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Research on How Obesity Damages the Skeletal Muscle Metabolism Reveals New Potential Drug for Treatment

Feeding obese mice with the natural bioavailable BDNF mimetic, 7,8-dihydroxyflavone, successfully alleviated obesity-induced mitochondrial dysfunction.

Obesity is a major risk factor for various chronic disorders including but not limited to cancer, diabetes, heart disease, osteoarthritis, and stroke. In recent years, the prevalence of overweight and obesity amongst children, adolescents, and adults has increased dramatically. According to the World Health Organization, around 1.9 billion adults worldwide were reported to be overweight in 2016, of which 650 million were obese. The number of overweight and obese children and teens has also risen from just 4 per cent in 1975 to just over 18 per cent in 2016.

Of their numerous consequences, scientists have found that obese patients tend to suffer from a decline in fat metabolism and endurance of skeletal muscle. While it is believed that this may be a consequence of abnormal functions in the mitochondria, the underlying pathways by which obesity impairs mitochondrial activity and the skeletal muscle have remained elusive.

Now, a team of scientists, led by Dr. Chi Bun Chan at the University of Hong Kong, has proposed a new mechanism to explain how obesity compromises the functions of skeletal muscle and identified a novel treatment strategy to overcome obesity.

In their study, Dr. Chan and colleagues engineered an obesified mouse model by depleting the gene expression of brain-derived neurotrophic factor (BDNF) exclusively in their skeletal muscle. Although BDNF was first identified as an important growth factor for maintaining the activity and survival of neurons, further research has shown that BDNF may also be a muscle-secreted protein, albeit its physiological significance is unknown.

By studying the obesified model, it was discovered for the first time that obesity reduced the amount of BDNF in the skeletal muscle of mice. Furthermore, when fed with a high-fat diet, mice without BDNF in their muscle, called the Muscle-specific BDNF Knockout (MBKO) mice, gained more body weight and developed a more severe insulin resistance compared to the unaltered mice. The MBKO group also displayed less energy expenditure.

Through a series of biochemical, histological, metabolomic, and molecular analyses, the researchers found that mitochondria in the muscle of MBKO mice could not be recycled and so led to the accumulation of damaged mitochondria in the tissues. This retarded lipid metabolism in the muscle of MBKO mice, which further aggravated the accumulation of lipids and interfered with insulin sensitivity.

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

Besides animal studies, the researchers also used cultured cell models to determine how defective mitochondria in BDNF-deficient muscle cells are replaced. Their results showed that muscle-secreted BDNF uses AMPK-activated protein kinase, a well-known energy sensor in cells, to trigger the Parkin/PINK1 pathway, which induces mitophagy in the skeletal muscle.

With the aim of extending their findings to therapeutic applications, the scientists were determined to test whether restoring BDNF signalling in muscles could rescue obesity-induced mitochondrial damage. Therefore, they fed the obese mice with a natural bioavailable BDNF mimetic, known as 7,8-dihydroxyflavone, derived from the leaves of Godmania aesculifolia, a plant species in South America. It was discovered that 7,8-dihydroxyflavone successfully alleviated obesity-induced mitochondrial dysfunction.

Combined with their previous findings that showed how 7,8-dihydroxyflavone is an effective agent to reduce body weight and improve insulin resistance in obese mice, their studies have successfully rationalised the emergence of obesity-related consequences and identified a prospective therapeutic strategy for obesity.

“BDNF has long been considered a brain-localised peptide, and its importance in peripheral tissues has been underestimated. Our study provides a new insight to this area, and hopefully, we can unlock more functions of this myokine using our MBKO mice,” said Dr. Chan. [APBN]

Source: Ahuja et al. (2021). Muscle-generated BDNF (brain derived neurotrophic factor) maintains mitochondrial quality control in female mice. Autophagy.