Inhibition of growth hormone action improves insulin sensitivity in liver IGF-1–deficient mice

Yakar, Shoshana; Setser, Jennifer; Zhao, Hong; Stannard, Bethel; Haluzı́k, Martin; Glatt, Vaida; Bouxsein, Mary L.; Kopchick, John J.; LeRoith, Derek

doi:10.1172/jci200417763

Cited by 205 publications

(122 citation statements)

References 64 publications

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“…This notion is consistent with results from a recent study where liver IGF-1-deficient (LID) mice-having increased plasma GH because of lack of IGF-1 negative feedback on GH secretion-were crossed with transgenic mice expressing a GH antagonist (GHa) to block GH action. The resulting LID ϩ GHa mice showed improved total body insulin sensitivity and increased insulin-stimulated glucose uptake in WAT and muscle, despite a twofold increase in adipose tissue mass (42). We propose that the dissociation between insulin sensitivity and adiposity in mouse models with altered GH action is best explained by direct effects of GH action in adipose tissue.…”

Section: Discussionmentioning

confidence: 86%

Growth Hormone Regulation of p85α Expression and Phosphoinositide 3-Kinase Activity in Adipose Tissue

et al. 2007

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Phosphoinositide (PI) 3-kinase is involved in insulin-mediated effects on glucose uptake, lipid deposition, and adiponectin secretion from adipocytes. Genetic disruption of the p85␣ regulatory subunit of PI 3-kinase increases insulin sensitivity, whereas elevated p85␣ levels are associated with insulin resistance through PI 3-kinase-dependent and -independent mechanisms. Adipose tissue plays a critical role in the antagonistic effects of growth hormone (GH) on insulin actions on carbohydrate and lipid metabolism through changes in gene transcription. The objective of this study was to assess the role of the p85␣ subunit of PI 3-kinase and PI 3-kinase signaling in GH-mediated insulin resistance in adipose tissue. To do this, p85␣ mRNA and protein expression and insulin receptor substrate (IRS)-1-associated PI 3-kinase activity were measured in white adipose tissue (WAT) of mice with GH excess, deficiency, and sufficiency. Additional studies using 3T3-F442A cells were conducted to confirm direct effects of GH on free p85␣ protein abundance. We found that p85␣ expression 1) is decreased in WAT from mice with isolated GH deficiency, 2) is increased in WAT from mice with chronic GH excess, 3) is acutely upregulated in WAT from GH-deficient and -sufficient mice after GH administration, and 4) is directly upregulated by GH in 3T3-F442A adipocytes. The insulininduced increase in PI 3-kinase activity was robust in mice with GH deficiency, but not in mice with GH excess. In conclusion, GH regulates p85␣ expression and PI 3-kinase activity in WAT and provides a potential explanation for 1) the insulin hypersensitivity and associated obesity and hyperadiponectinemia of GH-deficient mice and 2) the insulin resistance and associated reduced fat mass and hypoadiponectinemia of mice with GH excess. Diabetes

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Section: Discussionmentioning

confidence: 86%

Growth Hormone Regulation of p85α Expression and Phosphoinositide 3-Kinase Activity in Adipose Tissue

et al. 2007

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“…Thus, it is possible that the observed supraphysiological circulating GH levels could directly elicit a variety of detrimental responses in peripheral tissues, which could contribute to the development of premature aging. Interestingly, liver-specific knockout mice with reduced IGF-1 and increased GH circulating levels exhibited metabolic defects that could be corrected by the administration of a GH antagonist (47). This demonstrates that high levels of circulating GH can be detrimental and contribute to a shortened lifespan.…”

Section: Discussionmentioning

confidence: 99%

Insulin-like growth factor 1 treatment extends longevity in a mouse model of human premature aging by restoring somatotroph axis function

Mariño¹,

Ugalde²,

Fernández³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

128

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Zmpste24 (also called FACE-1) is a metalloproteinase involved in the maturation of lamin A, an essential component of the nuclear envelope. Zmpste24-deficient mice exhibit multiple defects that phenocopy human accelerated aging processes such as HutchinsonGilford progeria syndrome. In this work, we report that progeroid Zmpste24 -/− mice present profound transcriptional alterations in genes that regulate the somatotroph axis, together with extremely high circulating levels of growth hormone (GH) and a drastic reduction in plasma insulin-like growth factor 1 (IGF-1). We also show that recombinant IGF-1 treatment restores the proper balance between IGF-1 and GH in Zmpste24 -/− mice, delays the onset of many progeroid features, and significantly extends the lifespan of these progeroid animals. Our findings highlight the importance of IGF/GH balance in longevity and may be of therapeutic interest for devastating human progeroid syndromes associated with nuclear envelope abnormalities.

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“…It is well known that growth hormone can exhibit diabetogenic or anti-insulin activities [24]. Indeed, it has been suspected to cause insulin resistance in tissues containing both growth hormone and insulin receptors, such as liver, muscle and fat, all of which [25][26][27][28] have been shown to be affected by acute growth hormone administration and to exhibit insulin resistance. The specific mechanisms responsible for insulin resistance caused by growth hormone remain unknown.…”

Section: Discussionmentioning

confidence: 99%

Growth hormone improves body composition, fasting blood glucose, glucose tolerance and liver triacylglycerol in a mouse model of diet-induced obesity and type 2 diabetes

et al. 2009

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Aims/hypothesis Growth hormone has been used experimentally in two studies to treat individuals with type 2 diabetes, with both reporting beneficial effects on glucose metabolism. However, concerns over potential diabetogenic actions of growth hormone complicate its anticipated use to treat type 2 diabetes. Thus, an animal model of type 2 diabetes could help evaluate the effects of growth hormone for treating this condition. Methods Male C57BL/6J mice were placed on a high-fat diet to induce obesity and type 2 diabetes. Starting at 16 weeks of age, mice were treated once daily for 6 weeks with one of four different doses of growth hormone. Body weight, body composition, fasting blood glucose, insulin, glucose tolerance, liver triacylglycerol, tissue weights and blood chemistries were determined. Results Body composition measurements revealed a dosedependent decrease in fat and an increase in lean mass. Analysis of fat loss by depot revealed that subcutaneous and mesenteric fat was the most sensitive to growth hormone treatment. In addition, growth hormone treatment resulted in improvement in glucose metabolism, with the highest dose normalising glucose, glucose tolerance and liver triacylglycerol. In contrast, insulin levels were not altered by the treatment, nor did organ weights change. However, fasting plasma leptin and resistin were significantly decreased after growth hormone treatment. Conclusions/interpretation Growth hormone therapy improves glucose metabolism in this mouse model of obesity and type 2 diabetes, providing a means to explore the molecular mechanism(s) of this treatment.

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Inhibition of growth hormone action improves insulin sensitivity in liver IGF-1–deficient mice

Cited by 205 publications

References 64 publications

Growth Hormone Regulation of p85α Expression and Phosphoinositide 3-Kinase Activity in Adipose Tissue

Growth Hormone Regulation of p85α Expression and Phosphoinositide 3-Kinase Activity in Adipose Tissue

Insulin-like growth factor 1 treatment extends longevity in a mouse model of human premature aging by restoring somatotroph axis function

Growth hormone improves body composition, fasting blood glucose, glucose tolerance and liver triacylglycerol in a mouse model of diet-induced obesity and type 2 diabetes

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