Induction of glucose uptake in skeletal muscle by central leptin is mediated by muscle \u03b22-adrenergic receptor but not by AMPK

Tetsuya Shiuchi,Shinji Miura,Chitoku Toda,Osamu Ezaki,Yasuhiko Minokoshi,Kumiko Saito,Shiki Okamoto,Eulalia A Coutinho

doi:10.1038/s41598-017-15548-6

Abstract

Leptin increases glucose uptake and fatty acid oxidation (FAO) in red-type skeletal muscle. However, the mechanism remains unknown. We have investigated the role of β2-adrenergic receptor (AR), the major β-AR isoform in skeletal muscle, and AMPK in leptin-induced muscle glucose uptake of mice. Leptin injection into the ventromedial hypothalamus (VMH) increased 2-deoxy-D-glucose (2DG) uptake in red-type skeletal muscle in wild-type (WT) mice accompanied with increased phosphorylation of the insulin receptor (IR) and Akt as well as of norepinephrine (NE) turnover in the muscle. Leptin-induced 2DG uptake was not observed in β-AR-deficient (β-less) mice despite that AMPK phosphorylation was increased in the muscle. Forced expression of β2-AR in the unilateral hind limb of β-less mice restored leptin-induced glucose uptake and enhancement of insulin signalling in red-type skeletal muscle. Leptin increased 2DG uptake and enhanced insulin signalling in red-type skeletal muscle of mice expressing a dominant negative form of AMPK (DN-AMPK) in skeletal muscle. Thus, leptin increases glucose uptake and enhances insulin signalling in red-type skeletal muscle via activation of sympathetic nerves and β2-AR in muscle and in a manner independent of muscle AMPK.

Highlights

Leptin inhibits food intake and increases energy expenditure in animals[1,2]
We recently showed that activation of steroidogenic factor 1 (SF1) neurons in the ventromedial hypothalamus (VMH) by DREADD (Designer Receptors Exclusively Activated by Designer Drug) technology increases insulin sensitivity in red-type of skeletal muscle, heart and BAT, but not WAT15
We examined the effects of leptin injection into the VMH on glucose uptake in peripheral tissues of β-less and WT mice

Summary

Introduction

Leptin inhibits food intake and increases energy expenditure in animals[1,2]. It increases glucose utilization and fatty acid oxidation (FAO) in certain peripheral tissues including skeletal muscle, without affecting plasma glucose and insulin levels, in rodents[3,4,5,6,7,8]. We and other previously showed that peripheral injection of leptin or leptin injection into the ventromedial hypothalamus (VMH) of rodents increases glucose uptake and insulin sensitivity in red-type skeletal muscle such as the soleus as well as in heart muscle and BAT (brown adipose tissue), Internal Medicine (Endocrinology, Diabetes and Metabolism, Hematology, Rheumatology), Graduate School of Medicine, University of the Ryukyus, Okinawa, 903-0215, Japan. Activation of SF1 neurons by DREADD as well as peripheral or VMH injection of leptin increased Rd (glucose disappearance rate) and glucose uptake in red-type skeletal muscles, heart and BAT. This effect was accompanied by an increase in Ra (glucose appearance rate) and activation of hepatic phosphorylase a activity, thereby maintaining blood glucose level. Previous studies revealed that β-AR agonist increases glucose uptake in skeletal muscle[17,18], but others showed that catecholamines inhibits or has no effect on glucose uptake in skeletal muscle[19,20]

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Conclusion