Open AccessSystemic LSD1 Inhibition Prevents Aberrant Remodeling of Metabolism in Obesity
Author(s) -
Bastian Ramms,
Dennis P. Pollow,
Han Zhu,
Chelsea Nora,
Austin R. Harrington,
Ibrahim Che Omar,
Philip L.S.M. Gordts,
Matthew Wortham,
Maike Sander
Publication year - 2022
Publication title -
diabetes
Language(s) - English
Resource type - Journals
eISSN - 1939-327X
pISSN - 0012-1797
DOI - 10.2337/db21-1131
Subject(s) - endocrinology , medicine , adipocyte , lipolysis , insulin resistance , adipose tissue , diabetes mellitus , nonalcoholic fatty liver disease , lipid metabolism , context (archaeology) , type 2 diabetes , insulin , biology , white adipose tissue , lipid droplet , fatty liver , disease , paleontology
The transition from lean to obese states involves systemic metabolic remodeling that impacts insulin sensitivity, lipid partitioning, inflammation, and glycemic control. Here, we have taken a pharmacological approach to test the role of a nutrient-regulated chromatin modifier, lysine-specific demethylase (LSD1), in obesity-associated metabolic reprogramming. We show that systemic administration of an LSD1 inhibitor (GSK-LSD1) reduces food intake and body weight, ameliorates nonalcoholic fatty liver disease (NAFLD), and improves insulin sensitivity and glycemic control in mouse models of obesity. GSK-LSD1 has little effect on systemic metabolism of lean mice, suggesting that LSD1 has a context-dependent role in promoting maladaptive changes in obesity. In analysis of insulin target tissues we identified white adipose tissue as the major site of insulin sensitization by GSK-LSD1, where it reduces adipocyte inflammation and lipolysis. We demonstrate that GSK-LSD1 reverses NAFLD in a non-hepatocyte-autonomous manner, suggesting an indirect mechanism potentially via inhibition of adipocyte lipolysis and subsequent effects on lipid partitioning. Pair-feeding experiments further revealed that effects of GSK-LSD1 on hyperglycemia and NAFLD are not a consequence of reduced food intake and weight loss. These findings suggest that targeting LSD1 could be a strategy for treatment of obesity and its associated complications including type 2 diabetes and NAFLD.