The messenger goddess of exercise

The switch from white fat to brown fat has attracted increased scientific and clinical attention, because while white fat is involved in energy storage and is increased in obesity, the much more metabolically active brown fat dissipates body energy as heat and is associated with weight loss⁵. Thus, like LDL and HDL, which have opposing effects on cardiovascular health, there's good fat and bad fat. In the midst of the scientific fervor to learn what can drive white fat to become brown fat, this team led by Dr. Bruce Spiegelman at Harvard discovered irisin (after the Greek messenger goddess Iris), a protein that endows skeletal muscle cells with the ability to instruct white fat stores to become more brown-fat-like.

This finding all began with an investigation of transgenic mice that over-expressed PGC1-α specifically in their muscle tissue⁶. PGC1-α allows the transcription of genes whose protein products regulate cellular mitochondrial number, respiration, and energy balance. Interestingly, the expression of PGC1-α in skeletal muscle is induced by exercise, therefore explaining the increased calorie consumption in muscle cells during physical activity. However, compared with normal mice, mice over-expressing muscle PGC1-α additionally exhibited resistance to age-related obesity and an increase in lifespan⁵. These broad extra-muscular effects indicated that elevated PGC1-α may have systemic effects extending beyond the local muscle cell environment. Indeed, the authors found that in the superficial layers of the groin of the transgenic mice, just under the skin, white fat expressed higher levels of Ucp1⁴, a gene encoding a mitochondrial protein responsible for heat generation in brown fat. Such an observation immediately sparked a search for a protein induced by muscle PGC1-α that could signal white fat to change into brown fat. The search yielded several candidates⁴, among them FNDC5, a gene whose expression is also high in skeletal muscle cells from mice and humans subjected to endurance exercise regimens. Furthermore, the product of this gene is a cell membrane protein that is cleaved into a shorter peptide enriched in the blood serum of mice and humans after exercise.

To show that this secreted peptide (irisin) can cause white fat cells to change into brown fat, the authors differentiated white fat cells in the presence of FNDC5. The data showed a dose-dependent increase of Ucp1 expression accompanied by increased expression of other brown fat markers and mitochondrial number⁴. In addition, there was a boost in oxygen consumption in the FNDC5-treated cells, showing a functional increase in cellular metabolism⁴. All these cellular changes are consistent with brown fat development, and provided evidence that at least on a dish, FNDC5 can somehow reprogram white fat cells into cells that display brown fat characteristics.

However, the most exciting part of the study came when the authors investigated whether increased levels of irisin could have any effects on mice rendered obese and insulin-resistant by a high-fat diet, thereby testing the hypothesis of whether irisin could have therapeutic effects on mice suffering from pathologies of high fat content. Consistently, they observed a reduction in the body weight and improved glucose tolerance in these mice, with no detectable signs of toxicity. Although such changes were relatively modest (~11% weight reduction), they resulted from only a 3-4 fold increase in plasma irisin levels (normal plasma concentration in mice is 40nM)⁴. A higher plasma level is expected to translate into more pronounced physiological benefits.

Could irisin be a novel agent in the fight against obesity and obesity-linked disease? Clinically, such findings point to a potential therapy in which irisin could be administered by injection to induce brown-fat formation from excess white fat. Because irisin is a secreted protein fragment, as is insulin, its production and administration would be technically feasible. But before such clinical applications can be considered, much more needs to be known about irisin and its mode of action. Though FNDC5 is expressed in skeletal muscle, we do not know the distribution of its expression in other tissues, and whether its processing and secretion are muscle-specific. In addition, the irisin receptor remains to be identified. Given the high evolutionary conservation of irisin (Its sequence is identical in humans and mice, which means its functional importance allowed it to remain intact through selection and speciation), the receptor is likely to be conserved as well. Is the receptor expressed only in white fat or in other cells also? If the latter is the case, then how do other non-fat cell types respond to irisin signaling? Does irisin have signaling roles besides brown fat induction? All these questions and many more are ripe for investigation following this study. Regardless of how irisin pans out therapeutically, its discovery has provided an important missing link between exercise and long-term metabolic changes. While irisin may not be the only mediator between skeletal muscle and white fat, it certainly has potent effects on the intricate energy balance in systemic metabolism.

Image credit: Wikimedia Commons and author

1. Myers, J. (2003). Exercise and cardiovascular health. Circulation, 107, 1-4.
2. Sigal, R. J. et al. (2006). Physical activity/exercise and type 2 diabetes. Diabetes Care, 29(6), 1433-1438.
3. Speakman, J. R., & Selman, C. (2003). Physical activity and resting metabolic rate. Proc Nutr Soc., 62(3), 621-34.
4. Bostrom, P. et al. (2012). A pgc1-a-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature, 481, 463-469.
5. Spiegelman, B. M., & Flier, J. S. (2001). Obesity and the regulation of energy balance. Cell, 104, 531-543.
6. Wenz, T. et al. (2009). Increased muscle pgc-1a expression protects from sarcopenia and metabolic disease during aging. Proc. Natl Acad. Sci. USA, 106, 20405-20410.