title: Skeletal muscle AMP-activated protein kinase phosphorylation parallels metabolic phenotype in leptin transgenic mice under dietary modification.
abstract: Leptin augments glucose and lipid metabolism independent of its effect on satiety. Administration of leptin in rodents increases skeletal muscle beta-oxidation by activating AMP-activated protein kinase (AMPK). We previously reported that, as hyperleptinemic as obese human subjects, transgenic skinny mice overexpressing leptin in liver (LepTg) exhibit enhanced insulin sensitivity and lipid clearance. To assess skeletal muscle AMPK activity in leptin-sensitive and -insensitive states, we examined phosphorylation of AMPK and its target, acetyl CoA carboxylase (ACC), in muscles from LepTg under dietary modification. Here we show that phosphorylation of AMPK and ACC are chronically augmented in LepTg soleus muscle, with a concomitant increase in the AMP-to-ATP ratio and a significant decrease in tissue triglyceride content. Despite preexisting hyperleptinemia, high-fat diet (HFD)-fed LepTg develop obesity, insulin-resistance, and hyperlipidemia. In parallel, elevated soleus AMPK and ACC phosphorylation in regular diet-fed LepTg is attenuated, and tissue triglyceride content is increased in those given HFD. Of note, substitution of HFD with regular diet causes a robust recovery of soleus AMPK and ACC phosphorylation in LepTg, with a higher rate of body weight reduction and a regain of insulin sensitivity. In conclusion, soleus AMPK and ACC phosphorylation in LepTg changes in parallel with its insulin sensitivity under dietary modification, suggesting a close association between skeletal muscle AMPK activity and sensitivity to leptin.
authors.affiliation: Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Tanaka
authors.forename: Shuji
authors.initials: S
authors.lastname: Hidaka
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Masuzaki
authors.forename: Shintaro
authors.initials: S
authors.lastname: Yasue
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Minokoshi
authors.forename: Ken
authors.initials: K
authors.lastname: Ebihara
authors.forename: Hideki
authors.initials: H
authors.lastname: Chusho
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Ogawa
authors.forename: Taro
authors.initials: T
authors.lastname: Toyoda
authors.forename: Kenji
authors.initials: K
authors.lastname: Sato
authors.forename: Fumiko
authors.initials: F
authors.lastname: Miyanaga
authors.forename: Muneya
authors.initials: M
authors.lastname: Fujimoto
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Tomita
authors.forename: Toru
authors.initials: T
authors.lastname: Kusakabe
authors.forename: Nozomi
authors.initials: N
authors.lastname: Kobayashi
authors.forename: Hideki
authors.initials: H
authors.lastname: Tanioka
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Hayashi
authors.forename: Kiminori
authors.initials: K
authors.lastname: Hosoda
authors.forename: Hironobu
authors.initials: H
authors.lastname: Yoshimatsu
authors.forename: Toshiie
authors.initials: T
authors.lastname: Sakata
authors.forename: Kazuwa
authors.initials: K
authors.lastname: Nakao
mesh_terms: D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000249:Adenosine Monophosphate / Q000032:analysis; D000255:Adenosine Triphosphate / Q000032:analysis; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics; D004032:Diet; D004041:Dietary Fats / Q000008:administration & dosage; D018149:Glucose Intolerance / Q000235:genetics; D006949:Hyperlipidemias / Q000235:genetics; D007333:Insulin Resistance / Q000235:genetics; D007473:Ion Channels; D020738:Leptin / Q000235:genetics*; D008099:Liver / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D024101:Mitochondrial Proteins; D009097:Multienzyme Complexes / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000737:chemistry / Q000201:enzymology*; D009765:Obesity / Q000235:genetics; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D013230:Stearoyl-CoA Desaturase / Q000235:genetics; D014280:Triglycerides / Q000032:analysis; D000071256:Uncoupling Protein 1; D015431:Weight Loss
chemical_list: D002352:Carrier Proteins; D004041:Dietary Fats; D007473:Ion Channels; D020738:Leptin; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D009097:Multienzyme Complexes; D012333:RNA, Messenger; D014280:Triglycerides; D000071256:Uncoupling Protein 1; D000249:Adenosine Monophosphate; D000255:Adenosine Triphosphate; C490333:Scd1 protein, mouse; D013230:Stearoyl-CoA Desaturase; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase