Adiponectin in mice with altered GH action: links to insulin sensitivity and longevity?

Lubbers, Ellen R.; List, Edward O.; Jara, Adam; Sackman-Sala, Lucila; Córdoba-Chacón, José; Gahete, Manuel D.; Kineman, Rhonda D; Boparai, Ravneet K.; Bartke, Andrzej; Kopchick, John J.; Berryman, Darlene E.

doi:10.1530/joe-12-0505

Cited by 53 publications

(55 citation statements)

References 58 publications

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“…Adapted with permission [91] fundamental requirement for GH action in one depot and the independence of GH action in the SubQ depot for proliferation/differentiation demonstrate an inherent difference in AT depots of GHR−/− mice. Further differences in adipokine secretions and expression of genes related to lipid metabolism among various depots (most notably, epididymal and SubQ depots) have been reported [138,140,141]. Cellular senescence, although apparently depot-dependent, is altered in the AT of these mice.…”

Section: Obesity and Depot-specific Alterations In Gh Mouse Linesmentioning

confidence: 90%

Living Large: What Mouse Models Reveal about Growth Hormone and Obesity

Berryman

Householder

Lesende

et al. 2015

Energy Balance and Cancer

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Growth hormone (GH) regulates a broad spectrum of biological processes in addition to promoting longitudinal growth. As such, GH influences most organ and cellular systems in the body with adipose tissue being one of its wellestablished targets. This chapter will describe mouse lines with specific alteration in GH action. Mice with increased, decreased, and absence of GH action have a unique phenotype for which clinical equivalents exist (acromegaly, GH deficiency, and Laron syndrome, respectively). Interestingly, these mouse lines demonstrate adiposity profiles that are counterintuitive to health and longevity. That is, mice with excess GH action are lean but insulin resistant, prone to cancer, and short-lived (or "unhealthy lean"). On the other hand, mice with no GH action are obese but insulin sensitive, resistant to cancer, and long-lived (or "healthy obesity"). These extremes in GH action provide fascinating mouse strains with which to study the features of fat that are responsible for metabolic dysfunction and to explore traits that are obligatory for cancer or lifespan.

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Section: Obesity and Depot-specific Alterations In Gh Mouse Linesmentioning

confidence: 90%

Living Large: What Mouse Models Reveal about Growth Hormone and Obesity

Berryman

Householder

Lesende

et al. 2015

Energy Balance and Cancer

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“…Several studies have shown that both GH and PRL can modulate adiponectin levels (2,3,6,34,40). Therefore, we investigated the effects of these STAT5 activators on adiponectin protein levels in fat cells.…”

Section: E131 Stat5 Regulates Adiponectinmentioning

confidence: 99%

“…Some studies have shown that STAT5 activator GH or PRL can reduce the production and secretion of adiponectin. Mice treated with bovine GH have decreased total and high-molecular weight adiponectin (34). In cultured human adipose tissue, adiponectin secretion is significantly suppressed by PRL (40).…”

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confidence: 98%

The modulation of adiponectin by STAT5-activating hormones

White

Maier

Zhao

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

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White UA, Maier J, Zhao P, Richard AJ, Stephens JM. The modulation of adiponectin by STAT5-activating hormones. Am J Physiol Endocrinol Metab 310: E129 -E136, 2016. First published November 25, 2015 doi:10.1152/ajpendo.00068.2015.-Adiponectin is a hormone secreted from adipocytes that plays an important role in insulin sensitivity and protects against metabolic syndrome. Growth hormone (GH) and prolactin (PRL) are potent STAT5 activators that regulate the expression of several genes in adipocytes. Studies have shown that the secretion of adiponectin from adipose tissue is decreased by treatment with PRL and GH. In this study, we demonstrate that 3T3-L1 adipocytes treated with GH or PRL exhibit a reduction in adiponectin protein levels. Furthermore, we identified three putative STAT5 binding sites in the murine adiponectin promoter and show that only one of these, located at Ϫ3,809, binds nuclear protein in a GH-or PRL-dependent manner. Mutation of the STAT5 binding site reduced PRL-dependent protein binding, and supershift analysis revealed that STAT5A and -5B, but not STAT1 and -3, bind to this site in response to PRL. Chromatin immunoprecipitation (IP) analysis demonstrated that only STAT5A, and not STAT1 and -3, bind to the murine adiponectin promoter in a GH-dependent manner in vivo. Adiponectin promoter/reporter constructs were responsive to GH, and chromatin IP analysis reveals that STAT5 binds the adiponectin promoter in vivo following GH stimulation. Overall, these data strongly suggest that STAT5 activators regulate adiponectin transcription through the binding of STAT5 to the Ϫ3,809 site that leads to decreased adiponectin expression and secretion. These mechanistic observations are highly consistent with studies in mice and humans that have high GH or PRL levels that are accompanied by lower circulating levels of adiponectin.signal transducer and activator of transcription 5 GROWTH HORMONE (GH) is known to have profound effects on adipocyte metabolism (reviewed in Ref. 8), such as attenuating lipogenesis and stimulating lipolysis (35,56). The effects of prolactin (PRL) have been well characterized in mammary tissues, and yet there is also evidence suggesting that this hormone can act within adipose tissue in mice and humans (31, 36) to modulate lipolysis (11,32). It is well known that GH and PRL induce signaling via the JAK/STAT pathway, and STAT5 proteins are potently activated by these hormones (reviewed in Ref. 46). However, few direct molecular targets for the actions of GH and PRL in fat cells have been identified.Multiple lines of evidence suggest that STAT5 proteins can modulate adipocyte function. During differentiation of 3T3-L1 adipocytes, the expression levels of STAT5A and -5B are highly induced (50). In addition, GH-dependent adipogenesis of 3T3-F442A cells is attenuated by STAT5 antisense oligonucleotides (58), and constitutively active STAT5 can replace the requirement for GH in adipogenesis of these cells (48). Moreover, ectopic expression of STAT5A has been shown to confer adipogenes...

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“…Results of an elegant studies of the relationship(s) between GH, adiposity, and adiponectin levels (including the bioactive high molecular weight variant of adiponectin) can be found in. 54 The epididymal WAT depot in Ames dwarf mice also has an upregulation in genes that are beneficial for metabolism, including insulin receptor and PGC-1a. 51 Interestingly, removal of visceral WAT in Ames dwarf mice downregulated genes in subcutaneous WAT (sWAT) that are involved in insulin signaling.…”

Section: Effects Of Altered Adipokine Production On Insulin Sensitivitymentioning

confidence: 99%

Altered structure and function of adipose tissue in long-lived mice with growth hormone-related mutations

2017

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A major focus of biogerontology is elucidating the role(s) of the endocrine system in aging and the accumulation of age-related diseases. Endocrine control of mammalian longevity was first reported in Ames dwarf (Prop1 df ) mice, which are long-lived due to a recessive Prop1 loss-of-function mutation resulting in deficiency of growth hormone (GH), thyroid-stimulating hormone, and prolactin. Following this report, several other GH-related mutants with altered longevity have been described including long-lived Snell dwarf and growth hormone receptor knockout mice, and shortlived GH overexpressing transgenic mice. One of the emerging areas of interest in these mutant mice is the role of adipose tissue in their altered healthspan and lifespan. Here, we provide an overview of the alterations in body composition of GH-related mutants, as well as the altered thermogenic potential of their brown adipose tissue and the altered cellular senescence and adipokine production of their white adipose tissue.

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Adiponectin in mice with altered GH action: links to insulin sensitivity and longevity?

Cited by 53 publications

References 58 publications

Living Large: What Mouse Models Reveal about Growth Hormone and Obesity

Living Large: What Mouse Models Reveal about Growth Hormone and Obesity

The modulation of adiponectin by STAT5-activating hormones

Altered structure and function of adipose tissue in long-lived mice with growth hormone-related mutations

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