title: Adipose triglyceride lipase deletion from adipocytes, but not skeletal myocytes, impairs acute exercise performance in mice.
abstract: Adipose triglyceride lipase (ATGL) is the rate-limiting enzyme mediating triacylglycerol hydrolysis in virtually all cells, including adipocytes and skeletal myocytes, and hence, plays a critical role in mobilizing fatty acids. Global ATGL deficiency promotes skeletal myopathy and exercise intolerance in mice and humans, and yet the tissue-specific contributions to these phenotypes remain unknown. The goal of this study was to determine the relative contribution of ATGL-mediated triacylglycerol hydrolysis in adipocytes vs. skeletal myocytes to acute exercise performance. To achieve this goal, we generated murine models with adipocyte- and skeletal myocyte-specific targeted deletion of ATGL. We then subjected untrained mice to acute peak and submaximal exercise interventions and assessed exercise performance and energy substrate metabolism. Impaired ATGL-mediated lipolysis within adipocytes reduced peak and submaximal exercise performance, reduced peripheral energy substrate availability, shifted energy substrate preference toward carbohydrate oxidation, and decreased HSL Ser(660) phosphorylation and mitochondrial respiration within skeletal muscle. In contrast, impaired ATGL-mediated lipolysis within skeletal myocytes was not sufficient to reduce peak and submaximal exercise performance or peripheral energy substrate availability and instead tended to enhance metabolic flexibility during peak exercise. Furthermore, the expanded intramyocellular triacylglycerol pool in these mice was reduced following exercise in association with preserved HSL phosphorylation, suggesting that HSL may compensate for impaired ATGL action in skeletal muscle during exercise. These data suggest that adipocyte rather than skeletal myocyte ATGL-mediated lipolysis plays a greater role during acute exercise in part because of compensatory mechanisms that maintain lipolysis in muscle, but not adipose tissue, when ATGL is absent.
authors.affiliation: Division of Endocrinology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; and.
authors.forename: John J
authors.initials: JJ
authors.lastname: Dubé
authors.affiliation: Division of Endocrinology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; and.
authors.forename: Mitch T
authors.initials: MT
authors.lastname: Sitnick
authors.affiliation: Division of Endocrinology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; and.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Schoiswohl
authors.affiliation: Division of Endocrinology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; and.
authors.forename: Rachel C
authors.initials: RC
authors.lastname: Wills
authors.affiliation: Division of Endocrinology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; and.
authors.forename: Mahesh K
authors.initials: MK
authors.lastname: Basantani
authors.affiliation: Division of Endocrinology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; and.
authors.forename: Lingzhi
authors.initials: L
authors.lastname: Cai
authors.affiliation: Department of Biochemistry and Molecular Biology, Dalhousie Medicine New Brunswick, Dalhousie University, Saint John, New Brunswick, Canada.
authors.forename: Thomas
authors.initials: T
authors.lastname: Pulinilkunnil
authors.affiliation: Division of Endocrinology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; and kershawe@pitt.edu.
authors.forename: Erin E
authors.initials: EE
authors.lastname: Kershaw
mesh_terms: D017667:Adipocytes / Q000378:metabolism*; D000818:Animals; D054874:Athletic Performance; D017079:Exercise Tolerance / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D008049:Lipase / Q000235:genetics* / Q000378:metabolism; D008066:Lipolysis / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018485:Muscle Fibers, Skeletal / Q000378:metabolism*; D010805:Physical Conditioning, Animal / Q000502:physiology*; D005082:Physical Exertion / Q000235:genetics*; D000217:Acyltransferases
chemical_list: D008049:Lipase; C494445:PNPLA2 protein, mouse; D000217:Acyltransferases
keywords: adipose triglyceride lipase; exercise; lipolysis