A mitochondrial hormone expressed by cells deep in the brain appears to play a role in improving metabolism and fighting obesity, according to a new study in mice.
A collaboration between the USC Leonard Davis School of Gerontology and researchers in South Korea has shown how moderate exercise causes cells in the hypothalamus, the small region in the brain that controls metabolism, to release a hormone called MOTS-c.
MOTS-c is a small protein that is encoded in the smaller mitochondrial genome of cells rather than the larger collection of genes in the nucleus, said Changhan David Lee, assistant professor of gerontology at USC Leonard Davis School and co-senior author of the new Study.
In recent years, it has been found that mitochondria, although commonly known as the energy-producing parts of cells, play a much larger role in health and aging by providing instructions for cellular processes. Subsequent studies by Lee and colleagues have shown how mitochondrially encoded MOTS-c interacts with the nuclear genome and regulates cell metabolism and stress responses.
Stress as a balancing act
The new study also shows how stress in the mitochondria can promote a healthy metabolism – if it’s carefully kept in balance.
Existing research has shown how low-level stress in mitochondria can promote health and longevity, a phenomenon known as mitohormesis, Lee said. While high levels of a stressor such as a toxin can do a lot of damage, a small amount of a stressor can actually strengthen healthy mitochondrial function.
“As [philosopher Friedrich] Nietzsche once said, “What doesn’t kill us makes us stronger,” observed Lee.
To study the effects of mitochondrial stress on metabolism, Lee and colleagues studied mice that were bred to be either partially or completely deficient within a particular type of brain cell, hypothalamic proopiomelanocortin (POMC) neurons. The missing gene, Crif1, controls how cells use proteins encoded by mitochondria.
The mice that were homodeficient in Crif1 – meaning they had no copies of the Crif1 gene at all – had severe mitochondrial stress and showed indicators of metabolic problems by the time they reached adulthood, including weight gain and reduced energy expenditure. In addition, the mice that were completely lacking Crif1 also had insulin resistance and high blood sugar, similar to type 2 diabetes in humans.
However, the mice that were heterodeficient in the Crif1 gene – they were able to partially express the gene but not as strongly as normal mice – experienced mild mitochondrial stress and protection from obesity or insulin resistance.
On a high-fat diet, the mice that lacked some of their Crif1 function gained less weight than normal mice that were on the same diet even though the former ate more calories. Further examination of the mice revealed that their affected neurons expressed both more MOTS-c and more beta-endorphin (β-END), a pain-suppressing molecule that is typically released during exercise.
The mice with mild mitochondrial stress in POMC neurons may have avoided obesity as the adipose tissue in their body changes. The researchers found that the heterodeficient Crif1 mice had greater thermogenesis – the ability to generate heat – and further examination of the fat cells revealed increased levels of brown fat cells.
Brown fat appears brown because there are more mitochondria than white fat. Babies who are unable to shiver to keep their bodies warm will have more of their brown fat consuming sugar and white fat to generate energy and generate heat.
Scientists are interested in the effects of “tanning” fat, or converting white fat to brown fat, to combat obesity in adults who normally only keep small pockets of brown fat.
MOTS-c treatment, exercise each offer similar benefits
In later experiments, the researchers were able to mimic these changes, including increases in brown fat and thermogenesis, in normal mice by delivering MOTS-c directly to the brain.
Significantly, the same benefits were seen in mice that were moderately moving. The results of the study suggest that the process of offsetting mild mitochondrial stress may be a major reason why exercise improves metabolism. The process appears to be mediated through MOTS-c, which supports research supporting the hormone’s metabolic involvement.
Our brain is a control center for many physiological functions. This is a new mechanism in movement physiology that may open new avenues for future therapeutic development of exercise mimetics. “
Changhan David Lee, co-senior writer and assistant professor of gerontology at the Leonard Davis School, University of Southern California
Lee and Pinchas Cohen, professor of gerontology, medicine and life sciences and dean of USC Leonard Davis School, first described MOTS-c in 2015 along with its role in restoring insulin sensitivity and combating diet-related and age-related insulin resistance. Effects often associated with exercise.
In a separate article published January 20 in Nature Communication, Lee, Cohen, and colleagues showed that MOTS-c levels increase with exercise in humans and, when administered to mice, double the running capacity of pups and adults can. These studies open up the possibility of developing drugs to provide the health benefits of exercise to frail or disabled people who cannot exercise safely.
The current study shows that the mitochondrial hormone not only acts locally in muscle tissue, but also comes from the brain’s headquarters for metabolism, Lee said.
“The question is, ‘Do mitochondria communicate with your command center after exercise or do they bypass it and speak directly to the target organs (peripheral organs)?'” Lee said of the research on the role of MOTS-c in exercise and metabolism. “We show that it can be both.”
University of Southern California