American Diabetes Association
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Systemic LSD1 Inhibition Prevents Aberrant Remodeling of Metabolism in Obesity

posted on 2022-09-09, 17:42 authored by Bastian Ramms, Dennis P. Pollow, Han Zhu, Chelsea Nora, Austin R. Harrington, Ibrahim Omar, Philip L.S.M. Gordts, Matthew Wortham, Maike Sander

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.


This work was supported by Larry L. Hillblom Foundation fellowship 2021-D-008-FEL (B.R.), JDRF postdoctoral fellowship 3-PDF-2014-193-A-N (M.W.) and John G. Davies Endowed Fellowships in Pancreatic Research S1079-1002614 and S1105-1002847-AWD (B.R. and M.W.), a Foundation Leducq grant 16CVD01 (P.L.S.M.G.), R01 DK068471 and R01 DK078803 (M.S.), UCSD School of Medicine Microscopy Core Grant NINDS P30 NS047101.


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