Growth Hormone Is Necessary for the p53-Mediated, Obesity-Induced Insulin Resistance in Male C57BL/6J × CBA Mice

Bogazzi, Fausto; Raggi, Francesco; Russo, Dania; Bohlooly‐Y, Mohammad; Sardella, Chiara; Urbani, Claudio; Lombardi, Martina; Manetti, Luca; Lupi, Isabella; Törnell, Jan; Martino, Enio

doi:10.1210/en.2013-1220

Cited by 19 publications

(15 citation statements)

References 47 publications

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“…GH effects appear to be cell-specific, as GH decreased colon but not liver p53. Transgenic mice overexpressing circulating bovine GH were also shown to exhibit induced p53 in white adipose tissue (93).…”

Section: Discussionmentioning

confidence: 99%

Growth hormone is permissive for neoplastic colon growth

Chesnokova

Zonis

Zhou

et al. 2016

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

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Fig. 6. GH induces EMT, suppresses apoptosis, and increases motility. Western blot analysis of PTEN and EMT factors in (A) hNCC and (B) HCT116 cells treated with indicated doses of GH for 24 h. (C) Western blot analysis of cleaved caspase 3 in cells treated with GH (500 ng/mL) for 24 h. Experiments were performed at least three times, and representative results shown. (D) Migration of hNCC and HCT116 cells treated with GH (500 ng/mL) and harvested 48 h after plating. (E) Migration of HCT116 cocultured for 48 h with hCF infected with lentivector or lentiGH. In D and E, for quantification, the number of migrated cells per 1,000 cells in five randomly chosen fields in each duplicate transwell were counted and means calculated. Results are presented as mean ± SEM of three independent experiments; *P < 0.05. (F) Number of colonies and arbitrary colony size formed in soft agar by HCT116 cells cocultured with hCF infected with lentivector or lentiGH, and tested for anchorage independent growth. Colony size was determined using ImageJ software. Results are presented as mean ± SEM of duplicates from two independent experiments; **P < 0.01 vs. control. In D-F, the differences between groups were analyzed using two-tailed unpaired Student t test.

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Section: Discussionmentioning

confidence: 99%

Growth hormone is permissive for neoplastic colon growth

Chesnokova

Zonis

Zhou

et al. 2016

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

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“…Interestingly increased DNA damage has been previously reported to result from the model of male obesity used in this study [22,44,64] and this potentially triggers the increased abundance of p53 and thus microRNA-143/microRNA-145. This would likely occur in concert with the increase in the abundance of p53 due to diet induced obesity [65,66], possibly resulting from p53’s role in adipogenesis [67]. Moreover microRNA-143 is known to accelerate adipogenesis and is also increased in adipose tissue of mice fed a high fat diet [68].…”

Section: Discussionmentioning

confidence: 99%

Sperm microRNA Content Is Altered in a Mouse Model of Male Obesity, but the Same Suite of microRNAs Are Not Altered in Offspring’s Sperm

Fullston

Ohlsson-Teague

et al. 2016

PLoS ONE

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The prevalence of obesity is increasing worldwide and has tripled in men of reproductive age since the 1970s. Concerningly, obesity is not only comorbid with other chronic diseases, but there is mounting evidence that it increases the non-communicable disease load in their children (eg mortality, obesity, autism). Animal studies have demonstrated that paternal obesity increases the risk of metabolic (eg glucose metabolism defects, obesity) and reproductive disorders in offspring. Epigenetic changes within sperm are clear mechanistic candidates that are associated with both changes to the father’s environment and offspring phenotype. Specifically there is emerging evidence that a father’s sperm microRNA content both responds to paternal environmental cues and alters the gene expression profile and subsequent development of the early embryo. We used a mouse model of high fat diet (HFD) induced obesity to investigate whether male obesity could modulate sperm microRNA content. We also investigated whether this alteration to a father’s sperm microRNA content lead to a similar change in the sperm of male offspring. Our investigations were initially guided by a Taqman PCR array, which indicated the differential abundance of 28 sperm borne microRNAs in HFD mice. qPCR confirmation in a much larger cohort of founder males demonstrated that 13 of these microRNAs were differentially abundant (11 up-regulated; 2 down-regulated) due to HFD feeding. Despite metabolic and reproductive phenotypes also being observed in grand-offspring fathered via the male offspring lineage, there was no evidence that any of the 13 microRNAs were also dysregulated in male offspring sperm. This was presumably due to the variation seen within both groups of offspring and suggests other mechanisms might act between offspring and grand-offspring. Thus 13 sperm borne microRNAs are modulated by a father’s HFD and the presumed transfer of this altered microRNA payload to the embryo at fertilisation potentially acts to alter the embryonic molecular makeup post-fertilisation, altering its growth trajectory, ultimately affecting adult offspring phenotype and may contribute to paternal programming.

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“…In response to a high-fat diet, p53 expression in adipose tissue is increased through activation of p38MAPK; the latter can be inhibited by GH antagonists (Bogazzi, et al 2013). This finding provides a potential link between diet-induced obesity and p53-mediated adipose tissue inflammation and insulin resistance.…”

Section: P53 Regulates Glucose Homeostasis: Glucose Transport Glycolmentioning

confidence: 99%

The role of the p53 tumor suppressor in metabolism and diabetes

Kung

Murphy

2016

Journal of Endocrinology

132

104

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In the context of tumor suppression, p53 is an undisputedly critical protein. Functioning primarily as a transcription factor, p53 helps fend off the initiation and progression of tumors by inducing cell cycle arrest, senescence or programmed cell death (apoptosis) in cells at the earliest stages of precancerous development. Compelling evidence, however, suggests that p53 is involved in other aspects of human physiology, including metabolism. Indeed, recent studies suggest that p53 plays a significant role in the development of metabolic diseases, including diabetes, and further that p53’s role in metabolism may also be consequential to tumor suppression. Here we present a review of the literature on the role of p53 in metabolism, diabetes, pancreatic function, glucose homeostasis, and insulin resistance. Additionally, we discuss the emerging role of genetic variation in the p53 pathway (single nucleotide polymorphisms) on the impact of p53 in metabolic disease and diabetes. A better understanding of the relationship between p53, metabolism and diabetes may one day better inform the existing and prospective therapeutic strategies to combat this rapidly growing epidemic.

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Growth Hormone Is Necessary for the p53-Mediated, Obesity-Induced Insulin Resistance in Male C57BL/6J × CBA Mice

Cited by 19 publications

References 47 publications

Growth hormone is permissive for neoplastic colon growth

Growth hormone is permissive for neoplastic colon growth

Sperm microRNA Content Is Altered in a Mouse Model of Male Obesity, but the Same Suite of microRNAs Are Not Altered in Offspring’s Sperm

The role of the p53 tumor suppressor in metabolism and diabetes

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