Open Access

Han Rae Kim, Dasol Kang, Dong Hee Kim, Bora Jeong, Kwangkon Kim, Byong Seo Park, Hye Rim Yang, Hyug Moo Kwon, Marco Koch, Colin N. Young, Byung Ju Lee, Jae Geun Kim

• 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 hypothalamicTonicity-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.…