Increased lipid accumulation and insulin resistance in transgenic mice expressing DGAT2 in glycolytic (type II) muscle

Abstract

October 16, 2007; doi:10.1152/ajpendo.00158.2007.-Insulin resistance and type 2 diabetes are frequently accompanied by lipid accumulation in skeletal muscle. However, it is unknown whether primary lipid deposition in skeletal muscle is sufficient to cause insulin resistance or whether the type of muscle fiber, oxidative or glycolytic fiber, is an important determinant of lipid-mediated insulin resistance. Here we utilized transgenic mice to test the hypothesis that lipid accumulation specifically in glycolytic muscle promotes insulin resistance. Overexpression of DGAT2, which encodes an acyl-CoA:diacylglycerol acyltransferase that catalyzes triacylglycerol (TG) synthesis, in glycolytic muscle of mice increased the content of TG, ceramides, and unsaturated long-chain fatty acyl-CoAs in young adult mice. This lipid accumulation was accompanied by impaired insulin signaling and insulin-mediated glucose uptake in glycolytic muscle and impaired whole body glucose and insulin tolerance. We conclude that DGAT2-mediated lipid deposition specifically in glycolytic muscle promotes insulin resistance in this tissue and may contribute to the development of diabetes. acyl-CoA:diacylglycerol acyltransferase 2; skeletal muscle; glycolytic fibers; triacylglycerols INSULIN RESISTANCE AND TYPE 2 DIABETES are frequently associated with lipid accumulation in skeletal muscle (30,48,56). In humans, increased intramyocellular lipid content correlates with insulin resistance (45). In both rodents and humans, intravenous infusion of lipid or chronic high-fat feeding results in the accumulation of lipids, including triacylglycerol (TG), and insulin resistance in skeletal muscle (6,12,23,33). Mice with genetic modifications that increase muscle lipids, such as muscle-specific overexpression of lipoprotein lipase and CD36 (26, 31), also exhibit insulin resistance. On the other hand, endurance exercise training increases TG deposition in skeletal muscle and is associated with increased insulin sensitivity (22). Thus, the relationship between lipid accumulation in muscle and insulin resistance remains incompletely understood.One factor that has not been extensively studied with respect to intramuscular lipid deposition is fiber type. Skeletal muscle is composed mainly of two types of fibers, oxidative (type I, slow-twitch, red) and glycolytic (type II, fast-twitch, white), whose proportions can vary greatly. Marathon runners, for example, have ϳ80% type I fibers in leg muscles (21), whereas sprinters have ϳ75% type II fibers (14). It is unknown whether the type of muscle fiber is an important consideration in lipid-associated insulin resistance. Oxidative muscle normally stores more TG and is more insulin sensitive than glycolytic muscle (43,44). Moreover, endurance training increases both TG content and insulin sensitivity in oxidative muscle (22). Thus, increased lipid content in oxidative muscle may not be detrimental. On the other hand, glycolytic muscle stores less TG and is less insulin sensitive than oxidative muscle (43,44). The re...

Storing Up Trouble: Does Accumulation of Intramyocellular Triglyceride Protect Skeletal Muscle From Insulin Resistance?

“…Overexpression of DGAT2 was induced in glycolytic muscle by using the muscle creatine kinase (MCK) promoter. 80 The MCK-DGAT2 mice stored more TG in glycolytic muscle and less DAG compared with wild-type control mice. Surprisingly, MCK-DGAT2 mice accumulated ceramide and LCFACoA in glycolytic muscle and this was associated with inhibition of IRS-1/PI3-K and PKC- activity and insulinstimulated glucose disposal.…”

“…80 Skeletal muscle is composed mainly of two different fibre types: (i) oxidative (type I, slow-twitch, red); and (ii) glycolytic (white, type II, fast-twitch, white) fibres. It is unknown whether the type of muscle fibre is an important consideration in TG associated insulin resistance.…”

Fats, inflammation and insulin resistance: insights to the role of macrophage and T-cell accumulation in adipose tissue

“…Overexpression of DGAT correlates with increased TAG storage in adipose tissue, skeletal muscle and liver (62)(63)(64) . DGAT1 expression in adipocytes and adipose tissue is up-regulated by PPARg (65)(66)(67) .…”

Identification and Validation of a Selective Small Molecule Inhibitor Targeting the Diacylglycerol Acyltransferase 2 Activity

“…8) In addition, hepatic suppression of DGAT2 with antisense oligonucleotides reduced hepatic TG content, increased fatty acid oxidation, and thereby reversed diet-induced hepatic steatosis and insulin resistance in rodents. 9,10) Conversely, upregulation of DGAT2 expression induced increase of cytoplasmic TG content and lipid droplets (LDs) in rat hepatocytes 11) and adipocytes, 12) and similarly liver-directed DGAT2 overexpression caused hepatic TG accumulation 11) and promoted hepatic insulin resistance 13) in mice. Therefore, inhibition of DGAT2 enzyme, particularly by small molecule, is expected to be a feasible therapeutic strategy for hepatic steatosis and its complications, such as insulin resistance.…”