BDNF mimetic alleviates body weight gain in obese mice by enhancing mitochondrial biogenesis in skeletal muscle

• Published in: Metabolism, clinical and experimental Vol. 87; pp. 113 - 122
• Main Authors: Wood, John, Tse, Margaret Chui Ling, Yang, Xiuying, Brobst, Daniel, Liu, Zhixue, Pang, Brian Pak Shing, Chan, Wing Suen, Zaw, Aung Moe, Chow, Billy K.C., Ye, Keqiang, Lee, Chi Wai, Chan, Chi Bun
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-10-2018
• Subjects: 7,8-Dihydroxyflavone; Adipocytes - drug effects; Adipocytes - ultrastructure; Animals; Anti-Obesity Agents - pharmacology; Biomimetics; Brain-Derived Neurotrophic Factor - pharmacology; Diet, High-Fat; Energy Metabolism - drug effects; Female; Flavones - pharmacology; Glucose Tolerance Test; Insulin Resistance; Mice; Mice, Inbred C57BL; Mice, Obese; Mitochondria, Muscle - drug effects; Mitochondrial; Muscle, Skeletal - drug effects; Obesity; Obesity - drug therapy; Organelle Biogenesis; Signal Transduction - drug effects; Skeletal muscle; Weight Gain - drug effects; CRP; FFA; M-CSF; Mitochondrial; HFD; UCP1; Nrf1; 7,8-DHF; IGFBP; CREB; PDH; Tfam; TIMP1; ANGPT-L3; DMH; Cyto c; ACC; Obesity; BDNF; HGF; VEGF; IR; PKC; PLCγ; PGC-1α; IGF1; SDHA; 7,8-Dihydroxyflavone; PPARγ; Skeletal muscle; iWAT; VMH; AdipoQ; TrkB; TG; BAT; FAO; VDAC; AMPK; RER
• ISSN: 0026-0495; 1532-8600
• DOI: 10.1016/j.metabol.2018.06.007

7,8-Dihydroxyflavone (7,8-DHF) is a small molecular weight compound that mimics the functions of brain-derived neurotrophic factor (BDNF). The current study aims to elucidate the molecular mechanism of 7,8-DHF-induced body weight regulation.
Obese female C57/BL6 (20-week-old) mice that have been fed with high-fat diet for 13 weeks were treated with 7,8-DHF for 9 weeks. Various biochemical and molecular analyses were performed to examine the signal transduction pathway, metabolite content, and mitochondrial mass in the animals. Moreover, systemic energy metabolism and insulin sensitivity were determined by indirect calorimetry and insulin/glucose-tolerance tests. We have also determined the metabolic actions of 7,8-DHF on cultured myotubes.
7,8-DHF treatment increased cellular respiration by promoting mitochondrial biogenesis in cultured skeletal muscle cells. In diet-induced obese mice, subsequent 7,8-DHF consumption triggered the AMPK/CREB/PGC-1α pathways to increase the muscular mitochondrial content. Systemic energy metabolism was thus elevated, which reduced the body weight gain in obese animals. Consequently, hyperlipidemia, hyperglycemia hyperinsulinemia, and ectopic lipid accumulation in skeletal muscle and liver of the obese animals were alleviated after 7,8-DHF treatment. Moreover, insulin sensitivity of the obese muscle was improved after 7,8-DHF consumption.
7,8-DHF treatment increases muscular mitochondrial respiration and systemic energy expenditure, which alleviates the body weight gain and partially reverse the metabolic abnormalities induced by obesity.
•7,8-DHF promoted mitochondrial biogenesis in skeletal muscle cells•7,8-DHF treatment increased the mitochondrial content in obese muscle•Energy expenditure was increased in 7,8-DHF-treated obese mice.•Obese mice treated with 7,8-DHF have lower body weight gain.•The insulin sensitivity of obese mice was improved after 7,8-DHF treatment.