Skeletal Muscle Triacylglycerol Hydrolysis Does Not Influence Metabolic Complications of Obesity

Abstract

Intramyocellular triacylglycerol (IMTG) accumulation is highly associated with insulin resistance and metabolic complications of obesity (lipotoxicity), whereas comparable IMTG accumulation in endurance-trained athletes is associated with insulin sensitivity (the athlete’s paradox). Despite these findings, it remains unclear whether changes in IMTG accumulation and metabolism per se influence muscle-specific and systemic metabolic homeostasis and insulin responsiveness. By mediating the rate-limiting step in triacylglycerol hydrolysis, adipose triglyceride lipase (ATGL) has been proposed to influence the storage/production of deleterious as well as essential lipid metabolites. However, the physiological relevance of ATGL-mediated triacylglycerol hydrolysis in skeletal muscle remains unknown. To determine the contribution of IMTG hydrolysis to tissue-specific and systemic metabolic phenotypes in the context of obesity, we generated mice with targeted deletion or transgenic overexpression of ATGL exclusively in skeletal muscle. Despite dramatic changes in IMTG content on both chow and high-fat diets, modulation of ATGL-mediated IMTG hydrolysis did not significantly influence systemic energy, lipid, or glucose homeostasis, nor did it influence insulin responsiveness or mitochondrial function. These data argue against a role for altered IMTG accumulation and lipolysis in muscle insulin resistance and metabolic complications of obesity.

Coupling of lipolysis and de novo lipogenesis in brown, beige, and white adipose tissues during chronic β3-adrenergic receptor activation

“…C57Bl/6 (BL6) mice at 7 weeks of age were obtained from the Jackson Laboratory and were fed a standard chow diet (LabDiet, Cat# 5L0D). Mice carrying a LoxP-modifi ed Atgl allele (B6N.129S-Pnpla2 tm1Eek mice; herein designated as Atgl -fl ox mice) on a BL6 background were created as described ( 22 www.jlr.org Downloaded from * P < 0.05; &&& P < 0.001, && P < 0.01, & P < 0.05; ### P < 0.001, ## P < 0.01, # P < 0.05; $$ P < 0.01, $ P < 0.05; ns, nonsignifi cant).…”

“…Experiments were performed on littermate CreER T2 -negative and CreER T2 -positive mice 10 days after the last treatment of tamoxifen. Mice were genotyped for the fl oxed allele as described ( 22 ). The presence of the Cre-ER T2 transgene was determined by PCR using forward primer 5 ′ -TGAAA-CAGGGGCAATGGTGCG-3 ′ and reverse primer 5 ′ -CGGAATA-GAGTATGGGGGGCTCAG-3 ′ .…”

Adipose triglyceride lipase deletion from adipocytes, but not skeletal myocytes, impairs acute exercise performance in mice

“…tm1eek (Atgl-flox) mice were generated as described (54). ATGL-flox mice were crossed to either MyoCre (40) or AdipoqCre (18) mice to generate skeletal myocyte-specific (SMAKO) (54) or adipocyte-specific (AAKO) ATGL knockout mice.…”

“…These data implicate either adipose tissue and/or skeletal muscle ATGL action in exercise performance. Previously, we reported that skeletal muscle-specific targeted deletion or overexpression of ATGL dramatically alters IMTG content but is not sufficient to alter metabolic phenotypes at baseline or in response to nutritional stress (i.e., diet-induced obesity) (54). Whether alterations in ATGL action in skeletal myocytes vs. adipocytes influence acute exercise performance remains unknown.…”

“…Adipose triglyceride lipase (ATGL) is the rate-limiting enzyme mediating TAG hydrolysis (69) and a major contributor to lipolysis in both adipose tissue (19,62,66) and skeletal muscle (54). Indeed, humans (20,53) and mice (24) with ATGL deficiency exhibit dramatic accumulation of IMTGs in cardiac and skeletal muscle despite markedly reduced adipocyte lipolysis and serum lipids, indicating a critical role for ATGL action in muscle.…”