Systemic LSD1 Inhibition Prevents Aberrant Remodeling of Metabolism in Obesity.
In: Diabetes, Jg. 71 (2022-12-01), Heft 12
Online
academicJournal
- 2513 - 2529
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.
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Systemic LSD1 Inhibition Prevents Aberrant Remodeling of Metabolism in Obesity.
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Autor/in / Beteiligte Person: | Ramms, Bastian ; Pollow, Dennis P ; Zhu, Han ; Nora, Chelsea ; Harrington, Austin R ; Omar, Ibrahim ; Gordts, Philip LSM ; Wortham, Matthew ; Sander, Maike |
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Zeitschrift: | Diabetes, Jg. 71 (2022-12-01), Heft 12 |
Veröffentlichung: | eScholarship, University of California, 2022 |
Medientyp: | academicJournal |
Umfang: | 2513 - 2529 |
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