Mutations in the BSCL2 gene underlie human type 2 Berardinelli-Seip congenital lipodystrophy (BSCL2) disease. Global Bscl2–/– mice recapitulate human BSCL2 lipodystrophy and results in the development of insulin resistance and hypertrophic cardiomyopathy. The pathological mechanisms underlying the development of lipodystrophy and cardiomyopathy in BSCL2 are controversial. Here we report that Bscl2–/– mice develop cardiac hypertrophy because of increased basal IGF1 receptor–mediated (IGF1R-mediated) PI3K/AKT signaling. Bscl2–/– hearts exhibited increased adipose triglyceride lipase (ATGL) protein stability and expression causing drastic reduction of glycerolipids. Excessive fatty acid oxidation was overt in Bscl2–/– hearts, partially attributing to the hyperacetylation of cardiac mitochondrial proteins. Intriguingly, pharmacological inhibition or genetic inactivation of ATGL could rescue adipocyte differentiation and lipodystrophy in Bscl2–/– cells and mice. Restoring a small portion of fat mass by ATGL partial deletion in Bscl2–/– mice not only reversed the systemic insulin resistance, but also ameliorated cardiac protein hyperacetylation, normalized cardiac substrate metabolism, and improved contractile function. Collectively, our study uncovers pathways underlying lipodystrophy-induced cardiac hypertrophy and metabolic remodeling and pinpoints ATGL as a downstream target of BSCL2 in regulating the development of lipodystrophy and its associated cardiomyopathy.
Hongyi Zhou, Xinnuo Lei, Yun Yan, Todd Lydic, Jie Li, Neal L. Weintraub, Huabo Su, Weiqin Chen
Usage data is cumulative from October 2021 through October 2022.
Usage information is collected from two different sources: this site (JCI) and Pubmed Central (PMC). JCI information (compiled daily) shows human readership based on methods we employ to screen out robotic usage. PMC information (aggregated monthly) is also similarly screened of robotic usage.
Various methods are used to distinguish robotic usage. For example, Google automatically scans articles to add to its search index and identifies itself as robotic; other services might not clearly identify themselves as robotic, or they are new or unknown as robotic. Because this activity can be misinterpreted as human readership, data may be re-processed periodically to reflect an improved understanding of robotic activity. Because of these factors, readers should consider usage information illustrative but subject to change.