FGF21 mediates the lipid metabolism response to amino acid starvation

Sousa‐Coelho, Ana Luísa De; Relat, Joana; Hondares, Elayne; Pérez-Martí, Albert; Ribas, Francesc; Villarroya, Francesc; Marrero, Pedro F.; Haro, Diego

doi:10.1194/jlr.m033415

Cited by 104 publications

(94 citation statements)

References 41 publications

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“…Furthermore, hepatic FGF21-mediated thermogenesis has also been described in response to maternal milk consumption in neonatal pups [35], and also in situations of metabolic stress, for example upon amino acid restriction [20]. These observations suggest that the hepatic FGF21-mediated increase in thermogenic capacity is an adaptive response to metabolic stress.…”

Section: Brown Adipose Tissue: Fgf21 Induces Thermogenic Capacitymentioning

confidence: 68%

“…In WAT, it decreases FAS activity and the expression of lipogenic genes and increases the expression of FAO genes. Finally, there is an induction of UCP1 expression in BAT [20,100,101]. In contrast, in Fgf21-deficient mice this metabolic response to leucine is impaired, thus indicating that FGF21 is a key hormone in the regulation of lipid metabolism during leucine deprivation [20,81].…”

Section: Amino Acid-deficient and Low-protein Diets Increase Energy Ementioning

confidence: 99%

“…Finally, FGF21 induces the expression of uncoupling protein 1 (Ucp1), thus producing the so-called browning process of WAT in an autocrine, paracrine or endocrine fashion [20,32]. Browning occurs in multilocular beige adipocytes in specific susceptible WAT depots, such as inguinal and perirenal tissue, through an increase in the expression of genes involved in thermogenesis and confers a brown fat-like phenotype to white adipocytes.…”

Section: White Adipose Tissue: Autocrine and Paracrine Effectsmentioning

confidence: 99%

“…As a hepatokine, FGF21 affects WAT and BAT, tissues in which it regulates lipid metabolism -mainly by inducing lipolysis and browning and by increasing thermogenic capacity [20,21]. It also exerts action in the brain, where it is able to reduce physical activity, induce torpor, and regulate circadian behavior [22,23].…”

Section: Fgf21 As a Hepatokine Myokine Adipokine And Other Kines LImentioning

confidence: 99%

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Nutritional regulation of fibroblast growth factor 21: from macronutrients to bioactive dietary compounds

Pérez-Martí

Sandoval

Marrero

et al. 2016

Hormone Molecular Biology and Clinical Investigation

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Abstract:Obesity is a worldwide health problem mainly due to its associated comorbidities. Fibroblast growth factor 21 (FGF21) is a peptide hormone involved in metabolic homeostasis in healthy individuals and considered a promising therapeutic candidate for the treatment of obesity. FGF21 is predominantly produced by the liver but also by other tissues, such as white adipose tissue (WAT), brown adipose tissue (BAT), skeletal muscle, and pancreas in response to different stimuli such as cold and different nutritional challenges that include fasting, high-fat diets (HFDs), ketogenic diets, some amino acid-deficient diets, low protein diets, high carbohydrate diets or specific dietary bioactive compounds. Its target tissues are essentially WAT, BAT, skeletal muscle, heart and brain. The effects of FGF21 in extra hepatic tissues occur through the fibroblast growth factor receptor (FGFR)-1c together with the co-receptor β-klotho (KLB). Mechanistically, FGF21 interacts directly with the extracellular domain of the membrane bound cofactor KLB in the FGF21-KLB-FGFR complex to activate FGFR substrate 2α and ERK1/2 phosphorylation. Mice lacking KLB are resistant to both acute and chronic effects of FGF21. Moreover, the acute insulin sensitizing effects of FGF21 are also absent in mice with specific deletion of adipose KLB or FGFR1. Most of the data show that pharmacological administration of FGF21 has metabolic beneficial effects. The objective of this review is to compile existing information about the mechanisms that could allow the control of endogenous FGF21 levels in order to obtain the beneficial metabolic effects of FGF21 by inducing its production instead of doing it by pharmacological administration.

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Section: Brown Adipose Tissue: Fgf21 Induces Thermogenic Capacitymentioning

confidence: 68%

Section: Amino Acid-deficient and Low-protein Diets Increase Energy Ementioning

confidence: 99%

Section: White Adipose Tissue: Autocrine and Paracrine Effectsmentioning

confidence: 99%

Section: Fgf21 As a Hepatokine Myokine Adipokine And Other Kines LImentioning

confidence: 99%

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Nutritional regulation of fibroblast growth factor 21: from macronutrients to bioactive dietary compounds

Pérez-Martí

Sandoval

Marrero

et al. 2016

Hormone Molecular Biology and Clinical Investigation

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“…It has been reported that FGF21 gene expression is directly regulated by ATF4 (7,8,12,22) and potentially XBP-1 (9). A previous study reported that FGF21 repressed ER stress by inhibiting phosphorylation of eIF2a, an upstream activating factor of ATF4 (9).…”

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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