Mice with gene alterations in the GH and IGF family

Qian, Yanrong; Berryman, Darlene E.; Basu, Reetobrata; List, Edward O.; Okada, Shigeru; Young, J. A.; Jensen, Elizabeth; Bell, Stephen; Kulkarni, Prateek; Duran‐Ortiz, Silvana; Mora‐Criollo, Patricia; Mathes, Samuel; Brittain, Alison; Buchman, Mathew; Davis, Emily; Funk, Kevin; Bogart, Jolie; Ibarra, Diego; Mendez-Gibson, Isaac; Slyby, Julie; Terry, Joseph; Kopchick, John J.

doi:10.1007/s11102-021-01191-y

Cited by 31 publications

(24 citation statements)

References 347 publications

(574 reference statements)

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“…Notably, there was low circulating IGF1 in Zfxh3 Sci/+ mice, an indicator of growth axis suppression. Indeed, the overall phenotype is reminiscent of a GH activity deficiency phenotype (22). IGF1 null mice have low viability and are born small, with inhibited growth (23).…”

Section: Discussionmentioning

confidence: 99%

A missense mutation in zinc finger homeobox-3 (ZFHX3) impedes growth and alters metabolism and hypothalamic gene expression in mice

Nolan

Banks

Bourbia

et al. 2022

Preprint

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ObjectiveA protein altering variant in the gene encoding zinc finger homeobox-3 (ZFHX3) has recently been associated with lower BMI in a human genome-wide association study. We investigated metabolic parameters in mice harbouring a missense mutation in Zfhx3 (Zfhx3Sci/+) and looked for altered expression of transcripts that are associated with energy balance in the hypothalamus to understand how ZFHX3 may influence metabolic effects.MethodsBody weight, length and composition were measured in 1 year old male and female Zfhx3Sci/+ and Zfhx3+/+ mice, and fat depot weights were measured along with fasted anabolic hormone concentrations. In a second cohort of male and female Zfhx3Sci/+ and Zfhx3+/+ mice weekly food intake was measured from the age of 9 – 20 weeks. A third cohort of female-only Zfhx3Sci/+ and Zfhx3+/+ mice underwent body composition analysis every two weeks from 6 - 14 weeks of age, and 24 h energy expenditure was assessed. At 16 weeks old, brains were collected in the light and dark phases for mRNA in situ hybridisation analysis of candidate genes identified in previous RNA-seq analysis of hypothalamic tissue of Zfhx3Sci/+ mice.ResultsWe found that 1 year old Zfhx3Sci/+ mice weighed less and had a shorter body length than wildtype littermates, and had reduced fat mass, smaller mesenteric fat depots, and lower circulating insulin, leptin and insulin-like growth factor-1 (IGF1) concentrations. Male and female Zfhx3Sci/+ mice ate less than wildtype controls from 10 weeks of age. In the final experiment, female Zfhx3Sci/+ mice weighed less and had lower lean mass, but fat mass didn’t differ. Energy expenditure was lower in Zfhx3Sci/+ mice. We detected increased expression of somatostatin, and decreased expression of growth hormone-releasing hormone and growth hormone-receptor mRNAs in the arcuate nucleus (ARC), but these transcripts were unaltered in other hypothalamic nuclei. Similarly, ARC expression of orexigenic neuropeptide Y was decreased and ventricular ependymal layer expression of orphan G protein-coupled receptor Gpr50 was decreased.ConclusionsThe Sci missense mutation conferred a protective metabolic phenotype in mice and implied a somatic growth effect. The promoters of mouse Sst and Gpr50 genes contain ZFHX3 binding AT-motifs, suggesting growth axis effects are driven by transcriptional activation of Sst in the ARC. It is likely that altered Gpr50 gene expression led to decreased energy expenditure and decreased Npy expression in the ARC decreased appetite. Together these results point to a pleiotropic effect of ZFHX3 in regulating energy balance, independent of its circadian effects.Highlights-Male and female Zfhx3Sci/+ mice have a shorter body length, eat less and weigh less-Zfhx3Sci/+ mice have lower insulin, leptin and IGF1 in circulation-Zfhx3Sci/+ mice have decreased Ghr, Ghrh and Npy expression in the arcuate nucleus-Arcuate nucleus expression of AT-motif containing Sst is increased in Zfhx3Sci/+ mice-This model may explain human protein altering ZFHX3 variant associated with low BMI

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Section: Discussionmentioning

confidence: 99%

A missense mutation in zinc finger homeobox-3 (ZFHX3) impedes growth and alters metabolism and hypothalamic gene expression in mice

Nolan

Banks

Bourbia

et al. 2022

Preprint

View full text Add to dashboard Cite

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“…Growth hormone is lipolytic, and lessons from mouse genetic models tell us that increasing growth hormone in circulation often leads to decreased fat mass. Mouse models of the growth axis have recently been thoroughly systematically reviewed 4 . Early mouse lines with spontaneous mutations in growth axis components have existed as early as the 1920s, and in general mice overexpressing growth hormone are larger, with increased circulating growth hormone and IGF1 levels and have decreased insulin sensitivity and decreased adiposity.…”

Section: The Growth Axis and Peripheral Metabolismmentioning

confidence: 99%

“…Mouse models of the growth axis have recently been thoroughly systematically reviewed. 4 Early mouse lines with spontaneous mutations in growth axis components have existed as early as the 1920s, and in general mice overexpressing growth hormone are larger, with increased circulating growth hormone and IGF1 levels and have decreased insulin sensitivity and decreased adiposity. The opposite is true for genetically altered mice or those with a spontaneous loss of function mutation leading to decreased circulating growth hormone and IGF1.…”

Section: The Growth Axis and Peripheral Metabolismmentioning

confidence: 99%

An appetite for growth: The role of the hypothalamic – pituitary – growth hormone axis in energy balance

Dumbell

2022

J Neuroendocrinology

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Links between the regulation of growth and energy balance are clear; to fuel growth, there must be consumption of energy. Therefore, it is perhaps intuitive that interactions between the hypothalamicpituitarygrowth hormone axis (growth axis) and pathways that drive metabolic processes exist. Overproduction of growth hormone has been associated with diabetes and metabolic disease for decades and the opposing effects of growth hormone and insulin have been studied since early experiments almost a century ago. The relationship between neuroendocrine axes can be complex and the growth axis is no exception, interacting with energy balance in several organ systems, both in the periphery and centrally in hypothalamic nuclei. Much is known about peripheral interactions between growth axis hormones and processes such as glucose homeostasis and adipogenesis. More is still being learned about the molecular actions of growth axis hormones in adipose and other metabolically active tissues, and recent findings are discussed in this perspective. However, less is known about interactions with central energy balance pathways in the hypothalamus. This perspective aims to summarise what is known about these interactions, taking lessons from human studies and animal genetic and seasonal models, and discusses what this may mean in an evolving landscape of personalised medicine.

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“…Also, long-term follow-up studies with the Israeli and Ecuadorian cohorts of individuals with Laron Syndrome (LS) (GH resistant due to dysfunctional mutations in GHR) remarkably find them to be completely resistant to all cancers ( 5 , 6 ). Moreover, numerous studies using GH transgenic (hGH or bGH) mice, GHR antagonist (GHA) transgenic mice, congenital and adult-onset GHR knockout (GHRKO, 6mGHRKO) mice and several mouse models of GH deficiency (Ames, Snell, lit/lit) confirm the tumor driving role of GH and IGF1 and also reveal several IGF1-independent actions of GH in favoring a therapy-resistant and metastatic cancer phenotype ( 7 – 12 ). A series of recent work by us and others has mechanistically described the repertoire of tumor-supportive effects of GH, beyond its well-known growth promoting action.…”

Section: Introductionmentioning

confidence: 99%

Growth hormone receptor antagonism downregulates ATP-binding cassette transporters contributing to improved drug efficacy against melanoma and hepatocarcinoma in vivo

et al. 2022

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Knockdown of GH receptor (GHR) in melanoma cells in vitro downregulates ATP-binding cassette-containing (ABC) transporters and sensitizes them to anti-cancer drug treatments. Here we aimed to determine whether a GHR antagonist (GHRA) could control cancer growth by sensitizing tumors to therapy through downregulation of ABC transporters in vivo. We intradermally inoculated Fluc-B16-F10 mouse melanoma cells into GHA mice, transgenic for a GHR antagonist (GHRA), and observed a marked reduction in tumor size, mass and tumoral GH signaling. Moreover, constitutive GHRA production in the transgenic mice significantly improved the response to cisplatin treatment by suppressing expression of multiple ABC transporters and sensitizing the tumors to the drug. We confirmed that presence of a GHRA and not a mere absence of GH is essential for this chemo-sensitizing effect using Fluc-B16-F10 allografts in GH knockout (GHKO) mice, where tumor growth was reduced relative to that in GH-sufficient controls but did not sensitize the tumor to cisplatin. We extended our investigation to hepatocellular carcinoma (HCC) using human HCC cells in vitro and a syngeneic mouse model of HCC with Hepa1-6 allografts in GHA mice. Gene expression analyses and drug-efflux assays confirm that blocking GH significantly suppresses the levels of ABC transporters and improves the efficacy of sorafenib towards almost complete tumor clearance. Human patient data for melanoma and HCC show that GHR RNA levels correlate with ABC transporter expression. Collectively, our results validate in vivo that combination of a GHRA with currently available anti-cancer therapies can be effective in attacking cancer drug resistance.

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Mice with gene alterations in the GH and IGF family

Cited by 31 publications

References 347 publications

A missense mutation in zinc finger homeobox-3 (ZFHX3) impedes growth and alters metabolism and hypothalamic gene expression in mice

A missense mutation in zinc finger homeobox-3 (ZFHX3) impedes growth and alters metabolism and hypothalamic gene expression in mice

An appetite for growth: The role of the hypothalamic – pituitary – growth hormone axis in energy balance

Growth hormone receptor antagonism downregulates ATP-binding cassette transporters contributing to improved drug efficacy against melanoma and hepatocarcinoma in vivo

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