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1 Medicine, University Of Pittsburgh, Pittsburgh, Pennsylvania, United States
2 Medicine of Endocrinology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States; Molecular Genetics and Biochemistry, University of Pittsburgh, Pittsburgh, Pennsylvania, 15261, United States
* To whom correspondence should be addressed. E-mail: huangw{at}dom.pitt.edu.
High sucrose (HS) feeding induces hepatic steatosis and plasma dyslipidemia. In previous reports we demonstrated a rapid leptin-induced decrease in liver and plasma VLDL triglycerides (TG) in lean rats, effects that were abolished in obese rats fed a high fat diet, a model that also presents with hepatic steatosis/plasma dyslipidemia. To further examine the capacity of acute leptin treatment to improve metabolic abnormalities induced by nutrient excess, hepatic leptin action was studied in rats after 5 weeks of HS feeding. HS induced hepatic steatosis (TG +80±8%, P=0.001), plasma hyperlipidemia (VLDL-TG +102±14%, P=0.001), hyperinsulinemia (plasma insulin +67±12%, P=0.04), and insulin resistance as measured by HOMA (+125±20%, P=0.02), without increases in adiposity or plasma leptin concentration when compared to standard chow (SC) fed controls. A 120-min leptin infusion (plasma leptin 13.6±0.7 ng/ml) in HS corrected hepatic steatosis (LTG -29±3%, P=0.003) and plasma hyperlipidemia (VLDL-TG -42±4%, P=0.001) and increased plasma ketones (+45±3%, P=0.006), without altering plasma glucose, insulin or HOMA compared to saline-infused HS controls. Additionally, leptin activated liver PI3-kinase (+70±18%, P=0.01) and Akt (+90±29%, P=0.02), and inhibited ACC (40±7%, P=0.04) in HS, further demonstrating that hepatic leptin action was intact in HS. We conclude that (1) leptin action on hepatic lipid metabolism remains intact in HS rats; (2) leptin rapidly reverses hepatic steatosis and plasma dyslipidemia induced by sucrose, and (3) the preservation of hepatic leptin action after a high sucrose diet is associated with the maintenance of low adiposity and plasma leptin concentrations.
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