Could New Hormone Compete With the Treadmill?

Although it might not make people buff, a newly identified hormone may trigger some of the benefits of exercise, according to a study published in Nature online on January 11. A research team lead by Bruce Spiegelman and first author Pontus Boström at the Dana-Farber Cancer Institute in Boston found that when people exercise for sustained periods, their muscles release a hormone, which they called irisin, into the blood. “It is interesting that people would produce a hormone in response to exercise,” said Suzanne De La Monte at Brown University in Providence, Rhode Island, who was not involved in the study. When the researchers gave irisin to mice, it increased the conversion of white adipose tissue to the more energy-efficient brown version, and improved glucose tolerance in mice fed a high-fat diet.

Although the study only focused on the effects of irisin on fat, the hormone may have therapeutic application for a host of ailments, said Spiegelman. “We are very interested in the potential effects on other conditions that respond to exercise,” he explained. “We would like to know whether people with those conditions, who are not able to exercise, could benefit from irisin.” Others caution that these are still early days in this research. “When leptin was first discovered, we thought that it would cure obesity, but it turned out that obese people already produce a lot of leptin,” said De La Monte. “We don’t yet know the relevance of irisin production in humans.”

The road to the irisin discovery started in 2009 when Spiegelman and collaborators published that transgenic mice expressing the transcription factor PGC-1α in muscle cells were resistant to age-related obesity and diabetes (Wenz et al., 2009). PGC-1α activates peroxisome proliferator-activated receptor γ (PPARγ), a well-studied mediator of glucose metabolism. A number of drugs targeting PPARγ are being tested for the treatment of diabetes as well as for Alzheimer’s disease, but without much success (see ARF related news story and ARF news story).

In this study, Boström, Spiegelman, and colleagues found that, over a three-week period, normal mice that spent time on the running wheel or doing repeated bouts of swimming converted more subcutaneous white adipose tissue to brown adipose tissue than did controls. Unlike white adipose tissue, which stores extra calories as fat, brown adipose tissue burns it off. Researchers have long been looking for ways to boost the conversion of white-to-brown fat cells as a therapeutic treatment for obesity and related disorders. Boström, found that the same white-to-brown fat conversion occurred in transgenic mice expressing high levels of PGC-1α in their muscles, without the need for exercise. This suggested that muscle PGC-1α, which is naturally triggered by exercise, might be sending some kind of signal to fat cells to change.

The researchers looked for muscle genes induced by PGC-1α. They found several, but the product of only one, FNDC5, triggered the conversion of white adipocytes to brown when applied to cells in culture. Further biochemical analysis revealed that after FNDC5 is produced in muscle cells, a fragment of the protein is cleaved off and released into the blood. Spiegelman called this polypeptide irisin after Iris, the Greek messenger goddess. After mice spent three weeks running on a wheel, their irisin blood levels increased by 65 percent. To see if the mouse data have any human relevance, Boström, tested volunteers doing endurance training. After 10 weeks, they also showed increased blood irisin.

Boström and Spiegelman suspected that it might be irisin that sends the “exercise message” from muscle to other tissues in the body. To test this, they injected an adenovirus vector carrying full-length FNDC5 into normal mice. Plasma levels of irisin increased three- to fourfold in these animals, similar to the increase seen in mice after exercise. Ten days later, the mice had more brown adipose tissue and a very slight decrease in weight. When the adenovirus was given to mice fed a high-fat diet, irisin caused a significant improvement in glucose tolerance, and fasting insulin was reduced. On the other hand, when normal mice were injected with anti-FNDC5 antibodies before they swam, the normally observed effects of exercise on adipose tissue were toned down.

Although brown fat is supposed to use up more energy than white fat, increasing irisin production only had a modest effect on the weight of the mice. But giving the hormone for more than 10 days could have a more profound effect, said Spiegelman. (Ten days was about as long as the irisin expression from the adenovirus lasted.) “We have now made a more stable form of the hormone that we can give directly to mice to look at chronic administration,” he added. Such results will be critical to evaluating the potential for irisin as a therapy.

The current study did not examine cognition, and it is not known whether irisin even enters the brain, but if it does, it might help explain some of the beneficial effects of exercise on cognition and dementia (see ARF related news story; ARF news story; ARF news story). But, said Spiegelman, “We are very interested in that aspect.” This possibility intrigued Suzanne Craft of the University of Washington School of Medicine, Seattle. “There is good evidence that exercise has very potent effects on the brain from many perspectives; this may be one of those mechanisms,” she told ARF. One of Spiegelman’s earlier studies reported that mice deficient in PGC-1α exhibit many of the symptoms of Huntington’s disease, suggesting that the transcription factor might play a role in the nervous system (see ARF related news story on Lin et al., 2004). A more recent study revealed that activating PGC-1α could slow the course of Parkinson’s disease (see ARF related news story on Zheng et al., 2010).—Laura Bonetta

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References

News Citations

  1. Outlook for PPARγ Agonists Not So Rosi
  2. Trial Updates: B Vitamin Back in Vogue? Diabetes Drug Less Sweet
  3. Exercise and the Brain: More Support for Protective Effects
  4. DC: Ways to Slow Brain Aging: Exercise, Estrogen, and Sleep?
  5. Work Up a Sweat to Stay Sharp, Randomized Trial Suggests
  6. PPARγ Partner PGC-1α Linked to Huntington Disease-Like Symptoms
  7. Gene Captain, PGC-1α, Abandons Mitochondria in PD

Paper Citations

  1. Wenz T, Rossi SG, Rotundo RL, Spiegelman BM, Moraes CT. Increased muscle PGC-1alpha expression protects from sarcopenia and metabolic disease during aging. Proc Natl Acad Sci U S A. 2009 Dec 1;106(48):20405-10. PubMed.
  2. Lin J, Wu PH, Tarr PT, Lindenberg KS, St-Pierre J, Zhang CY, Mootha VK, Jäger S, Vianna CR, Reznick RM, Cui L, Manieri M, Donovan MX, Wu Z, Cooper MP, Fan MC, Rohas LM, Zavacki AM, Cinti S, Shulman GI, Lowell BB, Krainc D, Spiegelman BM. Defects in adaptive energy metabolism with CNS-linked hyperactivity in PGC-1alpha null mice. Cell. 2004 Oct 1;119(1):121-35. PubMed.
  3. Zheng B, Liao Z, Locascio JJ, Lesniak KA, Roderick SS, Watt ML, Eklund AC, Zhang-James Y, Kim PD, Hauser MA, Grünblatt E, Moran LB, Mandel SA, Riederer P, Miller RM, Federoff HJ, Wüllner U, Papapetropoulos S, Youdim MB, Cantuti-Castelvetri I, Young AB, Vance JM, Davis RL, Hedreen JC, Adler CH, Beach TG, Graeber MB, Middleton FA, Rochet JC, Scherzer CR, . PGC-1α, a potential therapeutic target for early intervention in Parkinson's disease. Sci Transl Med. 2010 Oct 6;2(52):52ra73. PubMed.

Further Reading

Primary Papers

  1. Boström P, Wu J, Jedrychowski MP, Korde A, Ye L, Lo JC, Rasbach KA, Boström EA, Choi JH, Long JZ, Kajimura S, Zingaretti MC, Vind BF, Tu H, Cinti S, Højlund K, Gygi SP, Spiegelman BM. A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature. 2012 Jan 11; PubMed.

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