Tonicity-responsive binding protein (TonEBP) is a widely expressed
transcription factor whose activity is regulated by extracellular tonicity.
Recent studies have reported tonicity-dependent interaction between TonEBP and
p65 subunit of NF-κB which results in an increase of NF-κB activity. Because
NF-κB plays an important role in the obesity-induced metabolic inflammation and
leptin resistance, TonEBP may also be involved in the metabolic diseases. In
the beginning of this study, we found that TonEBP expression was increased in the
hypothalamus of mice by feeding high-fat diet (HFD). Mice with heterozygous
TonEBP deficiency [TonEBP (+/-)] revealed higher sensitivity to leptin compared
to wild type littermate. When fed HFD, TonEBP (+/-) mice were significantly
less obese and showed an alleviated leptin resistance, compared to the wild type. Because
suppressor of cytokine signaling 3 (SOCS3) is a negative regulator of leptin
signaling, we next addressed change in SOCS3 expression by TonEBP. Leptin-induced
SOCS3 expression was significantly decreased in the hypothalamus of TonEBP (+/-) mice. Moreover, our promoter
analysis revealed that NF-κB-TonEBP complex markedly
stimulated transcriptional activity of SOCS3. These results suggest that
TonEBP is involved in the leptin signaling pathway through controlling SOCS3
expression in the hypothalamus, and thereby plays an important role in
generation of metabolic disorder