Growth hormone signaling and action in obese versus lean human subjects

Høgild, Morten Lyng; Bak, Ann Mosegaard; Pedersen, Steen B.; Rungby, Jørgen; Frystyk, Jan; Møller, Niels; Jessen, Niels; Jørgensen, Jens Otto Lunde

doi:10.1152/ajpendo.00431.2018

Cited by 15 publications

(11 citation statements)

References 49 publications

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“…Since rodents do not express GH-V, the high secretion of the pituitary version of GH, especially during late pregnancy (23,32,77), may be associated with the gestational insulin resistance. It is well known that GH from pituitary also possesses potent diabetogenic effects and inhibits insulin action (19,37,38,44,45). Thus, our findings provide new evidence indicating that central GH action regulates insulin sensitivity during pregnancy, since ablation of GHR in the entire brain or in LepR-expressing cells protects mice from gestational insulin resistance (Fig.…”

Section: Discussionsupporting

confidence: 65%

Central growth hormone action regulates metabolism during pregnancy

Teixeira

Couto

Furigo

et al. 2019

American Journal of Physiology-Endocrinology and Metabolism

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The maternal organism undergoes numerous metabolic adaptations to become prepared for the demands associated with the coming offspring. These metabolic adaptations involve changes induced by several hormones that act at multiple levels, ultimately influencing energy and glucose homeostasis during pregnancy and lactation. Previous studies have shown that central growth hormone (GH) action modulates glucose and energy homeostasis. However, whether central GH action regulates metabolism during pregnancy and lactation is still unknown. In the present study, we generated mice carrying ablation of GH receptor (GHR) in agouti-related protein (AgRP)–expressing neurons, in leptin receptor (LepR)–expressing cells or in the entire brain to investigate the role played by central GH action during pregnancy and lactation. AgRP-specific GHR ablation led to minor metabolic changes during pregnancy and lactation. However, while brain-specific GHR ablation reduced food intake and body adiposity during gestation, LepR GHR knockout (KO) mice exhibited increased leptin responsiveness in the ventromedial nucleus of the hypothalamus during late pregnancy, although their offspring showed reduced growth rate. Additionally, both Brain GHR KO and LepR GHR KO mice had lower glucose tolerance and glucose-stimulated insulin secretion during pregnancy, despite presenting increased insulin sensitivity, compared with control pregnant animals. Our findings revealed that during pregnancy central GH action regulates food intake, fat retention, as well as the sensitivity to insulin and leptin in a cell-specific manner. Together, the results suggest that GH acts in concert with other “gestational hormones” to prepare the maternal organism for the metabolic demands of the offspring.

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Section: Discussionsupporting

confidence: 65%

Central growth hormone action regulates metabolism during pregnancy

Teixeira

Couto

Furigo

et al. 2019

American Journal of Physiology-Endocrinology and Metabolism

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“…We have repeatedly observed STAT5 activation in human skeletal muscle and adipose tissue in vivo following exogenous GH exposure together with increased mRNA expression of CISH and SOCS . 16 , 32 , 33 , 34 , 35 The present study is the first to document that sustained endogenous GH overproduction induces detectable activation of STAT5 signalling in adipose tissue, which illustrates the importance of adipose tissue as a direct GH target. We have previously reported that fatty acid infusion dampens GH-induced pSTAT5 expression in adipose tissue in healthy human subjects, 36 but the present data suggest that active acromegaly may override any such feedback suppression.…”

Section: Discussionsupporting

confidence: 53%

Reversible insulin resistance in muscle and fat unrelated to the metabolic syndrome in patients with acromegaly

et al. 2022

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Summary Background Patients with active acromegaly exhibit insulin resistance despite a lean phenotype whereas controlled disease improves insulin sensitivity and increases fat mass. The mechanisms underlying this paradox remain elusive, but growth hormone (GH)-induced lipolysis plays a central role. The aim of the study was to investigative the molecular mechanisms of insulin resistance dissociated from obesity in patients with acromegaly. Methods In a prospective study, twenty-one patients with newly diagnosed acromegaly were studied at diagnosis and after disease control obtained by either surgery alone (n=10) or somatostatin analogue (SA) treatment (n=11) with assessment of body composition (DXA scan), whole body and tissue-specific insulin sensitivity and GH and insulin signalling in adipose tissue and skeletal muscle. Findings Disease control of acromegaly significantly reduced lean body mass (p<0.001) and increased fat mass (p<0.001). At diagnosis, GH signalling (pSTAT5) was constitutively activated in fat and enhanced expression of GH-regulated genes (CISH and IGF-I) were detected in muscle and fat. Insulin sensitivity in skeletal muscle, liver and adipose tissue increased after disease control regardless of treatment modality. This was associated with enhanced insulin signalling in both muscle and fat including downregulation of phosphatase and tensin homolog (PTEN) together with reduced signalling of GH and lipolytic activators in fat. Interpretation In conclusion, the study support that uncontrolled lipolysis is a major feature of insulin resistance in active acromegaly, and is characterized by upregulation of PTEN and suppression of insulin signalling in both muscle and fat. Funding This work was supported by a grant from the Independent Research Fund, Denmark (7016-00303A) and from the Alfred Benzon Foundation, Denmark.

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“…GH signaling and action has been evaluated in obese patients. Hogild et al have found that GH signaling is normal in obesity and there is increased hepatic GH sensitivity, suggesting that the blunted GH levels in obesity may protect against insulin resistance without compromising IGF-1 levels [ 54 ]. In another study Glad et al have found that GH receptor expression was decreased in subjects with obesity compared with subjects with normal weight; GH receptor was increased in response to energy restriction and decreased in response to overfeeding.…”

Section: Discussionmentioning

confidence: 99%

Altered GH-IGF-1 Axis in Severe Obese Subjects is Reversed after Bariatric Surgery-Induced Weight Loss and Related with Low-Grade Chronic Inflammation

Juiz-Valiña

Pena-Bello

Cordido

et al. 2020

JCM

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Endocrine disorders are common in obesity, including altered somatotropic axis. Obesity is characterized by reduced growth hormone (GH) secretion, although the insulin-like growth factor-1 (IGF-1) values are controversial. The aim of this study was to evaluate the effect of weight loss after bariatric surgery in the GH–IGF-1 axis in extreme obesity, in order to investigate IGF-1 values and the mechanism responsible for the alteration of the GH–IGF-1 axis in obesity. We performed an interventional trial in morbidly obese patients who underwent bariatric surgery. We included 116 patients (97 women) and 41 controls (30 women). The primary endpoint was circulating GH and IGF-1 values. Circulating IGF-1 values were lower in the obese patients than in the controls. Circulating GH and IGF-1 values increased significantly over time after surgery. Post-surgery changes in IGF-1 and GH values were significantly negatively correlated with changes in C-reactive protein (CRP) and free T4 values. After adjusting for preoperative body mass index (BMI), free T4 and CRP in a multivariate model, only CRP was independently associated with IGF-1 values in the follow-up. In summary, severe obesity is characterized by a functional hyposomatotropism at central and peripheral level that is progressively reversible with weight loss, and low-grade chronic inflammation could be the principal mediator.

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Growth hormone signaling and action in obese versus lean human subjects

Cited by 15 publications

References 49 publications

Central growth hormone action regulates metabolism during pregnancy

Central growth hormone action regulates metabolism during pregnancy

Reversible insulin resistance in muscle and fat unrelated to the metabolic syndrome in patients with acromegaly

Altered GH-IGF-1 Axis in Severe Obese Subjects is Reversed after Bariatric Surgery-Induced Weight Loss and Related with Low-Grade Chronic Inflammation

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