Growth hormone decreases the response to anti-lipolytic agonists and decreases the levels of Gi2 in rat adipocytes

Doris, Rosemarie; Vernon, Richard G.; Houslay, Miles D.; Kilgour, Elaine

doi:10.1042/bj2970041

Cited by 37 publications

(32 citation statements)

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“…In this study we could show that the effect of GH on lipid oxidation (and presumably lipolysis) is an acute effect, as the first injection of GH already increased the rate of lipid oxidation by 35%, and consequently decreased glucose oxidation by 26%. The mechanism by which GH stimulates lipolysis may involve several key steps including increased expression of b-adrenergic receptors (22), enhanced activity of the hormone-sensitive lipase (23) and inhibition of inhibitory G i proteins (24). A reduction in fat oxidation could shuttle FFA to re-esterification and fat synthesis unless this pathway is inhibited.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of lipolysis during acute GH exposure increases insulin sensitivity in previously untreated GH-deficient adults

Segerlantz¹,

Bramnert²,

Manhem³

et al. 2003

European Journal of Endocrinology

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Objective: Previous studies evaluating the lipolytic effect of GH have in general been performed in subjects on chronic GH therapy. In this study we assessed the lipolytic effect of GH in previously untreated patients and examined whether the negative effect of enhanced lipolysis on glucose metabolism could be counteracted by acute antilipolysis achieved with acipimox. Methods: Ten GH-deficient (GHD) adults participated in four experiments each, during which they received in a double-blind manner: placebo (A); GH (0.88^0.13 mg) (B); GH þ acipimox 250 mg b.i.d. (C); and acipimox b.i.d. (no GH) (D), where GH was given the night before a 2 h euglycemic, hyperinsulinemic clamp combined with infusion of [3-3 H]glucose and indirect calorimetry. Results: GH increased basal free fatty acid (FFA) levels by 74% (P ¼ 0.0051) and insulin levels by 93% (P ¼ 0.0051). This resulted in a non-significant decrease in insulin-stimulated glucose uptakes (16.61^8.03 vs 12.74^5.50 mmol/kg per min (S.D.), P ¼ 0.07 for A vs B). The rates of insulin-stimulated glucose uptake correlated negatively with the FFA concentrations (r ¼ 2 0.638, P , 0.0001). However, acipimox caused a significant improvement in insulin-stimulated glucose uptake in the GH-treated patients (17.35^5.65 vs 12.74^5.50 mmol/kg per min, P ¼ 0.012 for C vs B). The acipimox-induced enhancement of insulin-stimulated glucose uptake was mainly due to an enhanced rate of glucose oxidation (8.32^3.00 vs 5.88^2.39 mmol/kg per min, P ¼ 0.07 for C vs B). The enhanced rates of glucose oxidation induced by acipimox correlated negatively with the rate of lipid oxidation in GH-treated subjects both in basal (r ¼ 2 0.867, P ¼ 0.0093) and during insulinstimulated (r ¼ 2 0.927, P ¼ 0.0054) conditions. GH did not significantly impair non-oxidative glucose metabolism (6.86^5.22 vs 8.67^6.65 mmol/kg per min, P ¼ NS for B vs A). The fasting rate of endogenous glucose production was unaffected by GH and acipimox administration (10.99^1.98 vs 11.73^2.38 mmol/kg per min, P ¼ NS for B vs A and 11.55^2.7 vs 10.99^1.98 mmol/kg per min, P ¼ NS for C vs B). On the other hand, acipimox alone improved glucose uptake in the untreated GHD patients (24.14^8.74 vs 16.61^8.03 mmol/kg per min, P ¼ 0.0077 for D vs A) and this was again due to enhanced fasting (7.90^2.68 vs 5.16^2.28 mmol/kg per min, P ¼ 0.01 for D vs A) and insulin-stimulated (9.78^3.68 vs 7.95^2.64 mmol/kg per min, P ¼ 0.07 for D vs A) glucose oxidation. Conclusion: The study of acute administration of GH to previously untreated GHD patients provides compelling evidence that (i) GH-induced insulin resistance is mainly due to induction of lipolysis by GH; and (ii) inhibition of lipolysis can prevent the deterioration of insulin sensitivity. The question remains whether GH replacement therapy should, at least at the beginning of therapy, be combined with means to prevent an excessive stimulation of lipolysis by GH.

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Section: Discussionmentioning

confidence: 99%

Inhibition of lipolysis during acute GH exposure increases insulin sensitivity in previously untreated GH-deficient adults

Segerlantz¹,

Bramnert²,

Manhem³

et al. 2003

European Journal of Endocrinology

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“…Thus this and our previous study (Doris et al 1994) show that GH can alter the ability of antilipolytic agents, which act via G i , to inhibit lipolysis by at least two mechanisms: through a change in the concentration of G i 2 and through a change in the ability of one or more isoforms of G i to interact with adenylate cyclase. The latter involves a mechanism that appears to involve both gene transcription and protein serine/threonine phosphorylation.…”

Section: ·6 0·58 0·16mentioning

confidence: 99%

“…Treatment of such rats with ovine GH reversed the effects of the antiserum on both sensitivity to PIA and amount of G i 2 (Doris et al 1994).…”

Section: Introductionmentioning

confidence: 99%

“…Lowering serum GH concentrations in rats with a specific antiserum increased sensitivity (but not maximum response) to the adenosine analogue N 6 -phenylisopropyladenosine (PIA), and this was associated with an increase in the amount of the subunit of G i 2; ligand binding to the adenosine receptor and the amounts of the subunits of G i 1 and G i 3 were unchanged (Doris et al 1994). Treatment of such rats with ovine GH reversed the effects of the antiserum on both sensitivity to PIA and amount of G i 2 (Doris et al 1994).…”

Section: Introductionmentioning

confidence: 99%

“…Growth hormone (GH) acts chronically to increase lipolysis in adipocytes by several mechanisms including both an increased response and sensitivity to -adrenergic agonists and a decreased response and sensitivity to antilipolytic factors such as adenosine and prostaglandin E, the relative importance of these mechanisms depending on the physiological state of the animal , 1993, Goodman et al 1988, Watt et al 1991, Beauville et al 1992, Yang et al 1995, Doris et al 1994, 1996, Dante et al 1995. The increased response and sensitivity to -adrenergic agents induced by GH appears to be due to increases in the number of -adrenergic receptors (Watt et al 1991, Vernon et al 1993, Yang et al 1995, Doris et al 1996 and also a change in the ability of hormone-sensitive lipase to translocate to the fat droplet on activation (Vernon et al 1993).…”

Section: Introductionmentioning

confidence: 99%

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Regulation of the GTP-binding protein-based antilipolytic system of sheep adipocytes by growth hormone

Doris¹,

Kilgour²,

Houslay³

et al. 1998

Journal of Endocrinology

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Chronic exposure of sheep adipose tissue to growth hormone (GH) in vitro decreases the ability of the adenosine analogue, N 6 -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, G i , or the maximum (forskolin-stimulated) adenylate cyclase activity. The ability of GH to modulate the PIA-activated adenosine receptor to stimulate dissociation of heterotrimeric G i was assessed by measurement of pertussis toxin-catalysed ADP-ribosylation of G i ; GH does not appear to alter the interaction between the activated receptor and G i . The ability of GH to alter the ability of activated G i to inhibit adenylate cyclase activity was assessed by measuring the ability of a GTP analogue, guanosine 5 -[ -imido]triphosphate (p[NH]ppG), to inhibit forskolinstimulated 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 subunit of one or more isoforms of G i .

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Signaling Pathways Controlling Lipolysis and Lipid Mobilization in Humans

Lafontan

2010

Adipose Tissue in Health and Disease

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Growth hormone decreases the response to anti-lipolytic agonists and decreases the levels of Gi2 in rat adipocytes

Cited by 37 publications

References 24 publications

Inhibition of lipolysis during acute GH exposure increases insulin sensitivity in previously untreated GH-deficient adults

Inhibition of lipolysis during acute GH exposure increases insulin sensitivity in previously untreated GH-deficient adults

Regulation of the GTP-binding protein-based antilipolytic system of sheep adipocytes by growth hormone

Signaling Pathways Controlling Lipolysis and Lipid Mobilization in Humans

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