Long‐lived hypopituitary Ames dwarf mice are resistant to the detrimental effects of high‐fat diet on metabolic function and energy expenditure

Hill, Cristal M.; Fang, Yimin; Miquet, Johanna G.; Sun, Liou Y.; Masternak, Michał M.; Bartke, Andrzej

doi:10.1111/acel.12467

Cited by 36 publications

(24 citation statements)

References 51 publications

(66 reference statements)

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“…7a). Consistent with previous studies4041, we found that an HFD resulted in adiponectin deficiency, including downregulation of AdipoR1 and reduction in serum adiponectin levels (Figs 6g and 7f,g). As expected, the supplementation of adiponectin showed protective effects against an HFD, alleviating mouse obesity and microscopic BPH.…”

Section: Resultssupporting

confidence: 92%

Adiponectin deficiency contributes to the development and progression of benign prostatic hyperplasia in obesity

et al. 2017

Sci Rep

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The incidence of benign prostatic hyperplasia (BPH) is increasing among obese individuals, but few studies have fully explained the underlying mechanisms. We aimed to elucidate the relationship between obesity and BPH. Herein, we show that in prostatic epithelial and stromal cells, adiponectin exerts multifunctional effects including anti-proliferation, blocking of G1/S-phase progression and the promotion of apoptosis via inhibiting the MEK-ERK-p90RSK axis. Furthermore, we found that a high-fat diet (HFD) led to adiponectin deficiency and microscopic BPH in a mouse model of obesity. And an adiponectin supplement protected the obese mice from microscopic BPH. The present study provides evidence that adiponectin is a protective regulator in the development and progression of BPH and that adiponectin deficiency causally links BPH with obesity.

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Section: Resultssupporting

confidence: 92%

Adiponectin deficiency contributes to the development and progression of benign prostatic hyperplasia in obesity

et al. 2017

Sci Rep

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“…In agreement with common signaling pathways associated with the three lifespan-extending interventions [15,18,19,[34][35][36][37], we found that DR and rapamycin treatment resembled functionally distinct epigenetic patterns of Ames dwarf mice. Metabolically, dwarfism protects from hepatic insulin resistance, reduces high-fat diet induced liver steatosis and suppresses denovo lipogenesis genes including Elovl6, Acly and Fasn [64,122,123], thus indicating reduced lipogenic activity through Srebf1 [108,[124][125][126]. Snell dwarf mice, another mouse model of reduced somatotropic signaling, also show age-independent down-regulation of Srebp1 and several downstream targets in the liver [127].…”

Section: Discussionmentioning

confidence: 99%

Hepatic gene body hypermethylation is a shared epigenetic signature of murine longevity

et al. 2018

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Dietary, pharmacological and genetic interventions can extend health-and lifespan in diverse mammalian species. DNA methylation has been implicated in mediating the beneficial effects of these interventions; methylation patterns deteriorate during ageing, and this is prevented by lifespan-extending interventions. However, whether these interventions also actively shape the epigenome, and whether such epigenetic reprogramming contributes to improved health at old age, remains underexplored. We analysed published, wholegenome, BS-seq data sets from mouse liver to explore DNA methylation patterns in aged mice in response to three lifespan-extending interventions: dietary restriction (DR), reduced TOR signaling (rapamycin), and reduced growth (Ames dwarf mice). Dwarf mice show enhanced DNA hypermethylation in the body of key genes in lipid biosynthesis, cell proliferation and somatotropic signaling, which strongly correlates with the pattern of transcriptional repression. Remarkably, DR causes a similar hypermethylation in lipid biosynthesis genes, while rapamycin treatment increases methylation signatures in genes coding for growth factor and growth hormone receptors. Shared changes of DNA methylation were restricted to hypermethylated regions, and they were not merely a consequence of slowed ageing, thus suggesting an active mechanism driving their formation. By comparing the overlap in ageing-independent hypermethylated patterns between all three interventions, we identified four regions, which, independent of genetic background or gender, may serve as novel biomarkers for longevity-extending interventions. In summary, we identified gene body hypermethylation as a novel and partly conserved signature of lifespan-extending interventions in mouse, highlighting epigenetic reprogramming as a possible intervention to improve health at old age.

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“…Body weights were recorded weekly during the feeding regimes. Visceral fat was isolated and weighed at the end of their diet regimes as described previously 38 …”

Section: Methodsmentioning

confidence: 99%

Sirt3 is dispensable for oocyte quality and female fertility in lean and obese mice

Iljas

Homer

2020

FASEB j.

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Mammalian oocytes rely heavily on mitochondrial oxidative phosphorylation (OXPHOS) for generating ATP. However, mitochondria are also the primary source of damaging reactive oxygen species (ROS). Mitochondrial de-regulation, therefore, underpins poor oocyte quality associated with conditions such as obesity and aging.The mitochondrial sirtuin, Sirt3, is critical for mitochondrial respiration and redox regulation. Interestingly, however, Sirt3 knockout (Sirt3 −/− ) mice do not exhibit systemic compromise under basal conditions, only doing so under stressed conditions such as high-fat diet (HFD)-induced obesity. Mouse oocytes depleted of Sirt3 exhibit increased ROS in vitro, but it is unknown whether Sirt3 is necessary for female fertility in vivo. Here, we test this for the first time by investigating ovarian follicular reserve, oocyte maturation (including detailed spindle assembly and chromosome segregation), and female fertility in Sirt3 −/− females. We find that under basal conditions, young Sirt3 −/− females exhibit no defects in any parameters. Surprisingly, all parameters also remain intact following HFD-induced obesity. Despite markedly increased ROS levels in HFD Sirt3 −/− oocytes, ATP levels nevertheless remain normal. Our data support that ATP is sustained in vivo through increased mitochondrial mass possibly secondary to compensatory upregulation of another sirtuin, Sirt1, which has overlapping functions with Sirt3.

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Long‐lived hypopituitary Ames dwarf mice are resistant to the detrimental effects of high‐fat diet on metabolic function and energy expenditure

Cited by 36 publications

References 51 publications

Adiponectin deficiency contributes to the development and progression of benign prostatic hyperplasia in obesity

Adiponectin deficiency contributes to the development and progression of benign prostatic hyperplasia in obesity

Hepatic gene body hypermethylation is a shared epigenetic signature of murine longevity

Sirt3 is dispensable for oocyte quality and female fertility in lean and obese mice

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