Follicle-stimulating hormone enhances hepatic gluconeogenesis by GRK2-mediated AMPK hyperphosphorylation at Ser485 in mice

Qi, Xiaoyi; Guo, Yanjing; Song, Yuelin; Yu, Chunxiao; Zhao, Lifang; Li, Fang; Kong, Dehuan; Zhao, Jiajun; Gao, Ling

doi:10.1007/s00125-018-4562-x

Cited by 29 publications

(19 citation statements)

References 52 publications

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“…FSH plays a vital role in energy metabolism. Higher serum FSH levels enhance hepatic gluconeogenesis [ 9 ] and lipid biosynthesis [ 10 ]. Blocking FSH with an FSHβ antibody or by FSHR inactivation induces thermogenic adipose tissue, reduces body fat [ 38 ], and conserves bone mass [ 39 ], providing a pharmacological target for treating menopause-related diseases.…”

Section: Discussionmentioning

confidence: 99%

“…FSH, a gonadotropin that triggers estrogen production, has been described to have significant extragonadal physiological functions, including promoting hepatic gluconeogenesis [ 9 ] and adipocytic lipid biosynthesis [ 10 ]. Higher FSH levels in the menopausal transition are associated with changes in brain function, such as sleep disturbance [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

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FSHR ablation induces depression-like behaviors

Shao

et al. 2020

Acta Pharmacol Sin

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Alteration in reproductive hormones profile is associated with the increasing risk of menopausal depression in women. Serum follicle-stimulating hormone (FSH) level is changed during the menopause transition, while the effect of FSH on menopausal depression has remained undefined. In this study we investigated whether or how FSH affected menopausal depression in postmenopausal (ovariectomized) FSHR knockout mice ( Fshr −/ − ). We found that Fshr −/− mice displayed aggravated depression-like behaviors, accompanied by severe oxidative stress in the whole brain, resulted from significantly reduced glutamate cysteine ligase modifier subunit (GCLm) in glutathione synthesis and glucose-6-phosphate dehydrogenase (G6PD) in NADP/NADPH transition. Importantly, administration of ROS scavenger N-acetyl cysteine (NAC, 150 mg · kg −1 · d −1 , i.p. for 12 weeks) attenuated the depression-like behaviors of Fshr −/ − mice. Consistent with these in vivo experiment results, we found that pretreatment with FSH (50, 100 ng/mL) dose-dependently increased protein levels of GCLm and G6PD, and decreased the ROS production in N2a mouse neuroblastoma cells. These findings demonstrate that FSH signaling is involved in pathogenesis of menopausal depression, and likely to maintain the redox-optimized ROS balance in neurons.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

FSHR ablation induces depression-like behaviors

Shao

et al. 2020

Acta Pharmacol Sin

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“…Our team previously found that FSH enhanced gluconeogenesis without effecting insulin, dependent on AMP-activated protein kinase (AMPK) phosphorylation via GRK2 in the liver. 53 FoxO1 could integrate insulin signaling to hepatic glucose and lipid metabolism. [54][55][56] AMPK is a major cellular energy sensor and a master regulator of metabolic homeostasis, involved in both glucose and lipid metabolism.…”

Section: Discussionmentioning

confidence: 99%

Blocking FSH inhibits hepatic cholesterol biosynthesis and reduces serum cholesterol

et al. 2018

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Menopause is associated with dyslipidemia and an increased risk of cardio-cerebrovascular disease. The classic view assumes that the underlying mechanism of dyslipidemia is attributed to an insufficiency of estrogen. In addition to a decrease in estrogen, circulating follicle-stimulating hormone (FSH) levels become elevated at menopause. In this study, we find that blocking FSH reduces serum cholesterol via inhibiting hepatic cholesterol biosynthesis. First, epidemiological results show that the serum FSH levels are positively correlated with the serum total cholesterol levels, even after adjustment by considering the effects of serum estrogen. In addition, the prevalence of hypercholesterolemia is significantly higher in peri-menopausal women than that in premenopausal women. Furthermore, we generated a mouse model of FSH elevation by intraperitoneally injecting exogenous FSH into ovariectomized (OVX) mice, in which a normal level of estrogen (E2) was maintained by exogenous supplementation. Consistently, the results indicate that FSH, independent of estrogen, increases the serum cholesterol level in this mouse model. Moreover, blocking FSH signaling by anti-FSHβ antibody or ablating the FSH receptor (FSHR) gene could effectively prevent hypercholesterolemia induced by FSH injection or high-cholesterol diet feeding. Mechanistically, FSH, via binding to hepatic FSHRs, activates the Gi2α/β-arrestin-2/Akt pathway and subsequently inhibits the binding of FoxO1 with the SREBP-2 promoter, thus preventing FoxO1 from repressing SREBP-2 gene transcription. This effect, in turn, results in the upregulation of SREBP-2, which drives HMGCR nascent transcription and de novo cholesterol biosynthesis, leading to the increase of cholesterol accumulation. This study uncovers that blocking FSH signaling might be a new strategy for treating hypercholesterolemia during menopause, particularly for women in peri-menopause characterized by FSH elevation only.

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“…Current in vitro studies claim that inhibition of gluconeogenesis in human cancer cells by itraconazole is mediated by AMPK pathway [44,45]. Moreover, suppression of AMPK by FSH (folliclestimulating hormone) in mice liver enhances transcription of PEPCK and G6P via CRTC2 [46]. Stimulation of glycolysis by AMPK involves activation of PFK-2 (phosphofructokinase 2, EC 2.7.1.105) by its phosphorylation at Ser466.…”

Section: Metabolism Of Carbohydratesmentioning

confidence: 99%

The role of AMPK in metabolism and its influence on DNA damage repair

et al. 2020

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One of the most complex health disproportions in the human body is the metabolic syndrome (MetS). It can result in serious health consequences such as type 2 diabetes mellitus, atherosclerosis or insulin resistance. The center of energy regulation in human is AMP-activated protein kinase (AMPK), which modulates cells’ metabolic pathways and protects them against negative effects of metabolic stress, e.g. reactive oxygen species. Moreover, recent studies show the relationship between the AMPK activity and the regulation of DNA damage repair such as base excision repair (BER) system, which is presented in relation to the influence of MetS on human genome. Hence, AMPK is studied not only in the field of counteracting MetS but also prevention of genetic alterations and cancer development. Through understanding AMPK pathways and its role in cells with damaged DNA it might be possible to improve cell’s repair processes and develop new therapies. This review presents AMPK role in eukaryotic cells and focuses on the relationship between AMPK activity and the regulation of BER system through its main component—8-oxoguanine glycosylase (OGG1).

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Follicle-stimulating hormone enhances hepatic gluconeogenesis by GRK2-mediated AMPK hyperphosphorylation at Ser485 in mice

Abstract: The results indicate that FSH enhances CRTC2-mediated gluconeogenesis dependent on AMPK Ser485 phosphorylation via GRK2 in the liver, suggesting an essential role of FSH in the pathogenesis of fasting hyperglycaemia.

Cited by 29 publications

References 52 publications

FSHR ablation induces depression-like behaviors

FSHR ablation induces depression-like behaviors

Blocking FSH inhibits hepatic cholesterol biosynthesis and reduces serum cholesterol

The role of AMPK in metabolism and its influence on DNA damage repair

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