title: Targeting pyruvate carboxylase reduces gluconeogenesis and adiposity and improves insulin resistance.
abstract: We measured the mRNA and protein expression of the key gluconeogenic enzymes in human liver biopsy specimens and found that only hepatic pyruvate carboxylase protein levels related strongly with glycemia. We assessed the role of pyruvate carboxylase in regulating glucose and lipid metabolism in rats through a loss-of-function approach using a specific antisense oligonucleotide (ASO) to decrease expression predominantly in liver and adipose tissue. Pyruvate carboxylase ASO reduced plasma glucose concentrations and the rate of endogenous glucose production in vivo. Interestingly, pyruvate carboxylase ASO also reduced adiposity, plasma lipid concentrations, and hepatic steatosis in high fat-fed rats and improved hepatic insulin sensitivity. Pyruvate carboxylase ASO had similar effects in Zucker Diabetic Fatty rats. Pyruvate carboxylase ASO did not alter de novo fatty acid synthesis, lipolysis, or hepatocyte fatty acid oxidation. In contrast, the lipid phenotype was attributed to a decrease in hepatic and adipose glycerol synthesis, which is important for fatty acid esterification when dietary fat is in excess. Tissue-specific inhibition of pyruvate carboxylase is a potential therapeutic approach for nonalcoholic fatty liver disease, hepatic insulin resistance, and type 2 diabetes.
authors: Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA.
authors: Naoki
authors: N
authors: Kumashiro
authors: Sara A
authors: SA
authors: Beddow
authors: Daniel F
authors: DF
authors: Vatner
authors: Sachin K
authors: SK
authors: Majumdar
authors: Jennifer L
authors: JL
authors: Cantley
authors: Fitsum
authors: F
authors: Guebre-Egziabher
authors: Ioana
authors: I
authors: Fat
authors: Blas
authors: B
authors: Guigni
authors: Michael J
authors: MJ
authors: Jurczak
authors: Andreas L
authors: AL
authors: Birkenfeld
authors: Mario
authors: M
authors: Kahn
authors: Bryce K
authors: BK
authors: Perler
authors: Michelle A
authors: MA
authors: Puchowicz
authors: Vara Prasad
authors: VP
authors: Manchem
authors: Sanjay
authors: S
authors: Bhanot
authors: Christopher D
authors: CD
authors: Still
authors: Glenn S
authors: GS
authors: Gerhard
authors: Kitt Falk
authors: KF
authors: Petersen
authors: Gary W
authors: GW
authors: Cline
authors: Gerald I
authors: GI
authors: Shulman
authors: Varman T
authors: VT
authors: Samuel
mesh_terms: D000273:Adipose Tissue / Q000201:enzymology; D050154:Adiposity / Q000502:physiology*; D000328:Adult; D000818:Animals; D005234:Fatty Liver / Q000201:enzymology; D005260:Female; D005943:Gluconeogenesis / Q000502:physiology*; D005990:Glycerol / Q000378:metabolism; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology*; D008099:Liver / Q000201:enzymology*; D008297:Male; D008875:Middle Aged; D011766:Pyruvate Carboxylase / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker
chemical_list: D011766:Pyruvate Carboxylase; D005990:Glycerol