Szanda Gergő, Jourdan Tony, Wisniewski Éva, Cinar Resat, Godlewski Grzegorz, Rajki Anikó, Liu Jie, Chedester Lee, Szalai Bence, Tóth András Dávid, Soltész-Katona Eszter, Hunyady László, Inoue Asuka, Horváth Viktória Bea, Spät András, Tam Joseph, Kunos George
Department of Physiology, Semmelweis University Medical School, 1094 Budapest, Hungary.
ELKH-SE Laboratory of Molecular Physiology Research Group, Eötvös Loránd Research Network, 1094 Budapest, Hungary.
iScience. 2023 Jun 25;26(7):107207. doi: 10.1016/j.isci.2023.107207. eCollection 2023 Jul 21.
Molecular interactions between anorexigenic leptin and orexigenic endocannabinoids, although of great metabolic significance, are not well understood. We report here that hypothalamic STAT3 signaling in mice, initiated by physiological elevations of leptin, is diminished by agonists of the cannabinoid receptor 1 (CBR). Measurement of STAT3 activation by semi-automated confocal microscopy in cultured neurons revealed that this CBR-mediated inhibition requires both T cell protein tyrosine phosphatase (TC-PTP) and β-arrestin1 but is independent of changes in cAMP. Moreover, β-arrestin1 translocates to the nucleus upon CBR activation and binds both STAT3 and TC-PTP. Consistently, CBR activation failed to suppress leptin signaling in β-arrestin1 knockout mice and in neural cells deficient in CBR, β-arrestin1 or TC-PTP. Altogether, CBR activation engages β-arrestin1 to coordinate the TC-PTP-mediated inhibition of the leptin-evoked neuronal STAT3 response. This mechanism may restrict the anorexigenic effects of leptin when hypothalamic endocannabinoid levels rise, as during fasting or in diet-induced obesity.
厌食性瘦素与促食欲内源性大麻素之间的分子相互作用虽然具有重要的代谢意义，但目前尚未完全明确。我们在此报告，在小鼠中，由瘦素生理性升高引发的下丘脑信号转导及转录激活因子3（STAT3）信号传导会被大麻素受体1（CBR）激动剂减弱。通过半自动共聚焦显微镜对培养神经元中STAT3激活情况的检测显示，这种CBR介导的抑制作用既需要T细胞蛋白酪氨酸磷酸酶（TC-PTP），也需要β-抑制蛋白1，但与环磷酸腺苷（cAMP）的变化无关。此外，CBR激活后，β-抑制蛋白1会转位至细胞核，并与STAT3和TC-PTP结合。同样，在β-抑制蛋白1基因敲除小鼠以及缺乏CBR、β-抑制蛋白1或TC-PTP的神经细胞中，CBR激活无法抑制瘦素信号传导。总之，CBR激活通过β-抑制蛋白1来协调TC-PTP介导的对瘦素诱发的神经元STAT3反应的抑制作用。当禁食期间或饮食诱导肥胖时，下丘脑内源性大麻素水平升高，这一机制可能会限制瘦素的厌食作用。
