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

Endocrinology. 2003 Aug;144(8):3456-62. doi: 10.1210/en.2002-0036.


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-(3)H-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 ( approximately 71% compared with approximately 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adiponectin
  • Animals
  • Blood Glucose / analysis
  • Cholesterol / blood
  • Fasting
  • Fatty Acids, Nonesterified / blood
  • Glucose / biosynthesis
  • Insulin / blood
  • Insulin / pharmacology*
  • Intercellular Signaling Peptides and Proteins*
  • Liver / chemistry
  • Liver / drug effects*
  • Liver / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Muscle, Skeletal / chemistry
  • Proteins / analysis
  • Receptor, Insulin / analysis
  • Sterol Esterase / deficiency*
  • Triglycerides / analysis
  • Triglycerides / blood
  • Triglycerides / metabolism*


  • Adiponectin
  • Blood Glucose
  • Fatty Acids, Nonesterified
  • Insulin
  • Intercellular Signaling Peptides and Proteins
  • Proteins
  • Triglycerides
  • Cholesterol
  • Receptor, Insulin
  • Sterol Esterase
  • Glucose