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

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

iScience. 2023 Jun 25;26(7):107207. doi: 10.1016/j.isci.2023.107207. eCollection 2023 Jul 21.

Authors

Gergő Szanda^{1

2}, Tony Jourdan³, Éva Wisniewski¹, Resat Cinar⁴, Grzegorz Godlewski⁴, Anikó Rajki^{1

2}, Jie Liu⁴, Lee Chedester⁴, Bence Szalai¹, András Dávid Tóth^{1

5}, Eszter Soltész-Katona^{1

6}, László Hunyady^{1

6}, Asuka Inoue⁷, Viktória Bea Horváth¹, András Spät¹, Joseph Tam⁸, George Kunos⁴

Affiliations

¹ Department of Physiology, Semmelweis University Medical School, 1094 Budapest, Hungary.
² ELKH-SE Laboratory of Molecular Physiology Research Group, Eötvös Loránd Research Network, 1094 Budapest, Hungary.
³ INSERM Center Lipids, Nutrition, Cancer LNC U1231, 21000 Dijon, France.
⁴ Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA.
⁵ Department of Internal Medicine and Haematology, Semmelweis University, 1085 Budapest, Hungary.
⁶ Institute of Enzymology, Research Centre for Natural Sciences, Centre of Excellence of the Hungarian Academy of Sciences, 1117 Budapest, Hungary.
⁷ Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan.
⁸ Obesity and Metabolism Laboratory, The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel.

Abstract

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.

Keywords: Cell biology; Molecular biology.