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Overexpression of Foxf2 in adipose tissue is associated with lower levels of IRS1 and decreased glucose uptake in vivo.

Journal article
Authors Rickard Westergren
Daniel Nilsson
Mikael Heglind
Zahra Arani
Mats Grände
Anna Cederberg
Bo Ahrén
Sven Enerbäck
Published in American journal of physiology. Endocrinology and metabolism
Volume 298
Issue 3
Pages E548-54
ISSN 1522-1555
Publication year 2010
Published at Institute of Biomedicine, Department of Medical and Clinical Genetics
Pages E548-54
Language en
Keywords 3T3 Cells, Adipocytes, Adipose Tissue, metabolism, Animals, Down-Regulation, Forkhead Transcription Factors, metabolism, Gene Expression, Glucose, metabolism, Homeostasis, genetics, Humans, Insulin Receptor Substrate Proteins, metabolism, Mice, Mice, Inbred C57BL
Subject categories Cell and Molecular Biology


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.

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