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. 2010 Jul 13;107(28):12553-8.
doi: 10.1073/pnas.1006962107. Epub 2010 Jun 28.

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

Mary D L Chau  1 , Jiaping Gao, Qing Yang, Zhidan Wu, Jesper Gromada
Affiliations

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

Mary D L Chau et al. Proc Natl Acad Sci U S A. .

Abstract

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-gamma coactivator-1alpha (PGC-1alpha) 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-1alpha 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-PGC1alpha-dependent mechanism in adipocytes.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
FGF21 increases AMPK activity. (A and B) Western blot and quantification of (A) p-AMPK in 3T3-L1 cells treated for 3 d with FGF21 (4.0 μg/mL) and (B) human adipocytes. Data are average of three independent experiments. (C and D) Western blot and quantification of (C) p-AMPK and (D) p-ACC in WAT from vehicle-treated (white bar), FGF21-treated (gray bar), and paired-fed (black bar) mice. n = 8 animals/group. *P < 0.05 (Student's t test). **P < 0.01.
Fig. 2.
Fig. 2.
FGF21 increases cellular NAD+ and decreases H3 acetylation. (A) NAD+/NADH levels in 3T3-L1 adipocytes. 3T3-L1 adipocytes were treated for 3 d with FGF21 (4.0 μg/mL; black bars) or PBS (white bars). (B) NAD+/NADH levels in WAT from vehicle-treated (white bar), FGF21-treated (gray bar), and paired-fed (black bar) mice. n = 8 animals/group. (C) NAD+/NADH levels in human adipocytes transduced with adenovirus expressing control vector or DN-AMPK. Transduced adipocytes were treated for 3 d with FGF21 (4.0 μg/mL; black bars) or PBS (white bars). (D) Western blot and quantification of acetylated PGC-1α (Ac-PGC-1α) in 3T3-L1 adipocytes. 3T3-L1 adipocytes were transduced with adenovirus expressing SIRT1-shRNA and Flag–PGC-1α. Flag–PGC-1α was immunoprecipitated and blotted with pan acetylated lysine antibody. t-PGC-1α, total PGC-1α. (E) Western blot and quantification of acetylated H3 (Ac-H3) in WAT from vehicle-treated (white bar), FGF21-treated (gray bar), and paired-fed (black bar) mice. All data are averages of three independent experiments. n = 8 animals/group. *P < 0.05 (Student's t test).
Fig. 3.
Fig. 3.
FGF21 increases mitochondrial protein expression and function. CytC protein levels in (A) FGF21-treated 3T3-L1 cells and (B) human adipocytes. White bars: PBS treatment; black bars: FGF21 treatment. (C) CytC protein levels in WAT from vehicle-treated (white bar), FGF21-treated (gray bar), and paired-fed (black bar) mice. n = 8 animals/group. (D) Citrate synthase (CS) activity in 3T3-L1 adipocytes treated with FGF21. Oxygen consumption rate (OCR) in (E) 3T3-L1 cells and (F) human adipocytes treated with PBS (white bars) or FGF21 (black bars). Data are averages of three independent experiments. *P < 0.05; **P < 0.01 (Student's t test).
Fig. 4.
Fig. 4.
FGF21 effects in adipocytes require AMPK activity. (A) Gene expression in human adipocytes infected with adenovirus expressing DN-AMPK or GFP (Ctrl) and treated with PBS (white bars) or FGF21 (black bars). (B) Oxygen consumption in human adipocytes infected with adenovirus expressing DN-AMPK or GFP (Ctrl) and treated with PBS (white bars) or FGF21 (black bars). (C) Gene expression in human adipocytes infected with lentivirus expressing shRNA against LKB1 or control shRNA (Ctrl) and treated with PBS (white bars) or FGF21 (black bars). (D) Oxygen consumption in 3T3-L1 adipocytes infected with lentivirus expressing shRNA against LKB1 or control shRNA (Ctrl) and treated with PBS (white bars) or FGF21 (black bars). (E) Gene expression in human adipocytes infected with adenovirus expressing shRNA against SIRT1 or control shRNA (Ctrl) and treated with PBS (white bars) or FGF21 (black bars). (F) Oxygen consumption in 3T3-L1 adipocytes infected with adenovirus expressing shRNA against SIRT1 or control shRNA (Ctrl) and treated with PBS (white bars) or FGF21 (black bars). Data are averages of three independent experiments. All gene-expression data are quantitative RT-PCRs, normalized to the housekeeping gene, TATA box binding protein. *P < 0.05; **P < 0.01 (Student's t test). ***P < 0.001.
Fig. 5.
Fig. 5.
FGF21 effects in adipocytes require PGC-1α. (A) PGC-1α expression in 3T3-L1 adipocytes infected with shRNA-cytomegalovirus (CMV) (Ctrl) or shRNA–PGC-1α adenovirus and treated with PBS (white bars) or FGF21 (black bars). Data shown are from quantitative RT-PCRs, normalized to the housekeeping gene, TATA box binding protein. (B) Oxygen consumption in 3T3-L1 adipocytes infected with shRNA-CMV (Ctrl) or shRNA–PGC-1α adenovirus and treated with PBS (white bars) or FGF21 (black bars). Data are averages of three independent experiments. *P < 0.05; **P < 0.01 (Student's t test). (C) Schematic diagram showing FGF21 activation of AMPK via LKB1, which indirectly activates SIRT1 by increasing the cellular NAD+/NADH ratio. The pathway converges on regulation of PGC-1α activity and, ultimately, on mitochondrial oxidative function.
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