Overconsumption of fat can lead to obesity and to insulin resistance, a condition that can also develop with age and often precedes diabetes. Investigators at the University of Southern California (Los Angeles) and University of California Los Angeles recently reported that the effects of a high-fat diet could be ameliorated by treatment with a newly identified hormone encoded in an unexpected location: the mitochondria. Mitochondria are the key sources of cellular energy, so it might not seem surprising that they are involved in metabolism, the interconversion of energy and organic material. But most peptides are encoded by nuclear DNA; this molecule is only the second peptide—and the first hormone—found to be encoded by mitochondrial DNA. “This discovery sheds new light on mitochondria and positions them as active regulators of metabolism,” said Changhan Lee, who led the study together with Pinchas Cohen, in a press release.

The mitochondrial hormone, referred to as MOTS-c, regulates insulin sensitivity and metabolic homeostasis. Lee and Cohen first investigated how MOTS-c affects metabolism in cell cultures and found that it stimulated glucose utilization. Next they evaluated whole-body metabolism in adult mice. Treatment with MOTS-c for 4 days resulted in modest reductions in body weight, food intake, blood glucose levels and biomarkers of obesity and insulin resistance in the mice. Glucose tolerance testing confirmed that treatment with MOTS-c for 7 days improved insulin sensitivity. Furthermore, MOTS-c administration for 7 days reversed age-dependent insulin resistance in treated mice.

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Finally, the investigators examined the effects of MOTS-c on diet-induced obesity and insulin resistance in mice. Mice were fed a high-fat diet in which 60% of total calories came from fat. Administration of MOTS-c for 8 weeks averted obesity in these mice without reducing total caloric intake and also prevented hyperinsulinemia, suggesting that it improved glucose homeostasis. Treatment with MOTS-c for 3 weeks also increased body heat production in the mice. Overall, MOTS-c prevented obesity by increasing energy expenditure and improving glucose utilization and insulin sensitivity in mice fed a high-fat diet (Cell Metab. 21, 443–454; 2015).

On the basis of these results, the research team suggests that MOTS-c or its derivatives might be useful in addressing the abnormal metabolism associated with aging in humans. As Cohen stated, “This represents a major advance in the identification of new treatments for age-related diseases such as diabetes.”