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Mitochondrial DNA (mtDNA) produces a "short open reading frame" or sOR, and may contain others. This particular sORF encodes a signaling peptide named MOTS-c. When given to mice, MOTS-c prevented age-dependent and high-fat-diet-induced insulin resistance — suggesting mitochondria may regulate metabolic stability in the cell. Image Credit: Cell Metabolism

New hormone mimics the effects of exercise

A new human hormone, MOTS-c, has just been identified that protects against obesity and diabetes. The research was done in mice, but the chemistry exists in all mammals. MOTS-c was found in mitochondrial DNA while other hormones are produced in the DNA nucleus. It primarily targets muscle tissue, where it surprisingly restores insulin sensitivity.

Scientists at the USC Leonard Davis School of Gerontology have discovered a new hormone that fights weight gain caused by a high-fat Western diet, and results in a normalized metabolism - commonly found only with exercise.

Hormones are molecules that act in the body as signals to trigger various physiologic responses. The newly discovered hormone, MOTS-c, primarily targets muscle tissue where it restores insulin sensitivity, counteracting diet-induced and age-dependent insulin resistance.

"This represents a major advance in the identification of new treatments for age-related diseases such as diabetes," said Pinchas Cohen, dean of the USC Davis school and senior author of a study on the research, which will appear in Cell Metabolism on March 3.

Until this discovery, the main function of mitochondria was seen as the production of adenosine triphosphate (ATP), a cell's energy source.

To test the effects of MOTS-c, the team injected the hormone into mice fed a high-fat diet, which typically causes them to grow obese and develop a resistance to insulin. However, the injections not only suppressed both effects in mice, they also reversed age-dependent insulin-resistance, a condition that precedes diabetes.

"This discovery sheds new light on mitochondria and positions them as active regulators of metabolism," said Changhan Lee, assistant professor at USC Davis and lead author of the study.

MOTS-c is unique among hormones as it is encoded in the DNA of mitochondria — the "powerhouses" of cells where food calories are converted into energy. Other hormones are encoded in DNA in the cell nucleus.

Lee and Cohen collaborated with scientists from the USC school as well as the David Geffen School of Medicine at UCLA and the National Institutes of Health. While all of the experiments on MOTS-c so far have been performed on lab mice, the molecular mechanisms that make it function in mice exist in all mammals, including humans.

The MOTS-c intellectual property has been licensed to a biotechnology company, and clinical trials in humans could begin within the next three years, added Pinchas Cohen, dean of the USC Davis school and senior author.

Abstract
MOTS-c, a mitochondrially encoded open reading frame-derived peptide recently discovered by Lee et al. 2015 (this issue of Cell Metabolism) promotes biosynthesis of an endogenous AMP analog, AICAR. As AICAR activates AMPK, the discovery of MOTS-c offers an unexpected therapeutic option to be exploited toward the prevention of type 2 diabetes and delaying of the aging processes.

This research was funded by National Institutes of Health (grants 1R01AG 034430 EUREKA Award, 1R01GM 090311 Transformative RO1, 1R01ES 020812), a Glenn Award, an Ellison Medical Foundation New Scholar Award, and a SC-CTSI grant.

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