Skeletal muscle AMP-activated protein kinase phosphorylation parallels metabolic phenotype in leptin transgenic mice under dietary modification

Tomohiro Tanaka, Shuji Hidaka, Hiroaki Masuzaki, Shintaro Yasue, Yasuhiko Minokoshi, Ken Ebihara, Hideki Chusho, Yoshihiro Ogawa, Taro Toyoda, Kenji Sato, Fumiko Miyanaga, Muneya Fujimoto, Tsutomu Tomita, Toru Kusakabe, Nozomi Kobayashi, Hideki Tanioka, Tatsuya Hayashi, Kiminori Hosoda, Hironobu Yoshimatsu, Toshiie SakataKazuwa Nakao

Research output: Contribution to journalArticlepeer-review

53 Citations (Scopus)

Abstract

Leptin augments glucose and lipid metabolism independent of its effect on satiety. Administration of leptin in rodents increases skeletal muscle β-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.

Original languageEnglish
Pages (from-to)2365-2374
Number of pages10
JournalDiabetes
Volume54
Issue number8
DOIs
Publication statusPublished - Aug 2005
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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