Pharmacological Inhibition of Lipolysis Prevents Adverse Outcomes during Glucocorticoid Therapy

Background: During prolonged fasting, glucocorticoids main-tain blood glucose by increasing gluconeogenesis and lipolysis. Glucocorticoids also have anti-i nflammatory effects and are prescribed to treat a variety of conditions; however, chronic use leads to many adverse consequences, including altered body composition and hyperglycemia. Little is known about the physiological link between glucocorticoid-induced lipolysis and hyperglycemia. The purpose of this study was to use a pharmacological ATGL inhibitor to limit excess lipolysis and assess outcomes that are adversely affected by glucocorticoid administration, including adiposity and glycemia. It was hypothesized that limiting lipolysis would prevent excess adiposity, excess ectopic lipid within tissues, and hyperglycemia. Methods: C57BL/6J mice were given 100 pg/mL corticosterone (Cort) in the drinking water for two weeks and were either fed a normal chow diet (TekLad 8640) or the same diet supplemented with an ATGL inhibitor, Atglistatin (ATGLi; 2 g/kg diet). Results: Cort-i nduced lipolysis (free glycerol release into blood) was negated by ATGLi. While ~75% of the mice receiving Cort became diabetic (glucose > 250 mg/dL) within two weeks, ATGLi prevented the onset of diabetes. Mice receiving ATGLi were also partially protected against Cort-induced hyperinsulinemia, hypertriglyceridemia, and increases in fat mass but were not protected from Cort-i nduced loss of lean mass. While Cort induced an increase in tissue triglyceride that was ~2.7-3.5 times higher than the control group within the skeletal muscle and liver, respectively (p < 0.0.001), this ectopic lipid deposition was prevented with ATGLi. Conclusions: These data support the idea that preventing excess lipolysis can improve clinical outcomes during a glucocorticoid regimen by mitigating several adverse metabolic outcomes that occur during drug therapy, including hyperglycemia.