Dr Chan’s team developed a special obesified mouse model by removing the gene of brain-derived neurotrophic factor (BDNF) exclusively in their skeletal muscle.
BDNF is 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, but its physiological significance is unknown.
Dr Chan’s team found that obesity reduced the amount of BDNF in the skeletal muscle of mice.
They also observed that the mice without BDNF in their muscle, called ‘MBKO’, gained more body weight and developed severer insulin resistance when the animals were fed with a high-fat diet. MBKO mice have less energy expenditure than their control cohort.
The research team also demonstrated that the mitochondria in the muscle of MBKO mice were unable to recycle, leading to the accumulation of damaged mitochondria in the tissues.
The lipid metabolism in the muscle of MBKO mice was retarded, causing more lipid accumulation to interfere with insulin sensitivity.
“Clearly, muscle-derived BDNF is a weight-control protein by increasing the energy expenditure and maintaining insulin sensitivity,” said Dr Chan.
“BDNF has long been considered a brain-localized 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,” Dr Chan further added.
Dr Chan’s team also used cultured cell models to know the molecular mechanism for the defective mitochondrial turnover in BDNF-deficient muscle cells.
They found that muscle-secreted BDNF used AMPK-activated protein kinase, the well-known energy sensor in cells, to trigger the Parkin/PINK1 pathway for inducing mitophagy in skeletal muscle.
The research team further tested if restoring the BDNF signaling in muscle would rescue the obesity-induced mitochondrial damage.
They fed the obese mice with 7,8-dihydroxyflavone, a natural bioavailable BDNF mimetic in plants used in the clinical trials of Alzheimer’s disease, and found that obesity-induced mitochondrial dysfunction was alleviated.
Together with their previous findings that 7,8-DHF is an effective agent in reducing body weight and improving the insulin sensitivity in obese mice, Dr Chan’s work provides a new explanation on the pernicious nature of obesity and suggests that BDNF-signaling enhancer such as 7,8-DHF is a potential drug for obesity treatment in human beings.
Source: Medindia
