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

Gergő Szanda, Tony Jourdan, Éva Wisniewski, Resat Cinar, Grzegorz Godlewski, Anikó Rajki, Jie Liu, Lee Chedester, Bence Szalai, András Dávid Tóth, Eszter Soltész-Katona, László Hunyady, Asuka Inoue, Viktória Bea Horváth, András Spät, Joseph Tam, George Kunos

doi:10.1016/j.isci.2023.107207

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 (CB(1)R). Measurement of STAT3 activation by semi-automated confocal microscopy in cultured neurons revealed that this CB(1)R-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 CB(1)R activation and binds both STAT3 and TC-PTP. Consistently, CB(1)R activation failed to suppress leptin signaling in β-arrestin1 knockout mice in vivo, and in neural cells deficient in CB(1)R, β-arrestin1 or TC-PTP. Altogether, CB(1)R 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.

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

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