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Skeletal Muscle AMP-Activated Protein Kinase Phosphorylation Parallels Metabolic Phenotype in Leptin Transgenic Mice Under Dietary Modification

¹ Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan
² Department of Internal Medicine, School of Medicine, Oita University, Oita, Japan
³ Department of Developmental Physiology, National Institute for Physiological Sciences, Okazaki, Japan
⁴ Department of Molecular Medicine and Metabolism, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
⁵ Division of Food Science and Biotechnology, Kyoto University Graduate School of Agriculture, Kyoto, Japan
⁶ Department of Food Sciences and Nutritional Health, Kyoto Prefectural University, Kyoto, Japan
⁷ Department of Human Coexistence, Kyoto University Graduate School of Human and Environmental Studies, Kyoto, Japan

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

Abbreviations: ACC, acetyl CoA carboxylase; AMPK, AMP-activated protein kinase; DIO, diet-induced obesity; EDL, extensor digitorum longus; FFA, free fatty acid; GTT, glucose tolerance test; HFD, high-fat diet; ITT, insulin tolerance test; SCD-1, stearoyl CoA desaturase-1; UCP-1, uncoupling protein-1

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