Rapid increase in fibroblast growth factor 21 in protein malnutrition and its impact on growth and lipid metabolism

Ozaki, Yori; Saito, Kenji; Nakazawa, Katsuhito; Konishi, Morichika; Itoh, Nobuyuki; Hakuno, Fumihiko; Takahashi, Shin‐Ichiro; Kato, Harubumi; Takenaka, Asako

doi:10.1017/s0007114515002846

Cited by 44 publications

(31 citation statements)

References 42 publications

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“…Therefore, we tested the possibility that endocrine Fgf21 from the liver regulates the development of thymocytes. To examine this possibility, we adopted a protein-free diet (PF), which was separately reported to induce upregulation of serum Fgf21 and alter cellularity of thymocytes 24, 25 . Three-week-old WT and Fgf21 KO male mice were fed with PF for 1 week.…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, we examined whether endocrine Fgf21 could regulate thymopoiesis under physiological conditions. To induce endocrine Fgf21 from the liver, we preliminarily tested several metabolic stresses such as fasting, drinking sucrose water, high-fat diet, and PF 24, 31–34 . Among these stresses, PF could induce the highest level of endocrine Fgf21, and only PF could alter the percentage of CD4SP and CD8SP cells accompanied by decreased cellularity as shown in FTOC with FGF21 (Figs 6, 8 and S5).…”

Section: Discussionmentioning

confidence: 99%

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Fgf21 regulates T-cell development in the neonatal and juvenile thymus

Nakayama

Masuda

Ohta

et al. 2017

Sci Rep

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We have previously shown that Fibroblast growth factor 21 (Fgf21) is expressed in the thymus as well as in the liver. In line with this expression profile, Fgf21 was recently reported to protect against ageing-related thymic senescence by improving the function of thymic epithelial cells (TECs). However, the function of Fgf21 in the juvenile thymus remained to be elucidated. We investigated the physiological roles of Fgf21 in the juvenile thymus and found that young Fgf21 knockout mice, but not β-Klotho knockout mice nor adult Fgf21 knockout mice, showed a significant reduction in the percentage of single-positive CD4+ and CD8+ thymocytes without obvious alteration in TECs. Furthermore, treatment with recombinant FGF21 protein rescued the impairment in fetal thymus organ culture (FTOC) of Fgf21 knockout mice. Annexin V staining revealed FGF21 protein enhanced apoptosis of immature thymocytes undergoing selection process in FTOC, suggesting that FGF21 may facilitate the selection of developing T cells. Endocrine Fgf21 from the liver induced by metabolic stimulation did not affect juvenile thymocyte development. Our data suggest that Fgf21 acts as one of intrathymic cytokines in the neonatal and juvenile thymus, involving thymocyte development in a β-Klotho-independent manner.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Fgf21 regulates T-cell development in the neonatal and juvenile thymus

Nakayama

Masuda

Ohta

et al. 2017

Sci Rep

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“…Since FGF21 is induced by both high and low carbohydrate diets, the view is that FGF21 is not regulated by carbohydrates alone but also by the reduction in protein [86]. Feeding a low-protein (5% casein) isoenergetic diet (vs. 15%-20% casein in the control diet) either short-term (8 h) in rats or longer-term (5-11 days) in mice led to an upregulation of FGF21 gene expression in the liver and an increase of FGF21 levels in plasma [87]. In humans, restricting dietary protein for 28 days caused plasma FGF21 to rise [86].…”

Section: Proteins (Low-protein Diet Methionine-or Leucinerestricted mentioning

confidence: 99%

The regulation of FGF21 gene expression by metabolic factors and nutrients

Erickson

Moreau

2016

Hormone Molecular Biology and Clinical Investigation

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Fibroblast growth factor 21 (FGF21) gene expression is altered by a wide array of physiological, metabolic, and environmental factors. Among dietary factors, high dextrose, low protein, methionine restriction, short-chain fatty acids (butyric acid and lipoic acid), and all-trans-retinoic acid were repeatedly shown to induce FGF21 expression and circulating levels. These effects are usually more pronounced in liver or isolated hepatocytes than in adipose tissue or isolated fat cells. Although peroxisome proliferator-activated receptor α (PPARα) is a key mediator of hepatic FGF21 expression and function, including the regulation of gluconeogenesis, ketogenesis, torpor, and growth inhibition, there is increasing evidence of PPARα-independent transactivation of the FGF21 gene by dietary molecules. FGF21 expression is believed to follow the circadian rhythm and be placed under the control of first order clock-controlled transcription factors, retinoic acid receptor-related orphan receptors (RORs) and nuclear receptors subfamily 1 group D (REV-ERBs), with FGF21 rhythm being anti-phase to REV-ERBs. Key metabolic hormones such as glucagon, insulin, and thyroid hormone have presumed or clearly demonstrated roles in regulating FGF21 transcription and secretion. The control of the FGF21 gene by glucagon and insulin appears more complex than first anticipated. Some discrepancies are noted and will need continued studies. The complexity in assessing the significance of FGF21 gene expression resides in the difficulty to ascertain (i) when transcription results in local or systemic increase of FGF21 protein; (ii) if FGF21 is among the first or second order genes upregulated by physiological, metabolic, and environmental stimuli, or merely an epiphenomenon; and (iii) whether FGF21 may have some adverse effects alongside beneficial outcomes.

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“…While FGF21 was originally discovered as a liver-enriched FGF [8], it was subsequently shown to be a non-mitogenic metabolic regulator with therapeutic potential for obesity-related-metabolic dysfunction [9], [10], [11], [12], [13], [14], even in humans [15], [16]. More recently, the physiological context of FGF21 has been increasingly explored [17], [18], [19], with several studies from diverse laboratories now having shown that it is an endocrine signal of dietary PD in rodents [5], [20], [21], [22], [23], [24], [25] and in humans [5], [21], [26], [27]. While the downstream mechanisms by which FGF21 improves metabolic health with dietary PD are yet to be fully resolved, it is required for increased energy expenditure, at least in mouse models [5], [21], [22], and heightened energy expenditure is thought to be a promising strategy to combat obesity-related-metabolic disease [28].…”

Section: Introductionmentioning

confidence: 99%

Repletion of branched chain amino acids reverses mTORC1 signaling but not improved metabolism during dietary protein dilution

Maida

Chan

Sjøberg

et al. 2017

Molecular Metabolism

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ObjectiveDietary protein dilution (PD) has been associated with metabolic advantages such as improved glucose homeostasis and increased energy expenditure. This phenotype involves liver-induced release of FGF21 in response to amino acid insufficiency; however, it has remained unclear whether dietary dilution of specific amino acids (AAs) is also required. Circulating branched chain amino acids (BCAAs) are sensitive to protein intake, elevated in the serum of obese humans and mice and thought to promote insulin resistance. We tested whether replenishment of dietary BCAAs to an AA-diluted (AAD) diet is sufficient to reverse the glucoregulatory benefits of dietary PD.MethodsWe conducted AA profiling of serum from healthy humans and lean and high fat-fed or New Zealand obese (NZO) mice following dietary PD. We fed wildtype and NZO mice one of three amino acid defined diets: control, total AAD, or the same diet with complete levels of BCAAs (AAD + BCAA). We quantified serum AAs and characterized mice in terms of metabolic efficiency, body composition, glucose homeostasis, serum FGF21, and tissue markers of the integrated stress response (ISR) and mTORC1 signaling.ResultsSerum BCAAs, while elevated in serum from hyperphagic NZO, were consistently reduced by dietary PD in humans and murine models. Repletion of dietary BCAAs modestly attenuated insulin sensitivity and metabolic efficiency in wildtype mice but did not restore hyperglycemia in NZO mice. While hepatic markers of the ISR such as P-eIF2α and FGF21 were unabated by dietary BCAA repletion, hepatic and peripheral mTORC1 signaling were fully or partially restored, independent of changes in circulating glucose or insulin.ConclusionsRepletion of BCAAs in dietary PD is sufficient to oppose changes in somatic mTORC1 signaling but does not reverse the hepatic ISR nor induce insulin resistance in type 2 diabetes during dietary PD.

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Rapid increase in fibroblast growth factor 21 in protein malnutrition and its impact on growth and lipid metabolism

Cited by 44 publications

References 42 publications

Fgf21 regulates T-cell development in the neonatal and juvenile thymus

Fgf21 regulates T-cell development in the neonatal and juvenile thymus

The regulation of FGF21 gene expression by metabolic factors and nutrients

Repletion of branched chain amino acids reverses mTORC1 signaling but not improved metabolism during dietary protein dilution

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