Early alteration of insulin stimulation of PI 3-kinase in muscle and adipocyte from gold thioglucose obese mice.
The activation of phosphatidylinositol 3-kinase (PIK) was studied in vivo and in vitro in soleus muscle and adipocytes from young (8 wk) and old (30 wk) gold thioglucose obese mice. Insulin resistance assessed from muscle glucose transport and glycogen synthesis was present both in young and old obese mice. Adipocyte lipid synthesis and muscle glycolysis or glucose oxidation are not defective in young obese mice but become resistant later on. After incubation with 50 nM insulin, muscle antiphosphotyrosine-immunoprecipitable PIK activity was stimulated 5- to 10-fold in both young and old animals. This response was impaired by 56 and 75% in muscles from young and old obese mice, respectively. Insulin stimulation of receptor tyrosine kinase activity was only slightly decreased in muscle of young obese mice, whereas insulin receptor substrate 1 (IRS-1) tyrosine phosphorylation was blunted. The altered PIK stimulation in muscle, which is present both in vivo and in vitro, is thus characterized by a reduced association of PIK activity with IRS-1 and appears to result from a diminished IRS-1 tyrosine phosphorylation. In adipocytes isolated from lean mice, antiphosphotyrosine-immunoprecipitable PIK increased 25-fold within 10 min of incubation with insulin. This stimulation was markedly altered both in young and old obese mice, whereas lipogenesis was insulin resistant only in old obese animals. In adipocytes from young obese mice, insulin's stimulatory effect on the phosphorylation of insulin receptor beta-subunit, pp60, and an exogenous substrate was normal, whereas IRS-1 tyrosine phosphorylation was markedly depressed.(ABSTRACT TRUNCATED AT 250 WORDS)
Heydrick
S J
SJ
Institut National de la Santé et de la Recherche Médicale U 145, Faculté de Médecine, Nice, France.
Gautier
N
N
Olichon-Berthe
C
C
Van Obberghen
E
E
Le Marchand-Brustel
Y
Y
D017667:Adipocytes / Q000201:enzymology*; D000273:Adipose Tissue / Q000201:enzymology; D000818:Animals; D006051:Aurothioglucose; D001692:Biological Transport; D004822:Epididymis; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009124:Muscle Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000201:enzymology; D009132:Muscles / Q000201:enzymology*; D009765:Obesity / Q000139:chemically induced / Q000201:enzymology*; D019869:Phosphatidylinositol 3-Kinases; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
D007328:Insulin; D009124:Muscle Proteins; D006051:Aurothioglucose; D014443:Tyrosine; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D020794:Receptor Protein-Tyrosine Kinases; D005947:Glucose