Systemic LSD1 inhibition prevents aberrant remodeling of metabolism in obesity

Item Type:	Article
Title:	Systemic LSD1 inhibition prevents aberrant remodeling of metabolism in obesity
Creators Name:	Ramms, B. and Pollow, D.P. and Zhu, H. and Nora, C. and Harrington, A.R. and Omar, I. and Gordts, P.L.S.M. and Wortham, M. and Sander, M.
Abstract:	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 non-alcoholic 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 LSD1 has a context-dependent role in promoting maladaptive changes in obesity. Analysis of insulin target tissues 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.
Keywords:	Type 2 Diabetes Mellitus, Histone Demethylases, Inflammation, Insulin, Insulin Resistance, Lipid Metabolism, Lipids, Liver, Lysine, Inbred C57BL Mice, Non-Alcoholic Fatty Liver Disease, Obesity, Animals, Mice
Source:	Diabetes
ISSN:	0012-1797
Publisher:	American Diabetes Association
Volume:	71
Number:	12
Page Range:	2513-2529
Date:	December 2022
Official Publication:	https://doi.org/10.2337/db21-1131
PubMed:	View item in PubMed

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