Integration of insulin and amino acid signals that regulate hepatic metabolism-related gene expression in rainbow trout: role of TOR
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Amino acids are considered to be regulators of metabolism in several species, and increasing importance has been accorded to the role of amino acids as signalling molecules regulating protein synthesis through the activation of the TOR transduction pathway. Using rainbow trout hepatocytes, we examined the ability of amino acids to regulate hepatic metabolism-related gene expression either alone or together with insulin, and the possible involvement of TOR. We demonstrated that amino acids alone regulate expression of several genes, including glucose-6-phosphatase, phosphoenolpyruvate carboxykinase, pyruvate kinase, 6-phospho-fructo-1-kinase and serine dehydratase, through an unknown molecular pathway that is independent of TOR activation. When insulin and amino acids were added together, a different pattern of regulation was observed that depended upon activation of the TOR pathway. This pattern included a dramatic up-regulation of lipogenic (fatty acid synthase, ATP-citrate lyase and sterol responsive element binding protein 1) and glycolytic (glucokinase, 6-phospho-fructo-1-kinase and pyruvate kinase) genes in a TOR-dependent manner. Regarding gluconeogenesis genes, only glucose-6-phosphatase was inhibited in a TOR-dependent manner by combination of insulin and amino acids and not by amino acids alone. This study is the first to demonstrate an important role of amino acids in combination with insulin in the molecular regulation of hepatic metabolism.
KeywordsAmino acids Insulin TOR Hepatic gene expression Metabolism
We thank M. Larquier and L. Gruyère for technical assistance, and F. Terrier, Y. Hontang and F. Sandres for fish rearing in the INRA experimental farm (Donzacq, France). This study was supported by the European Union 6th Framework project (Contract No. 016249-2, Sustainable aquafeeds to maximise the health benefits of farmed fish for consumers—AQUAMAX), French national research agency (ANR-08-JCJC-0025, Low utilisation of dietary carbohydrates in carnivorous rainbow trout: role of amino acids, glucose and insulin interactions?) and the Aquitaine Region (No. CCRRDT-20051303004AB). The AQUAMAX European project (Contract No. 016249-2) also provided M.L. with a fellowship.
Conflict of interest statement
- Barbosa-Tessmann IP, Chen C, Zhong C, Siu F, Schuster SM, Nick HS, Kilberg MS (2000) Activation of the human asparagine synthetase gene by the amino acid response and the endoplasmic reticulum stress response pathways occurs by common genomic elements. J Biol Chem 275:26976–26985PubMedGoogle Scholar
- Barthel A, Schmoll D (2003) Novel concepts in insulin regulation of hepatic gluconeogenesis. Am J Physiol 285:E685–E692Google Scholar
- Committee on Animal Nutrition, Board of Agriculture, National Research Council (1993) Nutrient requirements of fish. National Academy Press, Washington, DCGoogle Scholar
- Mommsen TP, Moon TW, Walsh TJ (1994) Hepatocytes: isolation, maintenance and utilization. In: Hochachka PW, Mommsen TP (eds) Biochemistry and molecular biology of fishes. Elsevier Science B.V, AmsterdamGoogle Scholar
- Plagnes-Juan E, Lansard M, Seiliez I, Medale F, Corraze G, Kaushik S, Panserat S, Skiba-Cassy S (2008) Insulin regulates the expression of several metabolism-related genes in the liver and primary hepatocytes of rainbow trout (Oncorhynchus mykiss). J Exp Biol 211:2510–2518CrossRefPubMedGoogle Scholar
- Polakof S, Skiba-Cassy S, Panserat S (2009) Glucose homeostasis is impaired by a paradoxical interaction between metformin and insulin in carnivorous rainbow trout. Am J Physiol Regul Integr Comp Physiol 297:R1769–R1776Google Scholar
- Seiliez I, Gabillard JC, Skiba-Cassy S, Garcia-Serrana D, Gutierrez J, Kaushik S, Panserat S, Tesseraud S (2008) An in vivo and in vitro assessment of TOR signaling cascade in rainbow trout (Oncorhynchus mykiss). Am J Physiol Regul Integr Comp Physiol 295:329–335Google Scholar
- Skiba-Cassy S, Lansard M, Panserat S, Medale F (2009) Rainbow trout genetically selected for greater muscle fat content display increased activation of liver TOR signaling and lipogenic gene expression 10.1152/ajpregu.00312.2009. Am J Physiol Regul Integr Comp Physiol 297:R1421–R1429PubMedGoogle Scholar
- Tremblay F, Lavigne C, Jacques H, Marette A (2007b) Role of dietary proteins and amino acids in the pathogenesis of insulin resistance. Annu Rev Nutr 27Google Scholar