New thesis on the role of skeletal muscle in the regulation of whole-body energy metabolism

Milena Schönke from the research group Integrative Physiology will defend her thesis "Regulation of whole-body glucose and lipid metabolism by skeletal muscle" on March 9, 2018. Her main supervisor is Professor Juleen R. Zierath.

What's the main focus of your thesis?

My thesis focuses on the role of skeletal muscle in the regulation of whole-body energy metabolism. Skeletal muscle is an important organ in glucose and lipid metabolism. Its regulatory function can be improved by exercise but also impaired by obesity, insulin resistance and type 2 diabetes. In relation to these metabolic disturbances we investigated the role of several enzymes involved in skeletal muscle energy metabolism and assessed the changes of the skeletal muscle proteome in obesity.

Which are the most important results?

We found that the loss of DGKe, an enzyme sitting at an intersection of lipid metabolism and signaling, promotes the accumulation of diacylglycerol in skeletal muscle. Although this is usually associated with insulin resistance, mice lacking DGKe cleared glucose from the blood more efficiently than wildtype mice. This indicates that reduced DGKe expression, for example found in obesity, is not associated with metabolic impairment.

We furthermore found that the chronic activation of the gamma1 subunit of the main energy sensor in the cell, AMP-activated protein kinase (AMPK), in skeletal muscle improves whole-body glucose metabolism and reduces fat mass specifically in female mice. With a newly adapted in vivo technique we were able to assess that the activation of AMPKgamma3, on the other hand, did not alter whole-body lipid oxidation. However, mice fed a high-fat diet showed elevated lipid oxidation rates. With an optimized proteomics approach we characterized the alterations of skeletal muscle from morbidly obese mice compared to lean mice. Obesity is associated with an upregulation of mitochondrial and peroxisomal proteins that constitute the machinery required for lipid oxidation. Together, these findings underline the importance of skeletal muscle energy metabolism for the whole body and further unravel alterations connected to common metabolic diseases like obesity and diabetes.

How can this new knowledge contribute to the improvement of people's health?

Improving our understanding of the function and regulation of key enzymes in the regulation of metabolic processes aids the development of targeted drugs. With 1.6 billion overweight adults in the world the need for better therapeutic approaches is eminent. The findings presented in my thesis further support the notion that skeletal muscle-specific activation of AMPK is beneficial and the field of specific AMPK activators is constantly developing. The deep proteome of insulin resistant skeletal muscle is now publicly available and serves as a valuable resource for the identification of new therapeutic targets in the battle against metabolic diseases.

What are your future ambitions?

I would like to further investigate the crosstalk between skeletal muscle and other metabolically active tissues like the liver or adipose tissue. Especially with regard to exercise and circadian rhythms, alterations in physiology associated with the rhythm of day and night, we are a long way from understanding the processes that modulate energy metabolism and affect our health.

Dissertation

Friday March 9, 2018 at 13:00, Hillarpsalen, Retzius väg 8, Karolinska Institutet, Solna

Thesis

Regulation of whole-body glucose and lipid metabolism by skeletal muscle