title: A PPARγ-FGF1 axis is required for adaptive adipose remodelling and metabolic homeostasis.
abstract: Although feast and famine cycles illustrate that remodelling of adipose tissue in response to fluctuations in nutrient availability is essential for maintaining metabolic homeostasis, the underlying mechanisms remain poorly understood. Here we identify fibroblast growth factor 1 (FGF1) as a critical transducer in this process in mice, and link its regulation to the nuclear receptor PPARγ (peroxisome proliferator activated receptor γ), which is the adipocyte master regulator and the target of the thiazolidinedione class of insulin sensitizing drugs. FGF1 is the prototype of the 22-member FGF family of proteins and has been implicated in a range of physiological processes, including development, wound healing and cardiovascular changes. Surprisingly, FGF1 knockout mice display no significant phenotype under standard laboratory conditions. We show that FGF1 is highly induced in adipose tissue in response to a high-fat diet and that mice lacking FGF1 develop an aggressive diabetic phenotype coupled to aberrant adipose expansion when challenged with a high-fat diet. Further analysis of adipose depots in FGF1-deficient mice revealed multiple histopathologies in the vasculature network, an accentuated inflammatory response, aberrant adipocyte size distribution and ectopic expression of pancreatic lipases. On withdrawal of the high-fat diet, this inflamed adipose tissue fails to properly resolve, resulting in extensive fat necrosis. In terms of mechanisms, we show that adipose induction of FGF1 in the fed state is regulated by PPARγ acting through an evolutionarily conserved promoter proximal PPAR response element within the FGF1 gene. The discovery of a phenotype for the FGF1 knockout mouse establishes the PPARγ–FGF1 axis as critical for maintaining metabolic homeostasis and insulin sensitization.
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Johan W
authors.initials: JW
authors.lastname: Jonker
authors.forename: Jae Myoung
authors.initials: JM
authors.lastname: Suh
authors.forename: Annette R
authors.initials: AR
authors.lastname: Atkins
authors.forename: Maryam
authors.initials: M
authors.lastname: Ahmadian
authors.forename: Pingping
authors.initials: P
authors.lastname: Li
authors.forename: Jamie
authors.initials: J
authors.lastname: Whyte
authors.forename: Mingxiao
authors.initials: M
authors.lastname: He
authors.forename: Henry
authors.initials: H
authors.lastname: Juguilon
authors.forename: Yun-Qiang
authors.initials: YQ
authors.lastname: Yin
authors.forename: Colin T
authors.initials: CT
authors.lastname: Phillips
authors.forename: Ruth T
authors.initials: RT
authors.lastname: Yu
authors.forename: Jerrold M
authors.initials: JM
authors.lastname: Olefsky
authors.forename: Robert R
authors.initials: RR
authors.lastname: Henry
authors.forename: Michael
authors.initials: M
authors.lastname: Downes
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Evans
mesh_terms: D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001483:Base Sequence; D048429:Cell Size / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D059305:Diet, High-Fat / Q000009:adverse effects; D016220:Fibroblast Growth Factor 1 / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000235:genetics; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D050152:Intra-Abdominal Fat / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009336:Necrosis / Q000201:enzymology; D047495:PPAR gamma / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D020218:Response Elements / Q000235:genetics
chemical_list: D007328:Insulin; D047495:PPAR gamma; D016220:Fibroblast Growth Factor 1