Lipolysis, and not hepatic lipogenesis, is the primary modulator of triglyceride levels in streptozotocin-induced diabetic mice.
OBJECTIVE
Diabetic hypertriglyceridemia is thought to be primarily driven by increased hepatic de novo lipogenesis. However, experiments in animal models indicated that insulin deficiency should decrease hepatic de novo lipogenesis and reduce plasma triglyceride levels.


RESULTS
To address the discrepancy between human data and genetically altered mouse models, we investigated whether insulin-deficient diabetic mice had triglyceride changes that resemble those in diabetic humans. Streptozotocin-induced insulin deficiency increased plasma triglyceride levels in mice. Contrary to the mouse models with impaired hepatic insulin receptor signaling, insulin deficiency did not reduce hepatic triglyceride secretion and de novo lipogenesis-related gene expression. Diabetic mice had a marked decrease in postprandial triglycerides clearance, which was associated with decreased lipoprotein lipase and peroxisome proliferator-activated receptor α mRNA levels in peripheral tissues and decreased lipoprotein lipase activity in skeletal muscle, heart, and brown adipose tissue. Diabetic heterozygous lipoprotein lipase knockout mice had markedly elevated fasting plasma triglyceride levels and prolonged postprandial triglycerides clearance.


CONCLUSIONS
Insulin deficiency causes hypertriglyceridemia by decreasing peripheral lipolysis and not by an increase in hepatic triglycerides production and secretion.
From the Division of Endocrinology, Diabetes and Metabolism, New York University School of Medicine, New York (F.W., D.S., M.L.A., C.M.T., L.A.H., I.J.G.); Department of Medicine, Columbia University, New York (F.W., D.S., M.L.A., C.M.T., L.A.H., I.J.G.); Saha Cardiovascular Research Center, University of Kentucky, Lexington (P.N.); Department of Biological Sciences, New York City College of Technology, City University of New York, Brooklyn (J.C.O.); Division of Cardiology and the Marc and Ruti Bell Program in Vascular Biology, Department of Medicine, New York University School of Medicine, New York (T.J.B., E.A.F.); and Department of Pharmacology, Temple University School of Medicine, Center for Translational Medicine, Philadelphia, PA (K.D.).
Florian
F
Willecke
From the Division of Endocrinology, Diabetes and Metabolism, New York University School of Medicine, New York (F.W., D.S., M.L.A., C.M.T., L.A.H., I.J.G.); Department of Medicine, Columbia University, New York (F.W., D.S., M.L.A., C.M.T., L.A.H., I.J.G.); Saha Cardiovascular Research Center, University of Kentucky, Lexington (P.N.); Department of Biological Sciences, New York City College of Technology, City University of New York, Brooklyn (J.C.O.); Division of Cardiology and the Marc and Ruti Bell Program in Vascular Biology, Department of Medicine, New York University School of Medicine, New York (T.J.B., E.A.F.); and Department of Pharmacology, Temple University School of Medicine, Center for Translational Medicine, Philadelphia, PA (K.D.).
Diego
D
Scerbo
From the Division of Endocrinology, Diabetes and Metabolism, New York University School of Medicine, New York (F.W., D.S., M.L.A., C.M.T., L.A.H., I.J.G.); Department of Medicine, Columbia University, New York (F.W., D.S., M.L.A., C.M.T., L.A.H., I.J.G.); Saha Cardiovascular Research Center, University of Kentucky, Lexington (P.N.); Department of Biological Sciences, New York City College of Technology, City University of New York, Brooklyn (J.C.O.); Division of Cardiology and the Marc and Ruti Bell Program in Vascular Biology, Department of Medicine, New York University School of Medicine, New York (T.J.B., E.A.F.); and Department of Pharmacology, Temple University School of Medicine, Center for Translational Medicine, Philadelphia, PA (K.D.).
Prabhakara
P
Nagareddy
From the Division of Endocrinology, Diabetes and Metabolism, New York University School of Medicine, New York (F.W., D.S., M.L.A., C.M.T., L.A.H., I.J.G.); Department of Medicine, Columbia University, New York (F.W., D.S., M.L.A., C.M.T., L.A.H., I.J.G.); Saha Cardiovascular Research Center, University of Kentucky, Lexington (P.N.); Department of Biological Sciences, New York City College of Technology, City University of New York, Brooklyn (J.C.O.); Division of Cardiology and the Marc and Ruti Bell Program in Vascular Biology, Department of Medicine, New York University School of Medicine, New York (T.J.B., E.A.F.); and Department of Pharmacology, Temple University School of Medicine, Center for Translational Medicine, Philadelphia, PA (K.D.).
Joseph C
JC
Obunike
From the Division of Endocrinology, Diabetes and Metabolism, New York University School of Medicine, New York (F.W., D.S., M.L.A., C.M.T., L.A.H., I.J.G.); Department of Medicine, Columbia University, New York (F.W., D.S., M.L.A., C.M.T., L.A.H., I.J.G.); Saha Cardiovascular Research Center, University of Kentucky, Lexington (P.N.); Department of Biological Sciences, New York City College of Technology, City University of New York, Brooklyn (J.C.O.); Division of Cardiology and the Marc and Ruti Bell Program in Vascular Biology, Department of Medicine, New York University School of Medicine, New York (T.J.B., E.A.F.); and Department of Pharmacology, Temple University School of Medicine, Center for Translational Medicine, Philadelphia, PA (K.D.).
Tessa J
TJ
Barrett
From the Division of Endocrinology, Diabetes and Metabolism, New York University School of Medicine, New York (F.W., D.S., M.L.A., C.M.T., L.A.H., I.J.G.); Department of Medicine, Columbia University, New York (F.W., D.S., M.L.A., C.M.T., L.A.H., I.J.G.); Saha Cardiovascular Research Center, University of Kentucky, Lexington (P.N.); Department of Biological Sciences, New York City College of Technology, City University of New York, Brooklyn (J.C.O.); Division of Cardiology and the Marc and Ruti Bell Program in Vascular Biology, Department of Medicine, New York University School of Medicine, New York (T.J.B., E.A.F.); and Department of Pharmacology, Temple University School of Medicine, Center for Translational Medicine, Philadelphia, PA (K.D.).
Mariane L
ML
Abdillahi
From the Division of Endocrinology, Diabetes and Metabolism, New York University School of Medicine, New York (F.W., D.S., M.L.A., C.M.T., L.A.H., I.J.G.); Department of Medicine, Columbia University, New York (F.W., D.S., M.L.A., C.M.T., L.A.H., I.J.G.); Saha Cardiovascular Research Center, University of Kentucky, Lexington (P.N.); Department of Biological Sciences, New York City College of Technology, City University of New York, Brooklyn (J.C.O.); Division of Cardiology and the Marc and Ruti Bell Program in Vascular Biology, Department of Medicine, New York University School of Medicine, New York (T.J.B., E.A.F.); and Department of Pharmacology, Temple University School of Medicine, Center for Translational Medicine, Philadelphia, PA (K.D.).
Chad M
CM
Trent
From the Division of Endocrinology, Diabetes and Metabolism, New York University School of Medicine, New York (F.W., D.S., M.L.A., C.M.T., L.A.H., I.J.G.); Department of Medicine, Columbia University, New York (F.W., D.S., M.L.A., C.M.T., L.A.H., I.J.G.); Saha Cardiovascular Research Center, University of Kentucky, Lexington (P.N.); Department of Biological Sciences, New York City College of Technology, City University of New York, Brooklyn (J.C.O.); Division of Cardiology and the Marc and Ruti Bell Program in Vascular Biology, Department of Medicine, New York University School of Medicine, New York (T.J.B., E.A.F.); and Department of Pharmacology, Temple University School of Medicine, Center for Translational Medicine, Philadelphia, PA (K.D.).
Lesley A
LA
Huggins
From the Division of Endocrinology, Diabetes and Metabolism, New York University School of Medicine, New York (F.W., D.S., M.L.A., C.M.T., L.A.H., I.J.G.); Department of Medicine, Columbia University, New York (F.W., D.S., M.L.A., C.M.T., L.A.H., I.J.G.); Saha Cardiovascular Research Center, University of Kentucky, Lexington (P.N.); Department of Biological Sciences, New York City College of Technology, City University of New York, Brooklyn (J.C.O.); Division of Cardiology and the Marc and Ruti Bell Program in Vascular Biology, Department of Medicine, New York University School of Medicine, New York (T.J.B., E.A.F.); and Department of Pharmacology, Temple University School of Medicine, Center for Translational Medicine, Philadelphia, PA (K.D.).
Edward A
EA
Fisher
From the Division of Endocrinology, Diabetes and Metabolism, New York University School of Medicine, New York (F.W., D.S., M.L.A., C.M.T., L.A.H., I.J.G.); Department of Medicine, Columbia University, New York (F.W., D.S., M.L.A., C.M.T., L.A.H., I.J.G.); Saha Cardiovascular Research Center, University of Kentucky, Lexington (P.N.); Department of Biological Sciences, New York City College of Technology, City University of New York, Brooklyn (J.C.O.); Division of Cardiology and the Marc and Ruti Bell Program in Vascular Biology, Department of Medicine, New York University School of Medicine, New York (T.J.B., E.A.F.); and Department of Pharmacology, Temple University School of Medicine, Center for Translational Medicine, Philadelphia, PA (K.D.).
Konstantinos
K
Drosatos
From the Division of Endocrinology, Diabetes and Metabolism, New York University School of Medicine, New York (F.W., D.S., M.L.A., C.M.T., L.A.H., I.J.G.); Department of Medicine, Columbia University, New York (F.W., D.S., M.L.A., C.M.T., L.A.H., I.J.G.); Saha Cardiovascular Research Center, University of Kentucky, Lexington (P.N.); Department of Biological Sciences, New York City College of Technology, City University of New York, Brooklyn (J.C.O.); Division of Cardiology and the Marc and Ruti Bell Program in Vascular Biology, Department of Medicine, New York University School of Medicine, New York (T.J.B., E.A.F.); and Department of Pharmacology, Temple University School of Medicine, Center for Translational Medicine, Philadelphia, PA (K.D.). Ira.Goldberg@NYUMC.org.
Ira J
IJ
Goldberg
D002001:Adipose Tissue, Brown / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D015228:Hypertriglyceridemia / Q000097:blood / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D007328:Insulin / Q000097:blood*; D050155:Lipogenesis; D008066:Lipolysis; D008071:Lipoprotein Lipase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism; D047494:PPAR delta / Q000235:genetics / Q000378:metabolism; D019518:Postprandial Period; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D013311:Streptozocin; D013997:Time Factors; D014280:Triglycerides / Q000097:blood*
D015415:Biomarkers; D001786:Blood Glucose; D007328:Insulin; D047493:PPAR alpha; D047494:PPAR delta; D012333:RNA, Messenger; D014280:Triglycerides; D013311:Streptozocin; D008071:Lipoprotein Lipase
diabetes mellitus; hypertriglyceridemia; lipoprotein lipase