fat, gave rise to only a 2-fold increase in UCP1 expression. Obese, insulin-resistant mice treated with an adenoviral vector expressing FNDC5 had slightly reduced body weight after 10 days compared with controls. In addition, glucose tolerance improved significantly in FNDC5 mice fed a high-fat diet. Although circulating irisin never rose above a 3-fold increase, similar to the irisin uptick generated by exercise, UCP1 expression rose 10to 20-fold. Subcutaneous white fat browned and increased its energy use. Finally, when The opinions expressed in News & Views are not necessarily those of the editors or of the American Heart Association. *News & Views are edited by Aruni Bhatnagar & Ali J. Marian. (Circ Res. 2012;110:1049-1051.) © 2012 American Heart Association, Inc.