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 Ser660 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.
Taxonomy: 2015
Insulin Signaling in Cardiac Health and Disease. Bartlett J, Trivedi P, Pulinilkunnil T. Chapter 12. In: Endocrinology of the Heart in Health and Disease. Jonathan Cummings Schisler, Charles Lang, Monte Willis (Eds.). Elsevier Press Publishers, 317-347.
Endocrinology of the Heart in Health and Disease: Integrated, Cellular, and Molecular Endocrinology of the Heart covers the traditional concepts of cardio-endocrinology, the role of the various hormone systems, both in health and disease, therapeutic implications, and other recent advances in the various fields represented.
The book explores how cardiac hormones are changed in various cardiac pathologies and the recent success that has been uncovered in their therapeutic use. Additional focus is placed on how the heart responds both physiologically and pathophysiologically to a plethora of circulating hormones, reinforcing the importance of the heart as a target of numerous endocrine systems, such as the brain, renal, and adipose. Significant advances have come from basic, clinical, and translational research from a multiplicity of investigators with diverse backgrounds.
Myocardial metabolic abnormalities and cardiac dysfunction. Kienesberger PC. Pathophysiology and Pharmacotherapy of Cardiovascular Disease. Springer, Part II, Chapter 17, p. 325-341.
To sustain contractile function, the myocardium has a very high and continuous demand for ATP, which it generates from a variety of carbon sources, including fatty acids, glucose, ketone bodies, pyruvate, and lactate. In the healthy adult heart, most of the ATP is generated via mitochondrial oxidation of fatty acids (50–70 {8617e24ab0b76aabcd10cf8004a7bdc562123dc1ea8adc37299158a7c05423e6}), and the balance between fatty acid oxidation and other forms of ATP production, such as glucose oxidation and glycolysis, is tightly regulated. In fact, dysregulation or inflexibility of myocardial energy metabolism has been linked to a number of major cardiac diseases including myocardial hypertrophy, heart failure, ischemic heart disease, and obesity and diabetes mellitus-associated cardiomyopathy. Deranged cardiac energy metabolism and impaired cardiac energetics have been suggested to contribute to these pathophysiological states, rendering metabolic modulators an attractive option for the management of various forms of heart disease. This chapter summarizes our current understanding of the role of cardiac energy metabolism in the development and progression of heart failure, pressure overload-induced hypertrophy, and obesity-related cardiomyopathy. In addition, potential therapies to restore metabolic balance and efficiency in the heart and ameliorate cardiac dysfunction are outlined.