FGF-21 Conducts a Liver-Brain-Kidney Axis to Promote Renal Cell Carcinoma

Metabolic homeostasis is one of the most exquisitely tuned systems in mammalian physiology. Metabolic homeostasis requires multiple redundant systems to cooperate to maintain blood glucose concentrations in a narrow range, despite a multitude of physiological and pathophysiological pressures. Cancer is one of the canonical pathophysiological settings in which metabolism plays a key role. In this study, we utilized REnal Gluconeogenesis Analytical Leads (REGAL), a liquid chromatography-mass spectrometry/mass spectrometry-based stable isotope tracer method that we developed to show that in conditions of metabolic stress, the fasting hepatokine fibroblast growth factor-21 (FGF-21)1, 2 coordinates a liver-brain-kidney axis to promote renal gluconeogenesis. FGF-21 promotes renal gluconeogenesis by enhancing β2 adrenergic receptor (Adrb2)-driven, adipose triglyceride lipase (ATGL)-mediated intrarenal lipolysis. Further, we show that this liver-brain-kidney axis promotes gluconeogenesis in the renal parenchyma in mice and humans with renal cell carcinoma (RCC). This increased gluconeogenesis is, in turn, associated with accelerated RCC progression. We identify Adrb2 blockade as a new class of therapy for RCC in mice, with confirmatory data in human patients. In summary, these data reveal a new metabolic function of FGF-21 in driving renal gluconeogenesis, and demonstrate that inhibition of renal gluconeogenesis by FGF-21 antagonism deserves attention as a new therapeutic approach to RCC.

[1]  U. Eriksson,et al.  Inhibition of VEGF-B signaling prevents non-alcoholic fatty liver disease development by targeting lipolysis in the white adipose tissue. , 2023, Journal of hepatology.

[2]  Jamey D. Young,et al.  Multitissue 2H/13C flux analysis reveals reciprocal upregulation of renal gluconeogenesis in hepatic PEPCK-C–knockout mice , 2021, JCI insight.

[3]  T. Shiomi,et al.  Renal neoplasms in tuberous sclerosis mice are neurocristopathies , 2021, iScience.

[4]  C. Drake,et al.  Kidney Cancer: An Overview of Current Therapeutic Approaches. , 2020, The Urologic clinics of North America.

[5]  T. Lüscher,et al.  Therapeutic Implications , 2020, The Endothelium: Modulator of Cardiovascular Function.

[6]  Gina M. Butrico,et al.  Glucagon stimulates gluconeogenesis by INSP3R1-mediated hepatic lipolysis , 2020, Nature.

[7]  A. Sanyal,et al.  Gene Expression Predicts Histological Severity and Reveals Distinct Molecular Profiles of Nonalcoholic Fatty Liver Disease , 2019, Scientific Reports.

[8]  Stephen J. Simpson,et al.  FGF21 Signals Protein Status to the Brain and Adaptively Regulates Food Choice and Metabolism , 2019, Cell reports.

[9]  Sushrut S. Waikar,et al.  The single-cell transcriptomic landscape of early human diabetic nephropathy , 2019, Proceedings of the National Academy of Sciences.

[10]  D. Keech,et al.  Pyruvate carboxylase. , 2018, Current topics in cellular regulation.

[11]  E. Pardon,et al.  Structures of β-klotho reveal a ‘zip code’-like mechanism for endocrine FGF signalling , 2018, Nature.

[12]  K. Petersen,et al.  Leptin Mediates a Glucose-Fatty Acid Cycle to Maintain Glucose Homeostasis in Starvation , 2018, Cell.

[13]  S. Kliewer,et al.  FGF19, FGF21, and an FGFR1/β-Klotho-Activating Antibody Act on the Nervous System to Regulate Body Weight and Glycemia. , 2017, Cell metabolism.

[14]  Gina M. Butrico,et al.  Non-invasive assessment of hepatic mitochondrial metabolism by positional isotopomer NMR tracer analysis (PINTA) , 2017, Nature Communications.

[15]  Joshua C. Chang,et al.  FGF21 mimetic antibody stimulates UCP1-independent brown fat thermogenesis via FGFR1/βKlotho complex in non-adipocytes , 2017, Molecular metabolism.

[16]  C. Lindskog,et al.  A pathology atlas of the human cancer transcriptome , 2017, Science.

[17]  A. Schürmann,et al.  FGF21 improves glucose homeostasis in an obese diabetes-prone mouse model independent of body fat changes , 2017, Diabetologia.

[18]  A. Perkins,et al.  Reduced adiposity attenuates FGF21 mediated metabolic improvements in the Siberian hamster , 2017, Scientific Reports.

[19]  T. Griffith,et al.  A Syngeneic Mouse Model of Metastatic Renal Cell Carcinoma for Quantitative and Longitudinal Assessment of Preclinical Therapies. , 2017, Journal of visualized experiments : JoVE.

[20]  Matthew J. Potthoff,et al.  FGF21 Regulates Metabolism Through Adipose-Dependent and -Independent Mechanisms. , 2017, Cell metabolism.

[21]  K. Petersen,et al.  A Non-invasive Method to Assess Hepatic Acetyl-CoA In Vivo. , 2017, Cell metabolism.

[22]  L. Puricelli,et al.  Circulating Fibroblast Growth Factor 21 (Fgf21) as Diagnostic and Prognostic Biomarker in Renal Cancer , 2016, Journal of molecular biomarkers & diagnosis.

[23]  R. Gimeno,et al.  Discrete Aspects of FGF21 In Vivo Pharmacology Do Not Require UCP1. , 2015, Cell reports.

[24]  M. Véniant,et al.  Pharmacologic Effects of FGF21 Are Independent of the "Browning" of White Adipose Tissue. , 2015, Cell metabolism.

[25]  J. Flier,et al.  Central Fibroblast Growth Factor 21 Browns White Fat via Sympathetic Action in Male Mice. , 2015, Endocrinology.

[26]  K. Petersen,et al.  Hepatic Acetyl CoA Links Adipose Tissue Inflammation to Hepatic Insulin Resistance and Type 2 Diabetes , 2015, Cell.

[27]  S. Kliewer,et al.  Circulating FGF21 Is Liver Derived and Enhances Glucose Uptake During Refeeding and Overfeeding , 2014, Diabetes.

[28]  R. Hammer,et al.  Bap1 is essential for kidney function and cooperates with Vhl in renal tumorigenesis , 2014, Proceedings of the National Academy of Sciences.

[29]  S. Kliewer,et al.  FGF21 acts centrally to induce sympathetic nerve activity, energy expenditure, and weight loss. , 2014, Cell metabolism.

[30]  M. Arumugam,et al.  Interplay between FGF21 and insulin action in the liver regulates metabolism. , 2014, The Journal of clinical investigation.

[31]  S. Kliewer,et al.  FGF21 regulates metabolism and circadian behavior by acting on the nervous system , 2013, Nature Medicine.

[32]  G. Shulman,et al.  Thyroid hormone receptor-β agonists prevent hepatic steatosis in fat-fed rats but impair insulin sensitivity via discrete pathways. , 2013, American journal of physiology. Endocrinology and metabolism.

[33]  S. Kliewer,et al.  FGF21 contributes to neuroendocrine control of female reproduction , 2013, Nature Medicine.

[34]  G. Shulman,et al.  Cellular mechanisms by which FGF21 improves insulin sensitivity in male mice. , 2013, Endocrinology.

[35]  S. Kliewer,et al.  Endocrine regulation of the fasting response by PPARalpha-mediated induction of fibroblast growth factor 21. , 2007, Cell metabolism.

[36]  J. Flier,et al.  Hepatic fibroblast growth factor 21 is regulated by PPARalpha and is a key mediator of hepatic lipid metabolism in ketotic states. , 2007, Cell metabolism.

[37]  N. Cook,et al.  Obesity and renal cell cancer – a quantitative review , 2001, British Journal of Cancer.

[38]  M. Konishi,et al.  Identification of a novel FGF, FGF-21, preferentially expressed in the liver. , 2000, Biochimica et biophysica acta.

[39]  G. Shulman,et al.  A critical evaluation of mass isotopomer distribution analysis of gluconeogenesis in vivo. , 1999, American journal of physiology. Endocrinology and metabolism.

[40]  J. Wahren,et al.  Contributions by kidney and liver to glucose production in the postabsorptive state and after 60 h of fasting. , 1999, Diabetes.

[41]  S. Hughes,et al.  Differential Expression of the Fibroblast Growth Factor Receptor (FGFR) Multigene Family in Normal Human Adult Tissues , 1997, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[42]  K. A. Taylor,et al.  A modification of the phenol/sulfuric acid assay for total carbohydrates giving more comparable absorbances , 1995 .

[43]  G. Brooks,et al.  Tracer mixing: sites of tracer infusion and sampling. , 1990, Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme.

[44]  M. Jensen,et al.  Choice of infusion-sampling mode for tracer studies of free fatty acid metabolism. , 1988, The American journal of physiology.

[45]  W. J. Dyer,et al.  A rapid method of total lipid extraction and purification. , 1959, Canadian journal of biochemistry and physiology.

[46]  M. Rasouli,et al.  Characterization and improvement of phenol-sulfuric acid microassay for glucose-based glycogen. , 2014, European review for medical and pharmacological sciences.

[47]  M. Utter,et al.  A possible role for acetyl CoA in the control of gluconeogenesis. , 1964, Advances in enzyme regulation.