Skeletal muscle increases FGF21 expression in mitochondrial disorders to compensate for energy metabolic insufficiency by activating the mTOR–YY1–PGC1α pathway

Ji, Kunqian; Zheng, Jieyun; Lv, Jima; Xu, Jingwen; Ji, Xinbo; Luo, Yue‐Bei; Li, Wei; Zhao, Yuying; Yan, Chuanzhu

doi:10.1016/j.freeradbiomed.2015.03.020

Cited by 75 publications

(62 citation statements)

References 30 publications

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“…FGF21 reduces WAT mass and enhances energy expenditure by activating BAT. Similar benefits have been shown with exercise training (Ji, et al 2015; Kim, et al 2013; Kim and Lee 2014), which has been shown to increase FGF21 secretion in some human and rodent studies (Kim et al 2013; Loyd, et al 2016; Tanimura, et al 2016). Recently, anti-inflammatory properties of FGF21 have been reported (Feingold, et al 2012; Singhal, et al 2016; Yu, et al 2016); however, whether exercise-induced anti-inflammatory actions in adipose tissue are mediated via FGF21 has not been addressed.…”

Section: Introductionsupporting

confidence: 70%

Anti-inflammatory effects of exercise training in adipose tissue do not require FGF21

Porter

Rowles

Fletcher

et al. 2017

Journal of Endocrinology

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Exercise enhances insulin sensitivity; it also improves adipocyte metabolism and reduces adipose tissue inflammation through poorly-defined mechanisms. Fibroblast growth factor 21 (FGF21) is a pleiotropic hormone-like protein whose insulin-sensitizing properties are predominantly mediated via receptor signaling in adipose tissue (AT). Recently, FGF21 has also been demonstrated to have anti-inflammatory properties. Meanwhile, an association between exercise and increased circulating FGF21 levels has been reported in some, but not all studies. Thus, the role that FGF21 plays in mediating the positive metabolic effects of exercise in AT are unclear. In this study, FGF21 knock-out (KO) mice were used to directly assess the role of FGF21 in mediating the metabolic and anti-inflammatory effects of exercise on white AT (WAT) and brown AT (BAT). Male FGF21KO and wild-type mice were provided running wheels or remained sedentary for 8 weeks (n=9–15/group) and compared for adiposity, insulin sensitivity (i.e., HOMA-IR, Adipo-IR), and AT inflammation and metabolic function (e.g., mitochondrial enzyme activity, subunit content). Adiposity and Adipo-IR were increased in FGF21KO mice and decreased by EX. The BAT of FGF21KO animals had reduced mitochondrial content and decreased relative mass, both normalized by EX. WAT and BAT inflammation was elevated in FGF21KO mice, reduced in both genotypes by EX. EX increased WAT Pgc1alpha gene expression, citrate synthase activity, COX I content, and total AMPK content in WT but not FGF21KO mice. Collectively, these findings reveal a previously unappreciated anti-inflammatory role for FGF21 in WAT and BAT, but do not support that FGF21 is necessary for EX-mediated anti-inflammatory effects.

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Section: Introductionsupporting

confidence: 70%

Anti-inflammatory effects of exercise training in adipose tissue do not require FGF21

Porter

Rowles

Fletcher

et al. 2017

Journal of Endocrinology

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“…Urine gas chromatography/mass spectrometry (GC/MS) and blood tandem mass spectrometry (TMS) did not reveal any abnormal metabolites. The blood FGF-21, a marker of mitochondrial disease [13], was 766 pg/ml (normal<13.5). A panel of nuclear encoded mitochondrial genes were analysed by next generation sequencing.…”

Section: Casementioning

confidence: 99%

Sengers syndrome in Asian Indians – two novel mutations and variant phenotype-genotype correlation

Khatter

Puri

Bijarnia‐Mahay

et al. 2017

TRD

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Abstract. Sengers syndrome is an autosomal recessive mitochondrial disease comprising a tetrad of congenital cataract, hypertrophic cardiomyopathy, skeletal myopathy and lactic acidosis. Mutations in the AGK gene cause Senger syndrome. We describe two unrelated Asian Indian families with two novel mutations, c.909 G>A (p.Trp303Ter) and c.982G>T (p.E328Ter), in the AGK gene. Similar nonsense mutations have previously been reported with a severe phenotype and early infantile death, while this patient is doing well at 3 years, suggesting a mild phenotype.The second child tested positive for two previously reported mutations, c.841C>T (p.Arg281Ter) and c.424-3C>G. The presence of a splice site mutation typically predicts a milder phenotype with one exception reported to date. The second patient we report died at 9 months of age adding to the one previously reported exception.Both these cases add onto the scant literature of genotype phenotype correlation in Sengers syndrome. We emphasize the importance of diagnosis of this clinically recognizable syndrome to counsel families of recurrence risks and option of prenatal diagnosis.

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“…Additionally, a large body of studies have indicated that FGF21 expression is up-regulated during different kinds of stresses, including chemicals such as acetaminophen, dioxin, cerulein, and phenylephrine (31)(32)(33), environmental stress such as cold, nutritional stress such as starvation (fasting) and overnutrition (obesity), endoplasmic reticulum (ER) stress (34,35), mitochondria stress (36,37), and oxidative stress (38,39). These facts suggest that FGF21 acts as a key regulator in the adaptation of the body or organs to various kinds of stress and may func- Figure 1.…”

Section: Fgf21 Identification and Its General Actionsmentioning

confidence: 99%

Minireview: Roles of Fibroblast Growth Factors 19 and 21 in Metabolic Regulation and Chronic Diseases

Zhang

Lin

et al. 2015

Molecular Endocrinology

106

113

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Fibroblast growth factor (FGF)19 and FGF21 are hormones that regulate metabolic processes particularly during feeding or starvation, thus ultimately influencing energy production. FGF19 is secreted by the intestines during feeding and negatively regulates bile acid synthesis and secretion, whereas FGF21 is produced in the liver during fasting and plays a crucial role in regulating glucose and lipid metabolism, as well as maintaining energy homeostasis. FGF19 and FGF21 are regarded as late-acting hormones because their functions are only used after insulin and glucagon have completed their actions. Although FGF19 and FGF21 are activated under different conditions, they show extensively functional overlap in terms of improving glucose tolerance, insulin sensitivity, weight loss, and lipid, and energy metabolism, particularly in pathological conditions such as diabetes, obesity, metabolic syndrome, and cardiovascular and renal diseases. Most patients with these metabolic diseases exhibit reduced serum FGF19 levels, which might contribute to its etiology. In addition, the simultaneous increase in serum FGF21 levels is likely a compensatory response to reduced FGF19 levels, and the 2 proteins concertedly maintain metabolic homeostasis. Here, we review the physiological and pharmacological cross talk between FGF19 and FGF21 in relation to the regulation of endocrine metabolism and various chronic diseases.

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Skeletal muscle increases FGF21 expression in mitochondrial disorders to compensate for energy metabolic insufficiency by activating the mTOR–YY1–PGC1α pathway

Cited by 75 publications

References 30 publications

Anti-inflammatory effects of exercise training in adipose tissue do not require FGF21

Anti-inflammatory effects of exercise training in adipose tissue do not require FGF21

Sengers syndrome in Asian Indians – two novel mutations and variant phenotype-genotype correlation

Minireview: Roles of Fibroblast Growth Factors 19 and 21 in Metabolic Regulation and Chronic Diseases

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