In Vivo Responses of Arcuate Tyrosine Hydroxylase (TH) Neurons to Hormonal Challenges Under Chronic High-Fat Diet Kronik Yüksek Yağlı Diyetin Arkuat Tirozin Hidroksilaz (TH) Nöronlarında Ghrelinle Uyarılan Kalsiyum Yanıtları Üzerindeki İn Vivo Etkileri

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Sümer E., Gören H., Barın B., Kosif Y., Başer Ö., Keleştemur M., ...Daha Fazla

Journal of Uludag University Medical Faculty, cilt.52, 2026 (Scopus)

Özet

Diet-induced obesity disrupts arcuate nucleus (ARC) hormonal signalling, including the development of ghrelin and leptin resistance, phenomena well-characterised in canonical AgRP/NPY neurons but largely unexplored in other orexigenic ARC populations. Tyrosine hydroxylase (TH)-expressing ARC neurons represent one such population with established roles in feeding control, yet whether chronic high-fat diet (HFD) exposure impairs their responsiveness to ghrelin and leptin in vivo remains unknown. Here, we investigated how HFD shapes ARC TH neuron Ca²⁺ dynamics across feeding-related states and during acute hormonal challenges using fibre photometry in freely moving TH-Cre mice. A total of 11 male TH-Cre mice were maintained on standard diet (SD, n=5) or HFD (n=6) for three months. A Cre-dependent AAV.Syn.Flex.GCaMP6s virus was injected into the ARC, followed by optical fibre implantation. After at least two weeks of expression, in vivo fiber photometry recordings were performed. Fluorescence signals were calculated as ΔF/F and summarized as area under the curve per minute (AUC/min). Basal activity was assessed during baseline (P1), food exposure (P2), and digestion (P3) under fed and fasted conditions. For hormonal challenges, fed mice received intraperitoneal ghrelin (1 mg/kg) and fasted mice received leptin (5 mg/kg), with analyses conducted across P1–P4 epochs. Basal ARC TH activity was comparable between chow and HFD groups across P1–P3 in both metabolic states. Ghrelin significantly increased ARC TH activity during P2 in chow controls, whereas this response was attenuated in HFD mice (p = 0.043). Leptin produced modest and similar effects in both groups. Chronic HFD selectively blunts ghrelin-evoked activation of ARC TH neurons while largely preserving basal activity and leptin responsiveness.