Endoplasmic Reticulum Stress Markers Are Associated with Obesity in Nondiabetic Subjects

Sharma, Neeraj Kumar; Das, Swapan K.; Mondal, Ashis; Hackney, Oksana G.; Chu, Winston; Kern, Philip A.; Rasouli, Neda; Spencer, Horace J.; Yao-Borengasser, Aiwei; Elbein, Steven C.

doi:10.1210/jc.2008-1001

Cited by 242 publications

(199 citation statements)

References 35 publications

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“…32,33 Moreover, the intrinsic follicular dysplasia associated with the ovarian granulosa cell apoptosis was observed with significantly higher apoptotic rates in granulosa cells of patients with PCOS. It was suggested that endoplasmic reticulum stress might be involved in the pathogenesis of anovulation in patients with PCOS.…”

Section: Resultsmentioning

confidence: 98%

Genome-wide association study identifies GYS2 as a novel genetic factor for polycystic ovary syndrome through obesity-related condition

Hwang

Lee

et al. 2012

J Hum Genet

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To investigate the role of genetic predisposition in the pathogenesis of polycystic ovary syndrome (PCOS) in relation to obesity, we performed a genome-wide association study of PCOS in Koreans (n ¼ 1741). PCOS is a heterogeneous endocrinal disorder of uncertain etiology. Obesity is one of the well-known risk factors for PCOS. Genome-wide association study. Women with or without PCOS. A total of 1881 samples were genotyped using Illumina HumanOmni1 Quad v1 and processed by R packages. The PCOS patients were divided into two subgroups according to PCOS diagnostic criteria (Rotterdam and National Institutes of Health (NIH)). For PCOS-associated loci in the two definitions, we successfully confirmed significant associations of GYS2 for body mass index in the discovery stage. We further replicated pleiotropic associations of GYS2 in a childhood obesity study (n ¼ 482) and in a gestational diabetes study (n ¼ 1710), respectively. Our study provides a preliminary framework upon diverse genetic effects underlying PCOS in Korean women. A newly identified GYS2 gene as a predisposing factor of PCOS might expand understanding of the biological pathways in metabolic and endocrine regulation.

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Section: Resultsmentioning

confidence: 98%

Genome-wide association study identifies GYS2 as a novel genetic factor for polycystic ovary syndrome through obesity-related condition

Hwang

Lee

et al. 2012

J Hum Genet

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“…Therefore, FGF21 appears to be a regulatory factor in the proteostasis network and not merely an end-point regulator in the negative feedback loop. ER stress is thought to be caused not only by accumulation of excess unfolded or misfolded proteins in the ER but also pathogenetic conditions, such as obesity and diabetes (23)(24)(25)(26)(27), and physiological conditions such as fasting and refeeding (18). In addition, treatment with chemical chaperones that reduce ER stress improved several metabolic parameters including insulin sensitivity (28).…”

Section: Discussionmentioning

confidence: 99%

FGF21 Alleviates Hepatic Endoplasmic Reticulum Stress under Physiological Conditions

Maruyama

Shimizu

Hashidume

et al. 2018

Journal of Nutritional Science and Vitaminology

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Summary Fibroblast growth factor 21 (FGF21), mainly synthesized and secreted from the liver, is an endocrine FGF that regulates glucose and fatty acid metabolism to maintain whole body energy homeostasis. Gene expression of FGF21 was previously reported to be induced by endoplasmic reticulum (ER) stress through activating transcription factor 4 (ATF4). It has been reported that drug-induced ER stress is reduced by overexpression of FGF21. However, the function of endogenous FGF21 under physiological conditions such as the postprandial state remains unknown. Here, we examined the effects of both endogenous and exogenous FGF21 on postprandial hepatic ER stress. In mice, postprandial and tunicamycin-induced ER stress was significantly reduced by overexpression of FGF21 using a recombinant adenovirus. FGF21-deficient mice exhibited a more considerable increase in drug-induced ER stress target gene expression than wild-type mice. Following refeeding after fasting, FGF21 deficiency caused severe ER stress in the liver. The postprandial ER stress response was significantly reduced when hepatic FGF21 gene expression was increased by feeding a diet containing the soy protein b-conglycinin which activates ATF4. Together, these results demonstrate that FGF21 reduces the increased expression of a subset of genes in the liver in response to ER stress and may correct metabolic disorders caused by ER stress. Key Words FGF21, ER stress, ATF4, b-conglycinin Fibroblast growth factor 21 (FGF21), a member of the endocrine FGF subfamily (also known as the FGF19 subfamily), is mainly produced by the liver. FGF21 is secreted into the blood circulation, after which it acts on target tissues through a cell-surface FGF receptor (FGFR) together with its coregulator, bKlotho (1). In adipose tissues, FGF21 induces lipolysis and glucose uptake by activation of hormone sensitive lipase and glucose transporter 4, respectively (2, 3). Some hepatic energy metabolic pathways, including ketogenesis and gluconeogenesis, are also regulated by FGF21 in response to fasting. Expression of FGF21 is transcriptionally regulated during fasting via peroxisome proliferator-activated receptor a (PPARa), a nuclear hormone receptor (2, 4). More importantly, several studies revealed that FGF21 improves whole-body insulin sensitivity, inhibits high-fat diet-induced body weight gain and reduces fatty liver disease. Thus, FGF21 is an attractive target molecule for the prevention of metabolic diseases.Endoplasmic reticulum (ER) stress is triggered by excess accumulation of either unfolded or misfolded proteins in the ER, which in turn activates three ER membrane proteins: activating transcription factor 6a (ATF6a), inositol-requiring enzyme 1 (IRE1), and protein kinase RNA-like ER kinase (PERK). During ER stress, activation of PERK results in the phosphorylation of eukaryotic initiation factor 2a (eIF2a) and translational activation of activating transcription factor 4 (ATF4). Subsequently, ATF4 induces a series of target genes involved in amino acid metabolism, red...

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“…For instance, a negative efect of excessive packing of fat by the adipocyte includes induction of cellular hypoxia through inhibition of efective oxygen supply from the circulation [46]. Another negative intracellular efect of adipocyte hypertrophy is a mechanical stress on the endoplasmic reticulum, condition that impairs protein folding [47]. Indeed, the adipocyte displays a potent inlammation as efect of the high storage of fat [48].…”

Section: Additional Considerations About Cell Biomechanics: the Casementioning

confidence: 99%

Mechanical Stimulation of Cells Through Scaffold Design for Tissue Engineering

Oliver-Urrutia¹,

García²,

Estrada³

et al. 2017

Scaffolds in Tissue Engineering - Materials, Technologies and Clinical Applications

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Tissue engineering scafolds atempt to mimic the stem cell environment by creating different biophysical and chemical signals. On the other hand, stem cells are able to sense these characteristics and change their destiny. Scientists try to explain these phenomena through scafold design and in vitro experiments, but the mechanisms implicated remain unclear. Moreover, environment-cell interactions are a key process to get organs and tissues arrangement. Therefore, this chapter deals with the mechanical signals and mechanism involved in cell behaviour through scafolds as a strategy in tissue engineering.

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Endoplasmic Reticulum Stress Markers Are Associated with Obesity in Nondiabetic Subjects

Abstract: Multiple markers of ER stress are activated in human adipose with obesity, particularly for protective chaperones downstream of activating transcription factor 6alpha.

Cited by 242 publications

References 35 publications

Genome-wide association study identifies GYS2 as a novel genetic factor for polycystic ovary syndrome through obesity-related condition

Genome-wide association study identifies GYS2 as a novel genetic factor for polycystic ovary syndrome through obesity-related condition

FGF21 Alleviates Hepatic Endoplasmic Reticulum Stress under Physiological Conditions

Mechanical Stimulation of Cells Through Scaffold Design for Tissue Engineering

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