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Insulin and TNF Induce Expression of the Forkhead Transcription Factor Gene Foxc2 in 3T3-L1 Adipocytes via PI3K and ERK 1/2-Dependent Pathways

Department of Medical Biochemistry (L.M.G., K.T.), Institute of Basic Medical Sciences, University of Oslo, N-0317 Oslo, Norway; Medical Genetics (A.C., S.E.), Department of Medical Biochemistry, Göteborg University, SE-405 30 Göteborg, Sweden; and Department of Biochemistry (N.M.), Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan

Address all correspondence and requests for reprints to: Kjetil Taskén, M.D., Ph.D., Department of Medical Biochemistry, Institute of Basic Medical Sciences, University of Oslo, P.O. Box 1112, Blindern, N-0317 Oslo, Norway. E-mail: kjetil.tasken{at}basalmed.uio.no.

We have recently identified the winged helix/forkhead gene Foxc2 as a key regulator of adipocyte metabolism that counteracts obesity and diet-induced insulin resistance. This study was performed to elucidate the hormonal regulation of Foxc2 in adipocytes. We find that TNF and insulin induce Foxc2 mRNA in differentiated 3T3-L1 cells with the kinetics of an immediate early response (1–2 h with 100 ng/ml insulin or 5 ng/ml TNF). This induction is, in both cases, attenuated by the PI3K inhibitor wortmannin as well as the MAPK kinase inhibitor PD98059. Furthermore, we show that stimulation of 3T3-L1 adipocytes with phorbol-12-myristate-13-acetate or 8-(4-chlorophenyl)thio-cAMP induces the expression of Foxc2. Interestingly, we find that the basal level of Foxc2 mRNA is down-regulated whereas hormonal responsiveness increases during differentiation of 3T3-L1 from preadipocytes to adipocytes. At the protein level, immunoblots with Foxc2 antibody demonstrated an induction of Foxc2 by insulin and TNF in nuclear extracts of 3T3-L1 adipocytes. EMSA of nuclear proteins from phorbol-12-myristate-13-acetate- and TNF-treated 3T3-L1 adipocytes using a forkhead consensus oligonucleotide revealed specific binding of a Foxc2/DNA complex. In conclusion, our data suggest that insulin and TNF regulate the expression of Foxc2 via a PI3K- and ERK 1/2-dependent pathway in 3T3-L1 adipocytes. Also, signaling pathways downstream of PKA and PKC induce the expression of Foxc2 mRNA.

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