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Alterations in mitochondrial structure and function are commonly observed in adult-onset neurodegenerative diseases. In ALS, mitochondrial dysfunction impairs the efficiency of electron transport chain (ETC) activity and ATP production and leads to the accumulation of reactive oxygen and nitrogen species, abnormal handling of intracellular calcium and cytochrome C release and apoptosis. The extent to which these alterations in mitochondrial functionimpair cellular operations is unclear. Therapeutic intervention based on combating these mitochondrial abnormalities have displayed variable success in mouse models of ALS and humans, as reviewed in Vandoorne et al.

Sean-Patrick Riechers, Jelena Mojsilovic-Petrovic, Tayler B. Belton, Ram P. Chakrabarty, ... Robert G. Kalb

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Current Issue

Hepatic adropin is regulated by estrogen and contributes to adverse metabolic phenotypes in ovariectomized mice

Joshua Stokar, Irina Gurt, Einav Cohen-Kfir, Oran Yakubovsky, ... Rivka Dresner-Pollak

Objective

Menopause is associated with visceral adiposity, hepatic steatosis and increased risk for cardiovascular disease. As estrogen replacement therapy is not suitable for all postmenopausal women, a need for alternative therapeutics and biomarkers has emerged.

Methods

9-week-old C57BL/6 J female mice were subjected to ovariectomy(OVX) or SHAM surgery (n = 10 per group), fed a standard diet and sacrificed 6- & 12 weeks post-surgery.

Results

Increased weight gain, hepatic triglyceride content and changes in hepatic gene expression of Cyp17a1, Rgs16Fitm1 as well as Il18, Rares2, RetnRbp4 in mesenteric visceral adipose tissue (VAT) were observed in OVX vs. SHAM. Liver RNA-sequencing 6-weeks post-surgery revealed changes in genes and microRNAs involved in fat metabolism in OVX vs. SHAM mice. Energy Homeostasis Associated gene (Enho) coding for the hepatokine adropin was significantly reduced in OVX mice livers and strongly inversely correlated with weight gain (r = −0.7 p < 0.001) and liver triglyceride content (r = −0.4, p = 0.04), with a similar trend for serum adropin. In vitroEnhoexpression was tripled by 17β-estradiol in BNL 1 ME liver cells with increased adropin in supernatant. Analysis of open-access datasets revealed increased hepatic Enho expression in estrogen treated OVX mice and estrogen dependent ERα binding to Enho. Treatment of 5-month-old OVX mice with Adropin (i.p. 450 nmol/kg/twice daily, n = 4,5 per group) for 6-weeks reversed adverse adipokine gene expression signature in VAT, with a trended increase in lean body mass and decreased liver TG content with upregulation of Rgs16.

Conclusions

OVX is sufficient to induce deranged metabolism in adult female mice. Hepatic adropin is regulated by estrogen, negatively correlated with adverse OVX-induced metabolic phenotypes, which were partially reversed with adropin treatment. Adropin should be further explored as a potential therapeutic target and biomarker for menopause-related metabolic derangement.

Hepatic adropin is regulated by estrogen and contributes to adverse metabolic phenotypes in ovariectomized mice

Joshua Stokar, Irina Gurt, Einav Cohen-Kfir, Oran Yakubovsky, ... Rivka Dresner-Pollak

Objective

Menopause is associated with visceral adiposity, hepatic steatosis and increased risk for cardiovascular disease. As estrogen replacement therapy is not suitable for all postmenopausal women, a need for alternative therapeutics and biomarkers has emerged.

Methods

9-week-old C57BL/6 J female mice were subjected to ovariectomy(OVX) or SHAM surgery (n = 10 per group), fed a standard diet and sacrificed 6- & 12 weeks post-surgery.

Results

Increased weight gain, hepatic triglyceride content and changes in hepatic gene expression of Cyp17a1, Rgs16Fitm1 as well as Il18, Rares2, RetnRbp4 in mesenteric visceral adipose tissue (VAT) were observed in OVX vs. SHAM. Liver RNA-sequencing 6-weeks post-surgery revealed changes in genes and microRNAs involved in fat metabolism in OVX vs. SHAM mice. Energy Homeostasis Associated gene (Enho) coding for the hepatokine adropin was significantly reduced in OVX mice livers and strongly inversely correlated with weight gain (r = −0.7 p < 0.001) and liver triglyceride content (r = −0.4, p = 0.04), with a similar trend for serum adropin. In vitroEnhoexpression was tripled by 17β-estradiol in BNL 1 ME liver cells with increased adropin in supernatant. Analysis of open-access datasets revealed increased hepatic Enho expression in estrogen treated OVX mice and estrogen dependent ERα binding to Enho. Treatment of 5-month-old OVX mice with Adropin (i.p. 450 nmol/kg/twice daily, n = 4,5 per group) for 6-weeks reversed adverse adipokine gene expression signature in VAT, with a trended increase in lean body mass and decreased liver TG content with upregulation of Rgs16.

Conclusions

OVX is sufficient to induce deranged metabolism in adult female mice. Hepatic adropin is regulated by estrogen, negatively correlated with adverse OVX-induced metabolic phenotypes, which were partially reversed with adropin treatment. Adropin should be further explored as a potential therapeutic target and biomarker for menopause-related metabolic derangement.

2021 impact factor: 7.422

The 60 Second Metabolist

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