Short term effects of leptin on hepatic gluconeogenesis and in vivo insulin action

Luciano Rossetti, Duna Massillon, Nir Barzilai, Patricia Vuguin, Wei Chen, Meredith A. Hawkins, Jie Wu, Jali Wang

Research output: Contribution to journalArticle

258 Citations (Scopus)

Abstract

Long term administration of leptin decreases caloric intake and fat mass and improves glucose tolerance. Here we examine whether leptin acutely regulates peripheral and hepatic insulin action. Recombinant mouse leptin (0.3 mg/kg · h, Leptin +) or vehicle (Leptin -) were administered for 6 h to 4-month-old rats (n = 20), and insulin (3 milliunits/kg · min) clamp studies were performed. During physiologic hyperinsulinemia (plasma insulin ~65 microunits/ml), the rates of whole body glucose uptake, glycolysis, and glycogen syntheses and the rates of 2-deoxyglucose uptake in individual tissues were similar in Leptin - and Leptin +. Post-absorptive hepatic glucose production (HGP) was similar in the two groups. However, leptin enhanced insulin's inhibition of HGP (4.1 ± 0.7 and 6.2 ± 0.7 mg/kg · min; p < 0.05). The decreased HGP in the Leptin + group was due to a marked suppression of hepatic glycogenolysis (0.7 ± 0.1 versus 4.1 ± 0.6 mg/kg · min, in Leptin + versus Leptin -, respectively; p < 0.001), whereas the % contribution of gluconeogenesis to HGP was markedly increased (82 ± 3% versus 36 ± 4% in Leptin + and Leptin -, respectively; p < 0.001). At the end of the 6-h leptin infusion, the hepatic abundance of glucokinase mRNA was decreased, whereas that of phosphoenolpyruvate carboxykinase mRNA was increased compared with Leptin -. We conclude that an acute increase in plasma leptin 1) enhances insulin's ability to inhibit HGP, 2) does not affect peripheral insulin action, and 3) induces a redistribution of intrahepatic glucose fluxes and changes in the gene expression of hepatic enzymes that closely resemble those of fasting.

Original languageEnglish (US)
Pages (from-to)27758-27763
Number of pages6
JournalJournal of Biological Chemistry
Volume272
Issue number44
DOIs
StatePublished - Oct 31 1997

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Gluconeogenesis
Leptin
Insulin
Liver
Glucose
Plasmas
Glucokinase
Glycogenolysis
Messenger RNA
Phosphoenolpyruvate
Aptitude
Deoxyglucose
Clamping devices
Hyperinsulinism
Glycolysis
Energy Intake
Glycogen
Gene expression

ASJC Scopus subject areas

  • Biochemistry

Cite this

Short term effects of leptin on hepatic gluconeogenesis and in vivo insulin action. / Rossetti, Luciano; Massillon, Duna; Barzilai, Nir; Vuguin, Patricia; Chen, Wei; Hawkins, Meredith A.; Wu, Jie; Wang, Jali.

In: Journal of Biological Chemistry, Vol. 272, No. 44, 31.10.1997, p. 27758-27763.

Research output: Contribution to journalArticle

Rossetti, Luciano ; Massillon, Duna ; Barzilai, Nir ; Vuguin, Patricia ; Chen, Wei ; Hawkins, Meredith A. ; Wu, Jie ; Wang, Jali. / Short term effects of leptin on hepatic gluconeogenesis and in vivo insulin action. In: Journal of Biological Chemistry. 1997 ; Vol. 272, No. 44. pp. 27758-27763.
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T1 - Short term effects of leptin on hepatic gluconeogenesis and in vivo insulin action

AU - Rossetti, Luciano

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AU - Hawkins, Meredith A.

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N2 - Long term administration of leptin decreases caloric intake and fat mass and improves glucose tolerance. Here we examine whether leptin acutely regulates peripheral and hepatic insulin action. Recombinant mouse leptin (0.3 mg/kg · h, Leptin +) or vehicle (Leptin -) were administered for 6 h to 4-month-old rats (n = 20), and insulin (3 milliunits/kg · min) clamp studies were performed. During physiologic hyperinsulinemia (plasma insulin ~65 microunits/ml), the rates of whole body glucose uptake, glycolysis, and glycogen syntheses and the rates of 2-deoxyglucose uptake in individual tissues were similar in Leptin - and Leptin +. Post-absorptive hepatic glucose production (HGP) was similar in the two groups. However, leptin enhanced insulin's inhibition of HGP (4.1 ± 0.7 and 6.2 ± 0.7 mg/kg · min; p < 0.05). The decreased HGP in the Leptin + group was due to a marked suppression of hepatic glycogenolysis (0.7 ± 0.1 versus 4.1 ± 0.6 mg/kg · min, in Leptin + versus Leptin -, respectively; p < 0.001), whereas the % contribution of gluconeogenesis to HGP was markedly increased (82 ± 3% versus 36 ± 4% in Leptin + and Leptin -, respectively; p < 0.001). At the end of the 6-h leptin infusion, the hepatic abundance of glucokinase mRNA was decreased, whereas that of phosphoenolpyruvate carboxykinase mRNA was increased compared with Leptin -. We conclude that an acute increase in plasma leptin 1) enhances insulin's ability to inhibit HGP, 2) does not affect peripheral insulin action, and 3) induces a redistribution of intrahepatic glucose fluxes and changes in the gene expression of hepatic enzymes that closely resemble those of fasting.

AB - Long term administration of leptin decreases caloric intake and fat mass and improves glucose tolerance. Here we examine whether leptin acutely regulates peripheral and hepatic insulin action. Recombinant mouse leptin (0.3 mg/kg · h, Leptin +) or vehicle (Leptin -) were administered for 6 h to 4-month-old rats (n = 20), and insulin (3 milliunits/kg · min) clamp studies were performed. During physiologic hyperinsulinemia (plasma insulin ~65 microunits/ml), the rates of whole body glucose uptake, glycolysis, and glycogen syntheses and the rates of 2-deoxyglucose uptake in individual tissues were similar in Leptin - and Leptin +. Post-absorptive hepatic glucose production (HGP) was similar in the two groups. However, leptin enhanced insulin's inhibition of HGP (4.1 ± 0.7 and 6.2 ± 0.7 mg/kg · min; p < 0.05). The decreased HGP in the Leptin + group was due to a marked suppression of hepatic glycogenolysis (0.7 ± 0.1 versus 4.1 ± 0.6 mg/kg · min, in Leptin + versus Leptin -, respectively; p < 0.001), whereas the % contribution of gluconeogenesis to HGP was markedly increased (82 ± 3% versus 36 ± 4% in Leptin + and Leptin -, respectively; p < 0.001). At the end of the 6-h leptin infusion, the hepatic abundance of glucokinase mRNA was decreased, whereas that of phosphoenolpyruvate carboxykinase mRNA was increased compared with Leptin -. We conclude that an acute increase in plasma leptin 1) enhances insulin's ability to inhibit HGP, 2) does not affect peripheral insulin action, and 3) induces a redistribution of intrahepatic glucose fluxes and changes in the gene expression of hepatic enzymes that closely resemble those of fasting.

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