Circulating FGF21 Is Liver Derived and Enhances Glucose Uptake During Refeeding and Overfeeding

Markan, Kathleen R.; Naber, Meghan C.; Ameka, Magdalene; Anderegg, Maxwell D.; Mangelsdorf, David J.; Kliewer, Steven A.; Mohammadi, Moosa; Potthoff, Matthew J.

doi:10.2337/db14-0595

Cited by 494 publications

(555 citation statements)

References 23 publications

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“…To investigate the effect of endogenous FGF21 in more detail, fasting-refeeding experiments were performed using WT and FGF21-deficient mice. Consistent with previous studies (2,19), detectable levels of plasma FGF21 were observed even during refeeding, although hepatic FGF21 mRNA levels were significantly decreased ( Fig. 6A and B).…”

Section: Fgf21 Reduces Postprandial Er Stresssupporting

confidence: 81%

“…Plasma FGF21 and hepatic FGF21 mRNA levels are known to increase during fasting via PPARa (2,4). Although FGF21 gene expression is reduced by refeeding, a significant amount of circulating FGF21 was reported during the postprandial state (19). Based on these reports, we hypothesized that FGF21 may regulate postprandial ER stress.…”

Section: Fgf21 Reduces Postprandial Er Stressmentioning

confidence: 95%

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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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Section: Fgf21 Reduces Postprandial Er Stresssupporting

confidence: 81%

Section: Fgf21 Reduces Postprandial Er Stressmentioning

confidence: 95%

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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“…FGF21 is induced by PPARα in the liver in response to fasting, PPARα agonists, and a highfat and low-carbohydrate ketogenic diet [8][9][10][11][12]. In addition, FGF21 is a downstream target of PPARγ and is required for the anti-diabetic effects of PPARγ agonists [13].…”

Section: Discussionmentioning

confidence: 99%

Section: Real-time Quantitative Reverse Transcription-polymerase Chaimentioning

confidence: 99%

“…Although FGF21 is expressed in multiple organs, including the adipose tissue, thymus, skeletal muscle, and pancreas, it is primarily secreted by the liver as an endocrine hormone [9,10]. Circulating FGF21 is liverderived and is elevated in mice fed a high-fat diet [10]. Peroxisome proliferator-activated receptor (PPAR) α, PPARγ, transcriptional factor 4 (ATF4), and nuclear factor (erythroid-derived 2)-like 2 (Nrf2) are transcriptional factors of FGF21 in the liver [11][12][13][14][15].…”

Section: Real-time Quantitative Reverse Transcription-polymerase Chaimentioning

confidence: 99%

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A Tryptophan Hydroxylase Inhibitor Decreases Hepatic FGF21 Expression and Circulating FGF21 in Mice Fed A High-Fat Diet

Nonogaki¹,

Kaji²,

Murakami³

2018

Neuropsychiatry

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Maintenance of liver glycogen during long‐term fasting preserves energy state in mice

et al. 2020

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Glycogen shortage during fasting coincides with dramatic changes in hepatic adenine nucleotide levels. The aim of this work was to study the relevance of liver glycogen in the regulation of the hepatic energy state during food deprivation. To this end, we examined the response of mice with sustained increased liver glycogen content to prolonged fasting. In order to increase hepatic glycogen content, we generated mice that overexpress protein targeting to glycogen (PTG) in the liver (PTG OE mice). Control and PTG OE mice were fed ad libitum or fasted for 36 h. Upon fasting, PTG OE mice retained significant hepatic glycogen stores and maintained hepatic energy status. Furthermore, we show that liver glycogen controls insulin sensitivity, gluconeogenesis, lipid metabolism, and ketogenesis upon nutrient deprivation.

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Circulating FGF21 Is Liver Derived and Enhances Glucose Uptake During Refeeding and Overfeeding

Cited by 494 publications

References 23 publications

FGF21 Alleviates Hepatic Endoplasmic Reticulum Stress under Physiological Conditions

FGF21 Alleviates Hepatic Endoplasmic Reticulum Stress under Physiological Conditions

A Tryptophan Hydroxylase Inhibitor Decreases Hepatic FGF21 Expression and Circulating FGF21 in Mice Fed A High-Fat Diet

Maintenance of liver glycogen during long‐term fasting preserves energy state in mice

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