title: In Vitro and in Vivo Analyses Reveal Profound Effects of Fibroblast Growth Factor 16 as a Metabolic Regulator.
abstract: The discovery of brown adipose tissue (BAT) as a key regulator of energy expenditure has sparked interest in identifying novel soluble factors capable of activating inducible BAT (iBAT) to combat obesity. Using a high content cell-based screen, we identified fibroblast growth factor 16 (FGF16) as a potent inducer of several physical and transcriptional characteristics analogous to those of both "classical" BAT and iBAT. Overexpression of Fgf16 in vivo recapitulated several of our in vitro findings, specifically the significant induction of the Ucp1 gene and UCP1 protein expression in inguinal white adipose tissue (iWAT), a common site for emergent active iBAT. Despite significant UCP1 up-regulation in iWAT and dramatic weight loss, the metabolic improvements observed due to Fgf16 overexpression in vivo were not the result of increased energy expenditure, as measured by indirect calorimetric assessment. Instead, a pattern of reduced food and water intake, combined with feces replete with lipid and bile acid, indicated a phenotype more akin to that of starvation and intestinal malabsorption. Gene expression analysis of the liver and ileum indicated alterations in several steps of bile acid metabolism, including hepatic synthesis and reabsorption. Histological analysis of intestinal tissue revealed profound abnormalities in support of this conclusion. The in vivo data, together with FGF receptor binding analysis, indicate that the in vivo outcome observed is the likely result of both direct and indirect mechanisms and probably involves multiple receptors. These results highlight the complexity of FGF signaling in the regulation of various metabolic processes.
authors.affiliation: From the Department of Cardiometabolic Disorders, South San Francisco, California 94080. Electronic address: ingridr@amgen.com.
authors.forename: Ingrid C
authors.initials: IC
authors.lastname: Rulifson
authors.affiliation: the Genome Analysis Unit, South San Francisco, California 94080.
authors.forename: Patrick
authors.initials: P
authors.lastname: Collins
authors.affiliation: From the Department of Cardiometabolic Disorders, South San Francisco, California 94080.
authors.forename: Li
authors.initials: L
authors.lastname: Miao
authors.affiliation: the Genome Analysis Unit, South San Francisco, California 94080.
authors.forename: Dana
authors.initials: D
authors.lastname: Nojima
authors.affiliation: the Genome Analysis Unit, Thousand Oaks, California 91320.
authors.forename: Ki Jeong
authors.initials: KJ
authors.lastname: Lee
authors.affiliation: the Genome Analysis Unit, South San Francisco, California 94080.
authors.forename: Miki
authors.initials: M
authors.lastname: Hardy
authors.affiliation: From the Department of Cardiometabolic Disorders, South San Francisco, California 94080.
authors.forename: Jamila
authors.initials: J
authors.lastname: Gupte
authors.affiliation: the Department of Pathology, South San Francisco, California 94080.
authors.forename: Kelly
authors.initials: K
authors.lastname: Hensley
authors.affiliation: the Department of Pathology, South San Francisco, California 94080.
authors.forename: Kim
authors.initials: K
authors.lastname: Samayoa
authors.affiliation: the Department of Comparative Animal Research, Amgen Inc., South San Francisco, California 94080.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Cam
authors.affiliation: the Department of Pathology, Amgen Inc., Cambridge, Massachusetts 02142.
authors.forename: James B
authors.initials: JB
authors.lastname: Rottman
authors.affiliation: the Genome Analysis Unit, South San Francisco, California 94080.
authors.forename: Mike
authors.initials: M
authors.lastname: Ollmann
authors.affiliation: the Department of Cardiometabolic Disorders, Amgen Inc., Thousand Oaks, California 91320.
authors.forename: William G
authors.initials: WG
authors.lastname: Richards
authors.affiliation: From the Department of Cardiometabolic Disorders, South San Francisco, California 94080. Electronic address: yangl@amgen.com.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
mesh_terms: D052436:Adipose Tissue, White / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002460:Cell Line; D004041:Dietary Fats / Q000009:adverse effects / Q000494:pharmacology; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009765:Obesity / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D022722:Thermogenesis; D064570:Ubiquitin-Specific Proteases / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D004041:Dietary Fats; C484686:Fgf16 protein, mouse; D005346:Fibroblast Growth Factors; D064570:Ubiquitin-Specific Proteases; C579227:Usp1 protein, mouse
keywords: adipogenesis; bile acid; fibroblast growth factor (FGF); fibroblast growth factor receptor (FGFR); intestinal metabolism; metabolism