Acipimox enhances spontaneous growth hormone secretion in obese women

Kok, Petra; Buijs, Madelon M.; Kok, Simon W.; Ierssel, Inge H. A. P. van; Frölich, Marijke; Roelfsema, Ferdinand; Voshol, Peter J.; Meinders, A. E.; Pijl, Hanno

doi:10.1152/ajpregu.00595.2003

Cited by 40 publications

(35 citation statements)

References 60 publications

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“…The dose used was 250 mg four times per day starting on the day before blood sampling till the end of sampling. Free fatty acids (FFAs) decreased from 0.52G0.04 to 0.40G0.03 mmol/l, PZ0.005, GH secretion increased by 70%, and ACTH secretion decrease by 30%, as reported previously (12,13). Fourteen other obese women were treated with 5 mg bromocriptine in two divided doses for 10 days in an attempt to improve the metabolic state.…”

Section: Subjectsmentioning

confidence: 62%

Diminished adrenal sensitivity and ACTH efficacy in obese premenopausal women

Roelfsema

Pijl

Keenan

et al. 2012

European Journal of Endocrinology

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Background: The ACTH-cortisol axis in women is activated and associated with decreased ACTH potency, estimated by relating ACTH and cortisol pulse masses. Recently, a new accurate method for constructing the endogenous dose-response relationship was introduced, which is based on the relation between ACTH concentrations and associated cortisol secretion rates within cortisol bursts. Hypothesis: The endogenous dose-response relation between ACTH and cortisol in obesity is changed, leading to diminished responsiveness. Subjects: Twenty-five obese premenopausal women and 16 normal weight premenopausal women were studied by 10-min blood sampling for 24 h. Outcomes: ACTH and cortisol secretion rates, analytical dose-response estimates of endogenous ACTH efficacy (maximal cortisol secretion), dynamic ACTH potency, and adrenal sensitivity (slope term) from 24-h ACTH-cortisol profiles were quantified. Results: The initial potency (negative logarithm) was K7.83G0.75 (meanGS.E.M.) in obese women and K10.14G1.08 in lean women (PZ0.10), and the corresponding values for the recovery phase were K26.62G2.21 and K36.67G1.66 (PZ0.004). The sensitivity (curve slope) amounted to 0.468G0.05 in obese women and 0.784G0.09 in normal weight women (PZ0.004). The efficacy (maximal value) was 17.6G4.9 nmol/l per min in obese women and 26.3G3.8 nmol/l per min in normal weight women (PZ0.009). Basal secretion rate, inflection point, and EC 50 values were not different. Bromocriptine or acipimox did not change the dose-response curve. Conclusion: The ACTH-cortisol relation in obesity in women is characterized by decreased sensitivity and efficacy, thus explaining non-elevated serum cortisol concentrations despite increased plasma ACTH levels.

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Section: Subjectsmentioning

confidence: 62%

Diminished adrenal sensitivity and ACTH efficacy in obese premenopausal women

Roelfsema

Pijl

Keenan

et al. 2012

European Journal of Endocrinology

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“…Figure 2 shows that this intervention did not reduce plasma PAI-1 levels but, on the contrary, resulted in a moderate increase in plasma PAI-1 levels in the group of obese women. Hence, these experimental findings along with findings for the acipimox intervention 15 exclude GH deficiency as the direct cause of elevated PAI-1 levels in individuals with visceral obesity.…”

Section: Visceral Adipose Tissue Is Not a Relevant Source Of Proinflamentioning

confidence: 64%

Section: Discussionmentioning

confidence: 99%

“…Short-term treatment with antilipolytic drug acipimox 15 has been shown to reduce FFA plasma levels and increase GH levels. 15 Yet, despite reduced plasma FFA levels, acipimox treatment did not influence plasma PAI-1 levels. Hence, these findings, along with the data from the short-term GH supplementation study, exclude increased FFA availability or the hyposomatropism of obesity as the direct cause of elevated PAI-1 levels in visceral obesity.…”

Section: Discussionmentioning

confidence: 99%

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Human visceral adipose tissue and the plasminogen activator inhibitor type 1

Lindeman

Pijl

Toet³

et al. 2007

Int J Obes

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Objective: The objective of this study was to systematically evaluate the molecular basis of the association between visceral fat mass and plasma plasminogen activator inhibitor-1 (PAI-1) levels in man. Design: A comprehensive approach comprising observational, in vitro, and human intervention studies. Measurements and results:We confirmed an exclusive relationship between visceral fat and plasma PAI-1 levels (r ¼ 0.79, Po0.001) and corroborated preferential PAI-1 release from adipose tissue explants. Yet, messenger RNA analysis and in vivo measurement of PAI-1 release from visceral fat (AV-differences over the omentum) not only excluded visceral adipose tissue as a relevant source of circulating PAI-1, but also excluded visceral fat as a significant source of proinflammatory mediators such as tumor necrosis factor-a, IL-1 or transforming growth factor-b that could induce PAI-1 expression in tissues other than visceral fat. Short-term interventions with acipimox and growth hormone (GH) as well as statistical evaluation excluded free fatty acids and GH as metabolic links. Further analysis of the metabolic data in a stepwise regression model indicated that plasma PAI-1 levels and visceral fat rather are co-correlates that both relate to impaired lipid handling. Conclusion: Our PAI-1 studies show that visceral fat mass and plasma PAI-1 levels are co-correlated rather than causatively related, with lipid load as common denominator.

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“…An acute elevation in circulating FFA can not only suppress GH release; conversely an acute reduction circulating FFA by acipimox (an anti-lipolytic agent), results in enhanced basal and GHRH-stimulated GH release in lean and obese subjects (Nam et al 1996, Kok et al 2004). However, GH release in obese subjects treated with acipimox is less than that observed in lean controls, suggesting FFA-mediated suppression of GH release may contribute to obesity-associated GH suppression, but it is not the only component.…”

Section: Direct Effects Of Ffamentioning

confidence: 99%

Examination of the direct effects of metabolic factors on somatotrope function in a non-human primate model, Papio anubis

Luque¹,

Gahete²,

Valentine³

et al. 2006

Journal of Molecular Endocrinology

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In humans, circulating GH levels are increased in catabolic states and suppressed in obesity. In both extremes, normalization of the metabolic environment normalizes GH release, leading to the conclusion that changes in metabolic hormones and/or metabolites promote changes in GH synthesis and release. Metabolic regulation of GH secretion can be mediated centrally by modulation of hypothalamic GHRH and somatostatin input to the pituitary and/or by direct regulation of pituitary somatotrope function. Although data are available showing glucocorticoids, free fatty acids (FFA), IGF-I, and insulin have direct effects on rat somatotrope function, little information is available regarding the direct pituitary effects of these metabolic factors in primates. Therefore, this study examined the effects of glucocorticoids (dexamethasone (0.1-100 nM) and hydrocortisone (10 nM)), FFA (oleic and linoleic acid, 100 and 400 mM each), IGF-I (0.5-50 nM), and insulin (0.5-50 nM) on GH release and GH, GHRH-receptor (GHRH-R) and ghrelin-receptor (GHS-R) mRNA levels, in primary pituitary cell cultures of baboons (Papio anubis) after 24 h treatment. A commercial ELISA kit was used to determine the amount of GH released into the media, while quantitative real-time reverse transcription-PCR was used to determine mRNA levels. To design species-specific primers for baboon GH, GHRH-R, GHS-R, insulin receptor (INSR), IGF-I receptor (IGF-IR), pituitary-specific transcription factor-1 (Pit-1), and cyclophilin A (used as a housekeeping gene) cDNA, sequence data for each baboon transcript were obtained and this data were submitted to Genbank. Glucocorticoids, FFA, insulin and IGF-I treatment did not significantly alter the expression of Pit-1, a transcription factor essential for normal somatotrope development and function. However, as previously reported in the rat, glucocorticoids increased, while FFA, IGF-I and insulin decreased GH release in baboon pituitary cell cultures, where changes in GH release were reflected by comparable changes in GH mRNA levels. In addition, glucocorticoids increased, while FFA, IGF-I and insulin decreased the expression of the GH stimulatory receptors, GHRH-R and GHS-R, without significantly altering cyclophilin A mRNA levels. A role of insulin/INSR pathway, independent of IGF-I, in regulating pituitary function is supported by the fact that (1) IGF-I and insulin significantly suppressed somatotrope function at doses (0.5 and 5 nM respectively) not anticipated to activate their respective receptors, and (2) the baboon pituitary expresses INSR mRNA at levels comparable to or greater than that of tissues commonly considered as insulin sensitive (i.e. liver, skeletal muscle, and fat). Taken together, these results demonstrate that metabolic factors can directly modulate primate somatotrope function through regulating GH synthesis and release, as well as mediating the expression of receptors important in central (GHRH) and systemic (ghrelin) regulation of GH secretion.

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Acipimox enhances spontaneous growth hormone secretion in obese women

Cited by 40 publications

References 60 publications

Diminished adrenal sensitivity and ACTH efficacy in obese premenopausal women

Diminished adrenal sensitivity and ACTH efficacy in obese premenopausal women

Human visceral adipose tissue and the plasminogen activator inhibitor type 1

Examination of the direct effects of metabolic factors on somatotrope function in a non-human primate model, Papio anubis

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