Increased hepatic insulin sensitivity together with decreased hepatic triglyceride stores in hormone-sensitive lipase-deficient mice.
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.
Voshol
Peter J
PJ
The Netherlands Organization for Applied Scientific Research-Prevention and Health, Leiden University Medical Centre, Department of Endocrinology and Metabolic Diseases, Leiden, The Netherlands. p.j.voshol@pg.tno.nl
Haemmerle
Guenter
G
Ouwens
D Margriet
DM
Zimmermann
Robert
R
Zechner
Rudolf
R
Teusink
Bas
B
Maassen
J Antonie
JA
Havekes
Louis M
LM
Romijn
Johannes A
JA
D052242:Adiponectin; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D002784:Cholesterol / Q000097:blood; D005215:Fasting; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005947:Glucose / Q000096:biosynthesis; D007328:Insulin / Q000097:blood / Q000494:pharmacology*; D036341:Intercellular Signaling Peptides and Proteins; D008099:Liver / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000737:chemistry; D011506:Proteins / Q000032:analysis; D011972:Receptor, Insulin / Q000032:analysis; D002787:Sterol Esterase / Q000172:deficiency*; D014280:Triglycerides / Q000032:analysis / Q000097:blood / Q000378:metabolism*
D052242:Adiponectin; D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; D011506:Proteins; D014280:Triglycerides; D002784:Cholesterol; D011972:Receptor, Insulin; D002787:Sterol Esterase; D005947:Glucose