title: Overexpression of Foxf2 in adipose tissue is associated with lower levels of IRS1 and decreased glucose uptake in vivo.
abstract: Many members of the forkhead genes family of transcription factors have been implicated as important regulators of metabolism, in particular, glucose homeostasis, e.g., Foxo1, Foxa3, and Foxc2. The purpose of this study was to exploit the possibility that yet unknown members of this gene family play a role in regulating glucose tolerance in adipocytes. We identified Foxf2 in a screen for adipose-expressed forkhead genes. In vivo overexpression of Foxf2 in an adipose tissue-restricted fashion demonstrated that such mice display a significantly induced insulin secretion in response to an intravenous glucose load compared with wild-type littermates. In response to increased Foxf2 expression, insulin receptor substrate 1 (IRS1) mRNA and protein levels are significantly downregulated in adipocytes; however, the ratio of serine vs. tyrosine phosphorylation of IRS1 seems to remain unaffected. Furthermore, adipocytes overexpressing Foxf2 have a significantly lower insulin-mediated glucose uptake compared with wild-type adipocytes. These findings argue that Foxf2 is a previously unrecognized regulator of cellular and systemic whole body glucose tolerance, at least in part, due to lower levels of IRS1. Foxf2 and its downstream target genes can provide new insights with regard to identification of novel therapeutic targets.
authors.affiliation: Dept. of Medical and Clinical Genetics, Institute of Biomedicine, Univ. of Göteborg, Sweden.
authors.forename: Rickard
authors.initials: R
authors.lastname: Westergren
authors.forename: Daniel
authors.initials: D
authors.lastname: Nilsson
authors.forename: Mikael
authors.initials: M
authors.lastname: Heglind
authors.forename: Zahra
authors.initials: Z
authors.lastname: Arani
authors.forename: Mats
authors.initials: M
authors.lastname: Grände
authors.forename: Anna
authors.initials: A
authors.lastname: Cederberg
authors.forename: Bo
authors.initials: B
authors.lastname: Ahrén
authors.forename: Sven
authors.initials: S
authors.lastname: Enerbäck
mesh_terms: D016475:3T3 Cells; D017667:Adipocytes; D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D015536:Down-Regulation; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D015870:Gene Expression; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: C486413:FOXF2 protein, human; D051858:Forkhead Transcription Factors; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D005947:Glucose