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Increased Hepatic Insulin Sensitivity Together with Decreased Hepatic Triglyceride Stores in Hormone-Sensitive Lipase-Deficient Mice

The Netherlands Organization for Applied Scientific Research–Prevention and Health (P.J.V., B.T., L.M.H.), Division of Vascular Biology, and Leiden University Medical Centre (P.J.V., J.A.R.), Department of Endocrinology and Metabolic Diseases, Leiden, The Netherlands; Institute of Molecular Biology, Biochemistry and Microbiology (G.H., R.Zi., R.Ze.), University of Graz, Graz, Austria; Leiden University Medical Centre (D.M.O., J.A.M.), Department of Molecular Cell Biology, and Departments of Cardiology and General Internal Medicine (L.M.H.), Leiden, The Netherlands

Address all correspondence and requests for reprints to: Peter J. Voshol, Ph.D., The Netherlands Organization for Applied Scientific Research-Prevention and Health, Division of Vascular Biology, Zernikedreef 9, NL-2333 CK Leiden, The Netherlands. E-mail: pj.voshol{at}pg.tno.nl.

Hormone-sensitive lipase (HSL) is a major enzyme for triglyceride (TG) lipolysis in adipose tissue. In HSL-knockout mice, plasma free fatty acid and TG levels are low, associated with low liver TG content. Because a decreased hepatic insulin sensitivity has been reported to be associated with high liver TG levels, our aim was to determine whether a hepatic TG content lower than normal, as observed in HSL-knockout mice, leads to increased hepatic insulin sensitivity. Therefore, hyperinsulinemic clamp experiments in combination with D-³H-glucose were used. Furthermore, hepatic insulin receptor and phosphorylated protein kinase B (PKB-P)/akt were analyzed by Western blotting. No significant differences where observed in insulin-mediated whole-body glucose uptake between HSL-knockout and control mice. Interestingly, hepatic insulin sensitivity of HSL-knockout mice was increased, because insulin caused a greater reduction in endogenous glucose production (71% compared with 31% in control mice; P < 0.05), despite decreased plasma adiponectin levels. PKB/akt phosphorylation and phosphatidylinositol-3-kinase activity was significantly higher in livers of HSL-knockout mice after insulin stimulation. In HSL-knockout mice, reduced hepatic TG stores result in an increased suppressive effect of insulin on hepatic glucose production, in line with an increased hepatic PKB-P/akt and phosphatidylinositol-3 kinase activity. Thus, hepatic insulin sensitivity is indeed increased after reducing hepatic TG stores below normal.

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