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 journalArticle

52 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 1 2005

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Diet Therapy
AMP-Activated Protein Kinases
Leptin
Transgenic Mice
Acetyl-CoA Carboxylase
Skeletal Muscle
Phosphorylation
Phenotype
Insulin Resistance
High Fat Diet
Triglycerides
Diet
Adenosine Monophosphate
Hyperlipidemias
Lipid Metabolism
Weight Loss
Rodentia
Obesity
Adenosine Triphosphate
Body Weight

All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Skeletal muscle AMP-activated protein kinase phosphorylation parallels metabolic phenotype in leptin transgenic mice under dietary modification. / Tanaka, Tomohiro; Hidaka, Shuji; Masuzaki, Hiroaki; Yasue, Shintaro; Minokoshi, Yasuhiko; Ebihara, Ken; Chusho, Hideki; Ogawa, Yoshihiro; Toyoda, Taro; Sato, Kenji; Miyanaga, Fumiko; Fujimoto, Muneya; Tomita, Tsutomu; Kusakabe, Toru; Kobayashi, Nozomi; Tanioka, Hideki; Hayashi, Tatsuya; Hosoda, Kiminori; Yoshimatsu, Hironobu; Sakata, Toshiie; Nakao, Kazuwa.

In: Diabetes, Vol. 54, No. 8, 01.08.2005, p. 2365-2374.

Research output: Contribution to journalArticle

Tanaka, T, Hidaka, S, Masuzaki, H, Yasue, S, Minokoshi, Y, Ebihara, K, Chusho, H, Ogawa, Y, Toyoda, T, Sato, K, Miyanaga, F, Fujimoto, M, Tomita, T, Kusakabe, T, Kobayashi, N, Tanioka, H, Hayashi, T, Hosoda, K, Yoshimatsu, H, Sakata, T & Nakao, K 2005, 'Skeletal muscle AMP-activated protein kinase phosphorylation parallels metabolic phenotype in leptin transgenic mice under dietary modification', Diabetes, vol. 54, no. 8, pp. 2365-2374. https://doi.org/10.2337/diabetes.54.8.2365
Tanaka, Tomohiro ; Hidaka, Shuji ; Masuzaki, Hiroaki ; Yasue, Shintaro ; Minokoshi, Yasuhiko ; Ebihara, Ken ; Chusho, Hideki ; Ogawa, Yoshihiro ; Toyoda, Taro ; Sato, Kenji ; Miyanaga, Fumiko ; Fujimoto, Muneya ; Tomita, Tsutomu ; Kusakabe, Toru ; Kobayashi, Nozomi ; Tanioka, Hideki ; Hayashi, Tatsuya ; Hosoda, Kiminori ; Yoshimatsu, Hironobu ; Sakata, Toshiie ; Nakao, Kazuwa. / Skeletal muscle AMP-activated protein kinase phosphorylation parallels metabolic phenotype in leptin transgenic mice under dietary modification. In: Diabetes. 2005 ; Vol. 54, No. 8. pp. 2365-2374.
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AU - Tanaka, Tomohiro

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AU - Masuzaki, Hiroaki

AU - Yasue, Shintaro

AU - Minokoshi, Yasuhiko

AU - Ebihara, Ken

AU - Chusho, Hideki

AU - Ogawa, Yoshihiro

AU - Toyoda, Taro

AU - Sato, Kenji

AU - Miyanaga, Fumiko

AU - Fujimoto, Muneya

AU - Tomita, Tsutomu

AU - Kusakabe, Toru

AU - Kobayashi, Nozomi

AU - Tanioka, Hideki

AU - Hayashi, Tatsuya

AU - Hosoda, Kiminori

AU - Yoshimatsu, Hironobu

AU - Sakata, Toshiie

AU - Nakao, Kazuwa

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N2 - 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.

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