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FGF21 Induces PGC-1 and Regulates Carbohydrate and Fatty Acid Metabolism During the Adaptive Starvation Response

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FGF21 Induces PGC-1 and Regulates Carbohydrate and Fatty Acid Metabolism During the Adaptive Starvation Response FGF21 induces PGC-1␣ and regulates carbohydrate and fatty acid metabolism during the adaptive starvation response Matthew J. Potthoffa,b,c, Takeshi Inagakid, Santhosh Satapatic, Xunshan Dinga,b, Tianteng Hec, Regina Goetze, Moosa Mohammadie, Brian N. Finckf,g, David J. Mangelsdorfa,b,1, Steven A. Kliewera,d,1, and Shawn C. Burgessa,c aDepartment of Pharmacology, bHoward Hughes Medical Institute, cAdvanced Imaging Center, and dDepartment of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390; eDepartment of Pharmacology, New York University School of Medicine, New York, NY 10016; and fCenter for Cardiovascular Research and gCenter for Human Nutrition, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110 Contributed by David J. Mangelsdorf, April 21, 2009 (sent for review March 17, 2009) The liver plays a crucial role in mobilizing energy during nutritional expression is induced in response to changes in nutritional status deprivation. During the early stages of fasting, hepatic glycogen- and other physiologic stimuli such as cold and exercise (18–21). olysis is a primary energy source. As fasting progresses and PGC-1␣ is enriched in metabolic tissues, such as muscle and glycogen stores are depleted, hepatic gluconeogenesis and keto- heart, where it interacts with multiple DNA-binding transcrip- genesis become major energy sources. Here, we show that fibro- tion factors to stimulate mitochondrial metabolic capacity. In blast growth factor 21 (FGF21), a hormone that is induced in liver liver, induction of PGC-1␣ by fasting stimulates the transcription by fasting, induces hepatic expression of peroxisome proliferator- of genes involved in fatty acid oxidation, tricarboxylic acid activated receptor ␥ coactivator protein-1␣ (PGC-1␣), a key tran- (TCA) cycle flux, mitochondrial oxidative phosphorylation, and scriptional regulator of energy homeostasis, and causes corre- gluconeogenesis (4, 22–24). Accordingly, these metabolic pro- sponding increases in fatty acid oxidation, tricarboxylic acid cycle cesses are impaired in mice in which PGC-1␣ function has been flux, and gluconeogenesis without increasing glycogenolysis. Mice disrupted in liver (4, 25–28). In this article, we show that FGF21 lacking FGF21 fail to fully induce PGC-1␣ expression in response to induces PGC-1␣ and has marked effects on carbohydrate and a prolonged fast and have impaired gluconeogenesis and keto- lipid metabolism. Our findings reveal a prominent role for genesis. These results reveal an unexpected relationship between FGF21 in coordinating the adaptive metabolic response to FGF21 and PGC-1␣ and demonstrate an important role for FGF21 in starvation. coordinately regulating carbohydrate and fatty acid metabolism during the progression from fasting to starvation. Results FGF21 Stimulates a Fasting Metabolic State. To examine how FGF21 lipid metabolism ͉ liver ͉ gluconeogenesis ͉ glycogenolysis ͉ ketogenesis affects liver metabolism, fatty acid and carbohydrate fluxes were measured by 2H/13C NMR isotopomer analysis in isolated liver n mammals, the liver plays a crucial role in maintaining from WT mice and transgenic mice overexpressing FGF21 in a Isystemic energy balance during fasting and starvation through liver-enriched manner (FGF21-TG) (6). As expected, hepatic coordinate effects on carbohydrate and lipid metabolism. During oxygen consumption was increased in response to fasting in WT the early stages of fasting, the liver mobilizes glucose from its liver (Fig. 1A). Importantly, FGF21-TG liver from fed mice glycogen stores. As fasting progresses and glycogen reserves are exhibited increased oxygen consumption rates that were equiv- depleted, the liver oxidizes fat to provide both energy for alent to those observed in WT fasted liver (Fig. 1A). No further gluconeogenesis and substrate for ketogenesis. This synchroni- increase in oxygen consumption occurred in FGF21-TG liver in zation of hepatic lipid and carbohydrate metabolism is critical for response to fasting (Fig. 1A). To characterize hepatic fat oxi- the normal fasting response; disruption of either one of these dation in more detail, we measured TCA cycle flux and keto- pathways has profound effects on the other (1–4). genesis. Ketogenesis was significantly increased, and there was a Hormones such as glucagon, catecholamines, and glucocorti- trend toward increased TCA cycle flux in fed FGF21-TG liver coids have important roles in controlling substrate utilization (Fig. 1A). Overall, hepatic ␤-oxidation nearly doubled in fed and maintaining energy balance during fasting. Recently, the FGF21-TG liver (Fig. 1A). These data are consistent with the hormone fibroblast growth factor 21 (FGF21) was shown to be previous description of FGF21 as a ketogenic factor (5, 6) and induced in the liver during fasting (5–7). FGF21 is an unusual provide additional evidence that FGF21 is critical for the FGF family member in that it lacks the conventional heparin- induction of hepatic fat oxidation during fasting. binding domain (8) and thus can diffuse away from its tissue of Overexpression of FGF21 also affected carbohydrate metab- origin and function as a hormone. FGF21 signals through olism. Notably, gluconeogenesis was increased 60% in fed cell-surface receptors composed of classic FGF receptors com- FGF21-TG liver compared with that of fed WT liver (Fig. 1B) plexed with ␤-klotho, a membrane-spanning protein (9–14). and was not induced any further by fasting (Fig. 1B). These data Induction of FGF21 during fasting occurs through a mechanism demonstrate that overexpression of FGF21 is sufficient to induce that requires peroxisome proliferator-activated receptor ␣ gluconeogenesis in the fed state to levels normally attained (PPAR␣) (5–7). FGF21 has diverse metabolic actions that include stimulating hepatic fatty acid oxidation and ketogenesis (5, 6, 15) and blocking the growth hormone signaling pathway Author contributions: M.J.P., T.I., D.J.M., S.A.K., and S.C.B. designed research; M.J.P., T.I., S.S., X.D., T.H., and B.N.F. performed research; R.G. and M.M. contributed new reagents/ (16). FGF21 also sensitizes mice to torpor, a short-term hiber- analytic tools; M.J.P., T.I., D.J.M., S.A.K., and S.C.B. analyzed data; and M.J.P., D.J.M., S.A.K., nation-like state of regulated hypothermia (6). Pharmacologic and S.C.B. wrote the paper. administration of FGF21 to insulin-resistant rodents and mon- The authors declare no conflict of interest. keys improves glucose tolerance and reduces plasma insulin and 1To whom correspondence may be addressed. E-mail: [email protected] triglyceride concentrations (15, 17). or [email protected]. ␥ PHYSIOLOGY Peroxisome proliferator-activated receptor coactivator pro- This article contains supporting information online at www.pnas.org/cgi/content/full/ tein-1␣ (PGC-1␣) is a transcriptional coactivator protein whose 0904187106/DCSupplemental. www.pnas.org͞cgi͞doi͞10.1073͞pnas.0904187106 PNAS ͉ June 30, 2009 ͉ vol. 106 ͉ no. 26 ͉ 10853–10858 Downloaded by guest on September 30, 2021 A WT FGF21-TG B WT FGF21-TG A WT FGF21-TG B β 2.0 O2 Consumption -Oxidation Gluconeogenesis Glycogenolysis 5 b a a a a c 1.0 1.6 d d 0.8 2.5 a a a 0.8 a a 4 2.0 1.2 0.6 1.5 WT WT TG TG 0.6 PGC-1α 1.5 l/min/g 0.8 0.4 3 0.4 β-actin 1.0 mo mol/min/g 1.0 µ 0.4 µ 0.2 0.5 0.2 2 0 0 0 0 0.5 Fed Fasted Fed Fasted Fed Fasted Fed Fasted 1 Relative mRNA level TCA Cycle Flux Ketogenesis Liver Glycogen 80 0 0 b α 0.6 0.3 a Pgc1 e b c a 5 3a as p 60 t Cytc b Idh 0.4 0.2 Pepck A a 40 G6p gliver / mol/min/g 0.2 0.1 µ mg 20 Vehicle FGF21 0 0 0 C Fed Fasted Fed Fasted Fed Fasted Pgc1α G6pase Pepck Cytc 2 3 15 6 d Fig. 1. FGF21 regulates hepatic lipid and glucose metabolism. (A and B) a d a Metabolic parameters of energy expenditure and lipid and glucose metabo- 4 a a b 2 10 lism were determined by NMR in livers from fed and fasted 16- to 20-week-old WT and FGF21 transgenic (FGF21-TG) male mice (n ϭ 5 per group). Livers were 1 perfused with nonrecirculating media, and absolute fluxes were determined 2 1 5 from the NMR data and rate of glucose production. Liver glycogen content (B) was analyzed in fed and fasted WT and FGF21-TG liver samples (n ϭ 6 per Relative mRNA level Ϯ 0 0 0 0 group) independent of those analyzed by NMR. Data are presented as mean 0.25 1 4 0.25 1 4 0.25 1 4 0.25 1 4 SEM (a, P Ͻ 0.05; b, P Ͻ 0.01; c, P Ͻ 0.005; d, P Ͻ 0.001). Time (h) Time (h) Time (h) Time (h) Fed vehicle Fed FGF21 Fasted vehicle during prolonged fasting. The concept that FGF21 expression D 5 a c a induces a metabolic state in liver that mimics long-term fasting 4 a a was reinforced by impaired glycogenolysis (Fig. 1B) and an b accompanying 50% increase in glycogen content in FGF21-TG 3 c b liver (Fig. 1B). There was no difference in plasma glucagon 2 concentrations between FGF21-TG and WT mice (Fig. S1A). 1 These data are consistent with an increased reliance on glu- Relative mRNA level coneogenesis and an autoregulatory sparing of glycogen (29). 0 WT KO WT KO WT KO Taken together, our findings reveal an important role for FGF21 in regulating changes in both fatty acid and carbohydrate me- Pgc1α G6pase Pepck tabolism during a prolonged fast. Fig. 2. FGF21 induces gluconeogenic gene expression. (A) Hepatic metabolic gene expression in fed WT and FGF21-TG male mice (n ϭ 5 per group).
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