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

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 (CB1R). Measurement of STAT3 activation by semi-automated confocal microscopy in cultured neurons revealed that this CB1R-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 CB1R activation and binds both STAT3 and TC-PTP. Consistently, CB1R activation failed to suppress leptin signaling in β-arrestin1 knockout mice in vivo, and in neural cells deficient in CB1R, β-arrestin1 or TC-PTP. Altogether, CB1R 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. © 2023 The Author(s)