Cannabinoid receptor type 1 (CB1R) inhibits hypothalamic leptin signaling via β-arrestin1 in complex with TC-PTP and STAT3

• DOI: 10.1016/j.isci.2023.107207
• Publication Date: 2023-06-25T09:52:09Z
• Authors: Gergő Szanda; Tony Jourdan; Éva Wisniewski; Resat Cinar; Grzegorz Godlewski; Anikó Rajki; Jie Liu; Lee Chedester; Bence Szalai; András Dávid Tóth; Eszter Soltész-Ka...; László Hunyady; Asuka Inoue; Viktória Bea Horváth; András Spät; Joseph Tam; George Kunos
• Keywords: Leptin receptor

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 leptin, is diminished agonists the cannabinoid receptor 1 (CB1R). Measurement activation semi-automated confocal microscopy cultured neurons revealed this CB1R-mediated inhibition requires both T cell protein tyrosine phosphatase (TC-PTP) β-arrestin1 but independent changes cAMP. Moreover, translocates to nucleus upon CB1R binds TC-PTP. Consistently, failed suppress knockout mice vivo, neural cells deficient CB1R, or Altogether, engages coordinate TC-PTP-mediated leptin-evoked neuronal response. This mechanism may restrict effects when endocannabinoid levels rise, as during fasting diet-induced obesity.