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Chronic exposure of sheep adipose tissue to growth hormone (GH) in vitro decreases the ability of the adenosine analogue, N6-phenylisopropyladenosine (PIA), to inhibit isoprenaline-stimulated lipolysis by a mechanism which is dependent on both gene transcription and protein serine/threonine phosphorylation. The inhibition is not due to a change in ligand binding to the adenosine receptor, the amounts of the three isoforms of the inhibitory GTP-binding protein, Gi, or the maximum (forskolin-stimulated) adenylate cyclase activity. The ability of GH to modulate the PIA-activated adenosine receptor to stimulate dissociation of heterotrimeric Gi was assessed by measurement of pertussis toxin-catalysed ADP-ribosylation of Gi; GH does not appear to alter the interaction between the activated receptor and Gi. The ability of GH to alter the ability of activated Gi to inhibit adenylate cyclase activity was assessed by measuring the ability of a GTP analogue, guanosine 5'-[beta gamma-imido]triphosphate (p[NH]ppG), to inhibit forskolin-stimulated adenylate cyclase activity; chronic exposure to GH prevented this effect of p[NH]ppG. Thus the attenuation of the inhibition of lipolysis by PIA by chronic exposure of adipocytes to GH appears to be due to an impairment in the interaction between adenylate cyclase and the alpha subunit of one or more isoforms of Gi.
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Abstract
The effect of GH, in vivo, on the glucose transport systems of rat adipocytes has been investigated. Lowering of serum GH levels, by treatment of rats with an antiserum specific for rat GH (anti-rGH), significantly decreased serum levels of both IGF-I and insulin. Treatment with anti-rGH also increased glucose oxidation and the conversion of glucose to lipid by isolated adipocytes. Adipocyte glucose oxidation and lipid synthesis were measured in the presence of a limiting concentration of glucose and therefore reflect changes in glucose transport. Immunoblot analysis of adipocyte subcellular fractions revealed that anti-rGH induced an increase in the amount of the glucose transporters GLUT1 (1·6-fold) and GLUT4 (2·5-fold) present in plasma membranes and a decrease (39%) in the amount of GLUT4 present in low-density microsomal fractions. Lowering of serum GH also increased, by 36%, the amount of GLUT1 present in a total membrane fraction but had no such effect on GLUT4 levels. Replenishment of serum GH, by concurrent administration of ovine GH to rats, prevented all of these effects of anti-rGH. It was concluded that GH in vivo down-regulates the amount of both GLUT1 and GLUT4 present in rat adipocyte plasma membranes. This reflects a decrease in the total cellular levels of GLUT1 and modification of the subcellular distribution of GLUT4 and results in restriction of adipocyte glucose uptake.
Journal of Endocrinology (1995) 145, 27–33
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Abstract
The molecular basis of the insulin resistance of adipocytes and skeletal muscle during lactation has been investigated in sheep. The number of insulin receptors per adipocyte or per unit membrane protein for skeletal muscle is unchanged by lactation. The ability of insulin to stimulate autophosphorylation of its β-subunit was enhanced in adipocytes but not in skeletal muscle during lactation. This increased autophosphorylation was due, at least in part, to enhanced tyrosine phosphorylation and was found when both solubilised, immunoprecipitated insulin receptors and intact adipocytes were incubated with insulin. The ability of the insulin receptor kinase to phosphorylate other proteins did not appear to be altered by lactation; this was shown with lectin-purified insulin receptors using the artificial substrate, polyglutamyl tyrosine, and in intact adipocytes. Lactation had no effect on the ability of insulin to activate two key downstream kinases, mitogenactivated protein kinase and phosphatidyl inositol-3-kinase in adipocytes. The study thus shows that the insulin resistance of lactation in sheep is due to changes downstream of the receptor in both adipocytes and skeletal muscle.
Journal of Endocrinology (1996) 151, 469–480
