title: Insulin-independent regulation of hepatic triglyceride synthesis by fatty acids.
abstract: A central paradox in type 2 diabetes is the apparent selective nature of hepatic insulin resistance--wherein insulin fails to suppress hepatic glucose production yet continues to stimulate lipogenesis, resulting in hyperglycemia, hyperlipidemia, and hepatic steatosis. Although efforts to explain this have focused on finding a branch point in insulin signaling where hepatic glucose and lipid metabolism diverge, we hypothesized that hepatic triglyceride synthesis could be driven by substrate, independent of changes in hepatic insulin signaling. We tested this hypothesis in rats by infusing [U-(13)C] palmitate to measure rates of fatty acid esterification into hepatic triglyceride while varying plasma fatty acid and insulin concentrations independently. These experiments were performed in normal rats, high fat-fed insulin-resistant rats, and insulin receptor 2'-O-methoxyethyl chimeric antisense oligonucleotide-treated rats. Rates of fatty acid esterification into hepatic triglyceride were found to be dependent on plasma fatty acid infusion rates, independent of changes in plasma insulin concentrations and independent of hepatocellular insulin signaling. Taken together, these results obviate a paradox of selective insulin resistance, because the major source of hepatic lipid synthesis, esterification of preformed fatty acids, is primarily dependent on substrate delivery and largely independent of hepatic insulin action.
authors.affiliation: Departments of Internal Medicine and.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Vatner
authors.affiliation: Departments of Internal Medicine and.
authors.forename: Sachin K
authors.initials: SK
authors.lastname: Majumdar
authors.affiliation: Departments of Internal Medicine and.
authors.forename: Naoki
authors.initials: N
authors.lastname: Kumashiro
authors.affiliation: Cellular and Molecular Physiology and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06536; and.
authors.forename: Max C
authors.initials: MC
authors.lastname: Petersen
authors.affiliation: Departments of Internal Medicine and.
authors.forename: Yasmeen
authors.initials: Y
authors.lastname: Rahimi
authors.affiliation: Department of Medicine, Veterans Affairs Medical Center, West Haven, CT 06516.
authors.forename: Arijeet K
authors.initials: AK
authors.lastname: Gattu
authors.affiliation: Departments of Internal Medicine and.
authors.forename: Mitchell
authors.initials: M
authors.lastname: Bears
authors.affiliation: Departments of Internal Medicine and.
authors.forename: João-Paulo G
authors.initials: JP
authors.lastname: Camporez
authors.affiliation: Departments of Internal Medicine and.
authors.forename: Gary W
authors.initials: GW
authors.lastname: Cline
authors.affiliation: Departments of Internal Medicine and.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Jurczak
authors.affiliation: Departments of Internal Medicine and Department of Medicine, Veterans Affairs Medical Center, West Haven, CT 06516.
authors.forename: Varman T
authors.initials: VT
authors.lastname: Samuel
authors.affiliation: Departments of Internal Medicine and Cellular and Molecular Physiology and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06536; and gerald.shulman@yale.edu.
authors.forename: Gerald I
authors.initials: GI
authors.lastname: Shulman
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000473:pathology; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism*; D019308:Palmitic Acid / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction; D014280:Triglycerides / Q000096:biosynthesis*
chemical_list: D004791:Enzyme Inhibitors; D007328:Insulin; D014280:Triglycerides; D019308:Palmitic Acid; D011972:Receptor, Insulin
keywords: esterification; hepatic insulin resistance; lipogenesis; mass spectrometry; nonalcoholic fatty liver disease