The transition from lean to obese states involves systemic metabolic remodeling that impacts insulin sensitivity, fat partitioning, inflammation, and glycemic control. Here, we’ve taken a medicinal method of test the function of the nutrient-controlled chromatin modifier, lysine-specific demethylase (LSD1), in weight problems-connected metabolic reprogramming. We reveal that systemic administration of the LSD1 inhibitor (GSK-LSD1) reduces intake of food and the body weight, ameliorates nonalcoholic fatty liver disease (NAFLD), and improves insulin sensitivity and glycemic control in mouse types of weight problems. GSK-LSD1 has little impact on systemic metabolic process of lean rodents, suggesting that LSD1 includes a context-dependent role to promote maladaptive alterations in weight problems. In analysis of insulin target tissues we identified white-colored adipose tissue because the major site of insulin sensitization by GSK-LSD1, where it cuts down on adipocyte inflammation and lipolysis. We show GSK-LSD1 reverses NAFLD inside a non-hepatocyte-autonomous manner, suggesting an indirect mechanism potentially via inhibition of adipocyte lipolysis and subsequent effects on fat partitioning. Pair-feeding experiments further says results of GSK-LSD1 on hyperglycemia and NAFLD aren’t due to reduced intake of food and weight reduction. These bits of information claim that targeting LSD1 might be a strategy to treat weight problems and it is connected complications including diabetes type 2 and NAFLD.