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Increased hepatic insulin sensitivity together with decreased hepatic triglyceride stores in hormone-sensitive lipase-deficient mice

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Author: Voshol, P.J. · Haemmerle, G. · Ouwens, D.M. · Zimmermann, R. · Zechner, R. · Teusink, B. · Maassen, J.A. · Havekes, L.M. · Romijn, J.A.
Type:article
Date:2003
Source:Endocrinology, 8, 144, 3456-3462
Identifier: 237212
doi: doi:10.1210/en.2002-0036
Keywords: Health · Glucose · Hormone sensitive lipase · Insulin receptor · Protein kinase B · Triacylglycerol · Triacylglycerol lipase · Unclassified drug · Animal tissue · Controlled study · Enzyme activity · Enzyme deficiency · Enzyme mechanism · Enzyme phosphorylation · Fatty acid blood level · Gluconeogenesis · Glucose transport · Hormone sensitivity · Hyperinsulinemia · Insulin sensitivity · Knockout mouse · Lipid liver level · Lipolysis · Mouse · Nonhuman · Western blotting · Adiponectin · Animals · Blood Glucose · Cholesterol · Cholesterol Esterase · Fasting · Fatty Acids, Nonesterified · Glucose · Insulin · Intercellular Signaling Peptides and Proteins · Liver · Male · Mice · Mice, Knockout · Muscle, Skeletal · Proteins · Receptor, Insulin · Triglycerides

Abstract

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.