FGF21 induces PGC-1α and regulates carbohydrate and fatty acid metabolism during the adaptive starvation response

Potthoff, Matthew J.; Inagaki, Takeshi; Satapati, Santhosh; Ding, Xunshan; He, TianTeng; Goetz, Regina; Mohammadi, Moosa; Finck, Brian N.; Mangelsdorf, David J.; Kliewer, Steven A.; Burgess, Shawn C.

doi:10.1073/pnas.0904187106

Cited by 632 publications

(621 citation statements)

References 49 publications

(79 reference statements)

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“…Our studies show that FGF21 stimulates AMPK and SIRT1 activities in adipose tissue. Recently, FGF21 was found to increase PGC-1α expression, fatty acid oxidation, and TCA cycle flux in the liver (30). It would be of interest to determine whether FGF21 also can activate AMPK and SIRT1 to act in concert with PGC-1α in the liver.…”

Section: Discussionmentioning

confidence: 99%

Fibroblast growth factor 21 regulates energy metabolism by activating the AMPK–SIRT1–PGC-1α pathway

Chau¹,

Gao²,

Yang³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

449

351

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Fibroblast growth factor 21 (FGF21) has been identified as a potent metabolic regulator. Administration of recombinant FGF21 protein to rodents and rhesus monkeys with diet-induced or genetic obesity and diabetes exerts strong antihyperglycemic and triglyceride-lowering effects and reduction of body weight. Despite the importance of FGF21 in the regulation of glucose, lipid, and energy homeostasis, the mechanisms by which FGF21 functions as a metabolic regulator remain largely unknown. Here we demonstrate that FGF21 regulates energy homeostasis in adipocytes through activation of AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1), resulting in enhanced mitochondrial oxidative function. AMPK phosphorylation levels were increased by FGF21 treatment in adipocytes as well as in white adipose tissue from ob/ob mice. FGF21 treatment increased cellular NAD + levels, leading to activation of SIRT1 and deacetylation of its downstream targets, peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) and histone 3. Activation of AMPK and SIRT1 by FGF21 in adipocytes enhanced mitochondrial oxidative capacity as demonstrated by increases in oxygen consumption, citrate synthase activity, and induction of key metabolic genes. The effects of FGF21 on mitochondrial function require serine/ threonine kinase 11 (STK11/LKB1), which activates AMPK. Inhibition of AMPK, SIRT1, and PGC-1α activities attenuated the effects of FGF21 on oxygen consumption and gene expression, indicating that FGF21 regulates mitochondrial activity and enhances oxidative capacity through an AMPK-SIRT1-PGC1α-dependent mechanism in adipocytes.A MP-activated protein kinase (AMPK) is a major metabolic energy sensor and master regulator of metabolic homeostasis (1). LKB1, a serine threonine kinase, is a major regulator of AMPK activation. LKB1 directly phosphorylates Thr-172 of AMPK and activates its kinase activity (2). LKB1 expression is induced upon exercise and acts as a critical mediator of gluconeogenesis in the liver (3). Recently, AMPK has been shown to play an important role in the therapeutic benefits of metformin (1, 4), thiazolidinediones (5), and exercise (6, 7), all cornerstones in the management of type 2 diabetes and metabolic syndrome. Activation of AMPK maintains energy balance by switching on catabolic pathways, enhancing oxidative metabolism and mitochondrial biogenesis (1). Recently, AMPK was found to enhance NAD + -dependent type III deacetylase sirtuin 1 (SIRT1) activity by increasing cellular NAD + levels, resulting in modulation of the activity of downstream SIRT1 targets (8).SIRT1 plays an important role in metabolic function and longevity in mammals (9, 10). Activation of SIRT1 also results in selective nutrient utilization and enhanced mitochondrial oxidative function to regulate energy balance. Both AMPK and SIRT1 act in concert with the master regulator of mitochondrial biogenesis, peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), to regulate energy homeostasis in response to environmental and ...

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Section: Discussionmentioning

confidence: 99%

Fibroblast growth factor 21 regulates energy metabolism by activating the AMPK–SIRT1–PGC-1α pathway

Chau¹,

Gao²,

Yang³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

449

351

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“…Recent studies suggest that adipose derived stem cells (ADSCs) show beneficial effects to improve liver fibrosis 4. In addition, fibroblast growth factor (FGF) 21 improves lipid profiles and hepatic steatosis 5. To enhance the therapeutic effects of ADSCs on liver fibrosis, we established FGF21‐secreting ADSCs (FGF21_ADSCs) and investigated their effects on thioacetamide (TAA)‐induced liver fibrosis in mice.…”

Section: Introductionmentioning

confidence: 99%

Effects of FGF21‐secreting adipose‐derived stem cells in thioacetamide‐induced hepatic fibrosis

Kang

Seo

Park

et al. 2018

J Cellular Molecular Medi

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Mesenchymal stem cells (MSCs) have been investigated to treat liver diseases, but the efficiency of MSCs to treat chronic liver diseases is conflicting. FGF21 can reduce inflammation and fibrosis. We established FGF21‐secreting adipose derived stem cells (FGF21_ADSCs) to enhance the effects of ADSCs and transplanted them into thioacetamide (TAA)‐induced liver fibrosis mice via the tail vein. Transplantation of FGF21_ADSCs significantly improved liver fibrosis by decreasing serum hyaluronic acid and reducing the expression of fibrosis‐related factors such as α‐smooth muscle actin (α‐SMA), collagen and tissue inhibitor of metalloproteinase‐1 (TIMP‐1) compared with the Empty_ADSCs by inhibition of p‐JNK, NF‐κB and p‐Smad2/3 signalling. α‐lactoalbumin (LA) and lactotransferrin (LTF), secretory factors produced from FGF21_ADSCs inhibited TGF‐β1‐induced expression of α‐SMA and collagen in LX‐2 cells. These results suggest that transplantation of FGF21_ADSCs inhibited liver fibrosis more effectively than Empty_ADSCs, possibly via secretion of α‐LA and LTF.

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“…Rodent studies have shown that during fasting FGF-21 stimulates hepatic fatty acid oxidation, ketogenesis, lipolysis and gluconeogenesis to supply metabolically active tissues with substrates [3,4]. However, another animal study showed that in the fasting state FGF-21 inhibits lipolysis, whereas in the fed state FGF-21 stimulates it [5].…”

Section: Introductionmentioning

confidence: 99%

Glucagon increases circulating fibroblast growth factor 21 independently of endogenous insulin levels: a novel mechanism of glucagon-stimulated lipolysis?

et al. 2012

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Aims/hypothesis Glucagon reduces body weight by modifying food intake, glucose/lipid metabolism and energy expenditure. All these physiological processes are also controlled by fibroblast growth factor 21 (FGF-21), a circulating hepatokine that improves the metabolic profile in obesity and type 2 diabetes. Animal experiments have suggested a possible interaction between glucagon and FGF-21 however, the metabolic consequences of this crosstalk are not understood. Methods The effects of exogenous glucagon on plasma FGF-21 levels and lipolysis were evaluated in healthy volunteers and humans with type 1 diabetes, as well as in rodents with streptozotocin (STZ)-induced insulinopenic diabetes. In vitro, the role of glucagon on FGF-21 secretion and lipolysis was studied using isolated primary rat hepatocytes and adipocytes. Fgf-21 expression in differentiated rat pre-adipocytes was suppressed by small interfering RNA and released FGF-21 was immunoneutralised by polyclonal antibodies. Results Glucagon induced lipolysis in healthy human volunteers, patients with type 1 diabetes, mice and rats with STZ-induced insulinopenic diabetes, and in adipocytes isolated from diabetic and non-diabetic animals. In addition, glucagon increased circulating FGF-21 in healthy humans and rodents, as well as in patients with type 1 diabetes, and insulinopenic rodents. Glucagon stimulated FGF-21 secretion from isolated primary hepatocytes and adipocytes derived from animals with insulinopenic diabetes. Furthermore, FGF-21 stimulated lipolysis in primary adipocytes isolated from non-diabetic and diabetic rats. Reduction of Fgf-21 expression (by approximately 66%) or immunoneutralisation of released FGF-21 markedly attenuated glucagon-stimulated lipolysis in adipocytes. Conclusions/interpretation These results indicate that glucagon increases circulating FGF-21 independently of endogenous insulin levels. FGF-21 participates in glucagon-induced stimulation of lipolysis.

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FGF21 induces PGC-1α and regulates carbohydrate and fatty acid metabolism during the adaptive starvation response

Cited by 632 publications

References 49 publications

Fibroblast growth factor 21 regulates energy metabolism by activating the AMPK–SIRT1–PGC-1α pathway

Fibroblast growth factor 21 regulates energy metabolism by activating the AMPK–SIRT1–PGC-1α pathway

Effects of FGF21‐secreting adipose‐derived stem cells in thioacetamide‐induced hepatic fibrosis

Glucagon increases circulating fibroblast growth factor 21 independently of endogenous insulin levels: a novel mechanism of glucagon-stimulated lipolysis?

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