title: Dihydromyricetin prevents obesity-induced slow-twitch-fiber reduction partially via FLCN/FNIP1/AMPK pathway.
abstract: Obesity is often accompanied by decreases in the proportion of skeletal muscle slow-twitch fibers and insulin sensitivity. Increased plasma non-esterified fatty acids (NEFA) levels are responsible for obesity-associated insulin resistance. Palmitate, one of the most elevated plasma NEFA in obesity, has been recognized as the principle inducer of insulin resistance. The present study showed that increased plasma NEFA levels were negatively linked to slow-twitch fiber proportion and insulin sensitivity, while slow-twitch fiber proportion was positively correlated to insulin sensitivity in high fat diet (HFD)-fed and ob/ob mice. Dihydromyricetin (DHM) intervention increased slow-twitch fiber proportion and improved insulin resistance. In cultured C2C12 myotubes, palmitate treatment resulted in decrease of slow-twitch fiber specific Myh7 expression and insulin resistance, concomitant with folliculin (FLCN) and folliculin-interacting protein 1 (FNIP1) expression increase, AMP-activated protein kinase (AMPK) inactivation and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) expression decrease. Those palmitate-induced effects could be blocked by knock-down of FLCN expression or DHM intervention. Meanwhile, the protective effects of DHM were alleviated by over-expression of FLCN. In addition, the changes in AMPK activity and expression of FLCN and FNIP1 in vivo were consistent with those occurring in vitro. These findings suggest that DHM treatment prevents palmitate-induced slow-twitch fibers decrease partially via FLCN-FNIP1-AMPK pathway thereby improving insulin resistance in obesity.
authors.affiliation: Research Center for Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing Key Laboratory of Nutrition and Food Safety, Chongqing Medical Nutrition Research Center, Chongqing 400038, PR China.
authors.forename: Qicheng
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: Research Center for Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing Key Laboratory of Nutrition and Food Safety, Chongqing Medical Nutrition Research Center, Chongqing 400038, PR China.
authors.forename: Yeyun
authors.initials: Y
authors.lastname: Gu
authors.affiliation: Research Center for Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing Key Laboratory of Nutrition and Food Safety, Chongqing Medical Nutrition Research Center, Chongqing 400038, PR China.
authors.forename: Hedong
authors.initials: H
authors.lastname: Lang
authors.affiliation: Research Center for Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing Key Laboratory of Nutrition and Food Safety, Chongqing Medical Nutrition Research Center, Chongqing 400038, PR China.
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Wang
authors.affiliation: Research Center for Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing Key Laboratory of Nutrition and Food Safety, Chongqing Medical Nutrition Research Center, Chongqing 400038, PR China.
authors.forename: Ka
authors.initials: K
authors.lastname: Chen
authors.affiliation: Research Center for Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing Key Laboratory of Nutrition and Food Safety, Chongqing Medical Nutrition Research Center, Chongqing 400038, PR China.
authors.forename: Xinhua
authors.initials: X
authors.lastname: Gong
authors.affiliation: Research Center for Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing Key Laboratory of Nutrition and Food Safety, Chongqing Medical Nutrition Research Center, Chongqing 400038, PR China.
authors.forename: Min
authors.initials: M
authors.lastname: Zhou
authors.affiliation: Research Center for Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing Key Laboratory of Nutrition and Food Safety, Chongqing Medical Nutrition Research Center, Chongqing 400038, PR China.
authors.forename: Li
authors.initials: L
authors.lastname: Ran
authors.affiliation: Research Center for Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing Key Laboratory of Nutrition and Food Safety, Chongqing Medical Nutrition Research Center, Chongqing 400038, PR China. Electronic address: zjdnfs@126.com.
authors.forename: Jundong
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Research Center for Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing Key Laboratory of Nutrition and Food Safety, Chongqing Medical Nutrition Research Center, Chongqing 400038, PR China. Electronic address: mi_mt2009@hotmail.com.
authors.forename: Mantian
authors.initials: M
authors.lastname: Mi
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D002352:Carrier Proteins / Q000096:biosynthesis*; D004041:Dietary Fats / Q000009:adverse effects / Q000494:pharmacology; D044948:Flavonols / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D018657:Muscle Fibers, Slow-Twitch / Q000378:metabolism* / Q000473:pathology; D009765:Obesity; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis*; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis*
chemical_list: C526060:Bhd protein, mouse; D002352:Carrier Proteins; D004041:Dietary Fats; C581709:FNIP1 protein, mouse; D044948:Flavonols; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; D055372:AMP-Activated Protein Kinases; C472036:dihydromyricetin
keywords: AMPK; Dihydromyricetin; FLCN; FNIP1; Slow fibers