TonEBP as a key regulator of hypothalamic leptin signaling and resistance.

Tonicity-responsive enhancer binding protein (TonEBP) is a transcription factor implicated in cellular stress and inflammation. Here, we explore the role of TonEBP as a key regulator of leptin signaling and resistance. Using TonEBP haploinsufficient [TonEBP (+/-)] mice, we demonstrated that TonEBP negatively regulates leptin sensitivity by upregulating suppressor of cytokine signaling 3 (SOCS3). TonEBP (+/-) mice exhibited heightened leptin-induced anorexia, increased energy expenditure, and elevated STAT3 phosphorylation in proopiomelanocortin (POMC) neurons compared to wild-type [TonEBP (+/+)] controls. Additionally, TonEBP (+/-) mice were protected from high-fat diet-induced obesity and retained leptin sensitivity during chronic energy surplus conditions. Mechanistically, TonEBP deficiency suppressed SOCS3 expression through decreased NF-κB-mediated transcriptional activation, thereby suppressing the negative feedback signal on leptin signaling. Furthermore, elevated hypothalamic TonEBP expression during high-fat diet feeding and leptin treatment implicates its role in regulating leptin sensitivity. Taken together, these findings identify a novel role for TonEBP as a molecular mediator of hypothalamic leptin signaling.