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| Item Type: | Article |
|---|---|
| Title: | Systemic LSD1 inhibition prevents aberrant remodeling of metabolism in obesity |
| Creators Name: | Ramms, B., Pollow, D.P., Zhu, H., Nora, C., Harrington, A.R., Omar, I., Gordts, P.L.S.M., 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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