title: FGF21 does not require interscapular brown adipose tissue and improves liver metabolic profile in animal models of obesity and insulin-resistance.
abstract: FGF21 is a key metabolic regulator modulating physiological processes and its pharmacological administration improves metabolic profile in preclinical species and humans. We used native-FGF21 and a long-acting FGF21 (PF-05231023), to determine the contribution of liver and brown adipose tissue (BAT) towards metabolic improvements in Zucker rats and DIO mice (DIOs). FGF21 improved glucose tolerance and liver insulin sensitivity in Zuckers without affecting BW and improved liver function by decreased lipogenesis, increased fatty acid oxidation and improved insulin signaling. Through detailed lipidomic analyses of liver metabolites in DIOs, we demonstrate that FGF21 favorably alters liver metabolism. We observed a dose-dependent increase of [(18)F]-FDG-glucose uptake in interscapular BAT (iBAT) of DIOs upon FGF21 administration. Upon excision of iBAT (X-BAT) and administration of FGF21 to mice housed at 80 °F or 72 °F, the favorable effects of FGF21 on BW and glucose excursion were fully retained in both sham and X-BAT animals. Taken together, we demonstrate the liver as an organ that integrates the actions of FGF21 and provide metabolic benefits of FGF21 in Zucker rats and DIOs. Finally, our data demonstrates iBAT does not play a role in mediating favorable metabolic effects of FGF21 administration in DIOs housed at 80 °F or 72 °F.
authors.affiliation: Cardiovascular Metabolic and Endocrine Diseases (CVMED) Pfizer, Inc. 610 Main Street, Cambridge, MA 02139, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Bernardo
authors.affiliation: 1] Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA [2] CovX Research, Pfizer WRD, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Lu
authors.affiliation: Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors.forename: Gautam
authors.initials: G
authors.lastname: Bandyopadhyay
authors.affiliation: Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors.forename: Pingping
authors.initials: P
authors.lastname: Li
authors.affiliation: Cardiovascular Metabolic and Endocrine Diseases (CVMED) Pfizer, Inc. 610 Main Street, Cambridge, MA 02139, USA.
authors.forename: Yingjiang
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: CovX Research, Pfizer WRD, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Huang
authors.affiliation: CovX Research, Pfizer WRD, USA.
authors.forename: Nancy
authors.initials: N
authors.lastname: Levin
authors.affiliation: Cardiovascular Metabolic and Endocrine Diseases (CVMED) Pfizer, Inc. 610 Main Street, Cambridge, MA 02139, USA.
authors.forename: Eva M
authors.initials: EM
authors.lastname: Tomas
authors.affiliation: Cardiovascular Metabolic and Endocrine Diseases (CVMED) Pfizer, Inc. 610 Main Street, Cambridge, MA 02139, USA.
authors.forename: Roberto A
authors.initials: RA
authors.lastname: Calle
authors.affiliation: Cardiovascular Metabolic and Endocrine Diseases (CVMED) Pfizer, Inc. 610 Main Street, Cambridge, MA 02139, USA.
authors.forename: Derek M
authors.initials: DM
authors.lastname: Erion
authors.affiliation: Cardiovascular Metabolic and Endocrine Diseases (CVMED) Pfizer, Inc. 610 Main Street, Cambridge, MA 02139, USA.
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Rolph
authors.affiliation: Cardiovascular Metabolic and Endocrine Diseases (CVMED) Pfizer, Inc. 610 Main Street, Cambridge, MA 02139, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Brenner
authors.affiliation: Cardiovascular Metabolic and Endocrine Diseases (CVMED) Pfizer, Inc. 610 Main Street, Cambridge, MA 02139, USA.
authors.forename: Saswata
authors.initials: S
authors.lastname: Talukdar
mesh_terms: D002001:Adipose Tissue, Brown / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D004195:Disease Models, Animal; D005227:Fatty Acids / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000378:metabolism* / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects; D007333:Insulin Resistance; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D009765:Obesity / Q000378:metabolism*; D051381:Rats; D011924:Rats, Zucker
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D005227:Fatty Acids; C000604284:PF-05231023; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D005947:Glucose