Factor Regulating Fat Metabolism In Muscle Discovered

When it comes to regulating glucose levels in the body, skeletal muscle plays a key role. With obesity, Type 2 diabetes and other metabolic diseases exploding in the US, understanding how this works might be a game-changer. Now a key factor in fat metabolism has been identified.

We’ve known for quite some time that skeletal muscle was the key to regulating glucose levels in the blood and fat metabolism. People with more skeletal muscle burn more calories at rest and seem to have a better ability to manage blood glucose levels. But how does that work? What factor or factors are responsible for fat metabolism in skeletal muscle?

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University Hospitals (UH) Cleveland Medical Center and Case Western Reserve University School of Medicine have found that skeletal muscle has profound effects on how the body stores and metabolizes fat, and have identified the key factor in those processes. Their findings were published in The Journal of Clinical Investigation.

A team led by Mukesh K Jain, MD, the Ellery Sedgwick, Jr. Chair & Distinguished Scientist and Chief Academic Officer at UH, looked into the role played by a gene called Kruppel-like factor 15, or KLF15, in skeletal muscle. To do this, they used a mouse model in which the KLF15 was specifically deleted from skeletal muscle.

When this genetic manipulation was done, something remarkable happened to the previously healthy mice. They developed a phenotype that included insulin resistance, glucose intolerance, obesity, dyslipidemia (abnormally high levels of fat circulating in the blood) and the propensity to develop NAFLD, or non-fatty fatty liver disease.

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They also found that, without the KLF15, fat couldn’t efficiently enter the skeletal muscle and was instead deposited in the white adipose tissue and in the liver. KLF15 controls the uptake and utilization of fat in skeletal muscle, according to the findings.

“We knew from prior work by our team that the role of KLF15 was critical for muscle health, because levels are increased in humans following exercise,” explained Dr. Jain, who is also a Professor of Medicine and Vice Dean of University Hospitals Affairs at Case Western Reserve, and Chief Scientific Officer, Harrington Discovery Institute at UH. “Experimentally, muscle loss of KLF15 led to a reduction in exercise capacity in mice. The fact that KLF15 is also important in metabolic health is really exciting as it provides a potential molecular link between exercise and overall health.”

Their research also revealed that aspects of metabolic disease can be improved by eating a diet rich in short-chain fatty acids (SCFAs.) The mice were given a diet which included high-fiber foods like vegetables, fruits, whole grains and beans (all high in SCFAs.) Weight gain decreased and blood glucose regulation improved.

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When obese mice were fed a similar diet, they lost weight and improved their insulin sensitivity. This is a strong indication that SCFA-rich diets may well be both therapeutic and preventive for metabolic disease, say the researchers.

“This predisposition to develop obesity and NAFLD both in the presence of caloric excess underscores the importance of skeletal muscle fat metabolism and organ cross-talk in the development of these serious diseases,” said Liyan Fan, first author on the study. “This helps us understand the different players that contribute to metabolic disease, and consequently, identify targets for effective therapies.”

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While more research is needed to look at the potential for therapeutics targeting muscle KLF15 and to assess how muscle KLF15 works in different nutritional states, such as fasting and during exercise, several important takeaways are evident. First, skeletal muscle has been identified as a key regulator of fat metabolism and liver health. Second, a diet rich in SCFAs may be an effective supplemental therapy option for those with metabolic disease stemming from impaired fat metabolism. That therapy is also readily accessible, since it can largely be found on the shelves at your local grocery.

Keep the faith and keep after it!

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Journal Reference – Liyan Fan, David R. Sweet, Domenick A. Prosdocimo, Vinesh Vinayachandran, Ernest R. Chan, Rongli Zhang, Olga Ilkayeva, Yuan Lu, Komal S. Keerthy, Chloe E. Booth, Christopher B. Newgard, Mukesh K. Jain. Muscle Krüppel-like factor 15 regulates lipid flux and systemic metabolic homeostasis. Journal of Clinical Investigation, 2021; 131 (4) DOI: 10.1172/JCI139496

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