Mitofusion-2-mediated alleviation of insulin resistance in rats through reduction in lipid intermediate accumulation in skeletal muscle

Xuemei Zhang,Kexin Gan,Qian Nie,Dexian Kong,Luping Ren,Chao Wang,Guangyao Song

doi:10.1186/1423-0127-20-45

Xuemei Zhang, Kexin Gan + Show 5 more

Open Access

https://doi.org/10.1186/1423-0127-20-45

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Abstract

BackgroundIncreased lipid accumulation and mitochondrial dysfunction within skeletal muscle have been shown to be strongly associated with insulin resistance. However, the role of mitofusion-2 (MFN2), a key factor in mitochondrial function and energy metabolism, in skeletal muscle lipid intermediate accumulation remains to be elucidated.ResultsA high-fat diet resulted in insulin resistance as well as accumulation of cytosolic lipid intermediates and down-regulation of MFN2 and CPT1 in skeletal muscle in rats, while MFN2 overexpression improved insulin sensitivity and reduced lipid intermediates in muscle, possibly by upregulation of CPT1 expression.ConclusionsMFN2 overexpression can rescue insulin resistance, possibly by upregulating CPT1 expression leading to reduction in the accumulation of lipid intermediates in skeletal muscle. These observations contribute to the investigations of new diabetes therapies.

Highlights

Increased lipid accumulation and mitochondrial dysfunction within skeletal muscle have been shown to be strongly associated with insulin resistance
Important studies have appeared in recent years to reinforce the view that it is active lipid intermediates such as long-chain fatty acid CoAs (LCCoAs), diacylglycerols (DAG) and ceramides (CEA) that result in lipid-induced muscle insulin resistance [3,4]
Evaluation of insulin sensitivity in high-fat diet treated rats Fasting plasma glucose levels, serum insulin levels and glucose infusion rates (GIR) in rats are presented as Figure 1

Summary

Introduction

Increased lipid accumulation and mitochondrial dysfunction within skeletal muscle have been shown to be strongly associated with insulin resistance. Increased adiposity and lipid accumulation within the skeletal muscle and mitochondrial dysfunction have been shown to be strongly associated with insulin resistance [2]. Important studies have appeared in recent years to reinforce the view that it is active lipid intermediates such as long-chain fatty acid CoAs (LCCoAs), diacylglycerols (DAG) and ceramides (CEA) that result in lipid-induced muscle insulin resistance [3,4]. Skeletal muscle is quantitatively the major contributor to whole body insulin-mediated glucose disposal. Fat accumulation in muscle negatively impacts insulin-mediated glucose uptake. The hypothesis that insulin resistance is related to lipid accumulation in muscle dates back to studies reported 15–20 years ago showing that triglycerides accumulate in muscle in rats fed a high-fat diet, which is

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