Abstract
The high abundance of mitochondria and the expression of mitochondrial uncoupling protein 1 (UCP1) confer upon brown adipose tissue (BAT) the unique capacity to convert chemical energy into heat at the expense of ATP synthesis. It was long believed that BAT is present only in infants, and so, it was not considered as a potential therapeutic target for metabolic syndrome; however, the discovery of metabolically active BAT in adult humans has re-stimulated interest in the contributions of BAT metabolic regulation and dysfunction to health and disease. Here we demonstrate that brown adipocyte autophagy plays a critical role in the regulation BAT activity and systemic energy metabolism. Mice deficient in brown adipocyte autophagy due to BAT-specific deletion of Atg7—a gene essential for autophagosome generation—maintained higher mitochondrial content due to suppression of mitochondrial clearance and exhibited improved insulin sensitivity and energy metabolism. Autophagy was upregulated in BAT of older mice compared to younger mice, suggesting its involvement in the age-dependent decline of BAT activity and metabolic rate. These findings suggest that brown adipocyte autophagy plays a crucial role in metabolism and that targeting this pathway may be a potential therapeutic strategy for metabolic syndrome.
Highlights
The maintenance of systemic energy homeostasis involves the precise sensing of energy levels, integration and transduction of metabolic signals, and co-ordinated regulation of energy intake and expenditure
Whereas other tissues use the proton gradient generated from mitochondrial respiration for ATP synthesis, Uncoupling protein 1 (UCP1) expressed in the mitochondrial inner membrane of brown adipose tissue (BAT) generates heat by allowing the ATP synthesis-independent translocation of protons to the mitochondrial matrix [2,3,4,5]
The protein autophagy related 7 (ATG7) is an essential regulator of autophagosome formation, and multiple in vitro and in vivo studies have demonstrated that the genetic ablation of Atg7 inactivates autophagy
Summary
The maintenance of systemic energy homeostasis involves the precise sensing of energy levels, integration and transduction of metabolic signals, and co-ordinated regulation of energy intake and expenditure. Unlike WAT, BAT contains lipid droplets in multilocular forms and instead of storing energy, it uses glucose and lipid as fuel to generate heat and regulate thermogenesis [1]. Martinez-Lopez et al (2013) reported that autophagy is involved in brown adipocyte differentiation, as knockout of Atg in mouse Myf5+ lineages—common progenitor cells for brown adipocytes and skeletal myocytes—exhibited defective BAT and skeletal muscle development [19]. While these studies demonstrate critical roles for autophagy in the metabolism, autophagic function in mature brown adipocytes has not been addressed. In this study, we investigated the role of autophagy in brown adipocytes and whole-body energy homeostasis
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