Pok Fu Lam: As for obese patients, it has been noticed that they have lower skeletal muscle metabolism and endurance. A research team led by Dr. Chi Bun Chan, assistant professor in the School of Biological Sciences, Faculty of Science, University of Hong Kong, explained how obesity compromises skeletal muscle functions and provided a potential treatment for the disease. The study was published in the ‘Autophagy Journal’.

Obesity is a metabolic disorder that is increasing in prevalence in modern society. Since the 1970s, the global number of obese people has tripled and reached 650 million (~ 13% of the total world population) in 2016. It is well known that obesity causes adverse effects in several human organs and causes many chronic disorders such as diabetes, hypertension, fatty liver and atherosclerosis. Fat metabolism in the skeletal muscle of obese patients is slower than that of healthy people, which scientists say is a consequence of the abnormal functions of mitochondria (the powerhouses of a cell that convert nutrients into biological energy). However, how obesity impairs the activity of mitochondria is a long unresolved question.

To study the functional impacts of obesity on skeletal muscle, Dr. Chan’s team developed a special obesified mouse model by deleting the brain-derived neurotrophic factor (BDNF) gene exclusively in their skeletal muscle. BDNF was originally identified as an important growth factor for maintaining the survival and activities of neurons. Recent studies have proposed that BDNF is also a muscle secreted protein (i.e. myokine), but its physiological significance is unknown.

For the first time, Dr. Chan’s team found that obesity reduced the amount of BDNF in the skeletal muscle of mice. They also observed that mice without BDNF in their muscles, called “MBKO” (Muscle-specific BDNF Knockout), gained more body weight and developed more severe insulin resistance when the animals were fed a diet rich in protein. fats. In addition, the research team found that the MBKO mice had lower energy expenditure than their control cohort.

Using several biochemical, histological, metabolomic and molecular analyzes, the research team further demonstrated that the muscle mitochondria of MBKO mice were unable to recycle, resulting in the accumulation of damaged mitochondria in the tissues. Therefore, lipid metabolism in muscle of MBKO mice was delayed, causing increased accumulation of lipids to interfere with insulin sensitivity.

“Obviously, muscle-derived BDNF is a weight control protein by increasing energy expenditure and maintaining insulin sensitivity,” said Dr. Chan.

“BDNF has long been considered a localized peptide in the brain, and its importance in peripheral tissues has been underestimated. Our study provides new insight into this area, and we hope to be able to unlock more functions of this myokine by using our MBKO mice, ”Dr. Chan added.

In addition to animal studies, Dr. Chan’s team also used cultured cell models to identify the molecular mechanism of faulty mitochondrial turnover in BDNF-deficient muscle cells. They found that muscle-secreted BDNF uses protein kinase activated by AMPK, the well-known energy scavenger in cells, to trigger the Parkin / PINK1 pathway to induce mitophagy (a highly regulated mechanism to recycle cells. materials in cells in response to various challenges) in skeletal muscle.

To extend these results to therapeutic applications, the research team also tested whether the restoration of BDNF signaling in muscle would save the mitochondrial damage induced by obesity. They fed the obese mice with 7,8-dihydroxyflavone, a natural mimetic of bioavailable BDNF in plants (found in the leaves of Godmania aesculifolia, a plant species from South America) currently used in clinical trials of the Alzheimer’s disease, and found that obesity- induced mitochondrial dysfunction was alleviated.

With their previous findings that 7,8-DHF is an effective agent for reducing body weight and improving insulin sensitivity in obese mice (Chem Biol 2015 22: 355-369; Metabolism 2018 87: 113-122 ), Dr. Chan’s work provided a new explanation for the pernicious nature of obesity and suggested that the BDNF signaling activator such as 7,8-DHF is a potential drug for the treatment of obesity in human beings.

This work was supported by the Hong Kong Research Grant Council, the Health and Medical Research Fund, and the HKU Seed Fund for Basic Research.