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
Affiliations
Gergő Szanda
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; Corresponding author
Tony Jourdan
INSERM Center Lipids, Nutrition, Cancer LNC U1231, 21000 Dijon, France
Éva Wisniewski
Department of Physiology, Semmelweis University Medical School, 1094 Budapest, Hungary
Resat Cinar
Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA
Grzegorz Godlewski
Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA
Anikó Rajki
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
Jie Liu
Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA
Lee Chedester
Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA
Bence Szalai
Department of Physiology, Semmelweis University Medical School, 1094 Budapest, Hungary
András Dávid Tóth
Department of Physiology, Semmelweis University Medical School, 1094 Budapest, Hungary; Department of Internal Medicine and Haematology, Semmelweis University, 1085 Budapest, Hungary
Eszter Soltész-Katona
Department of Physiology, Semmelweis University Medical School, 1094 Budapest, Hungary; Institute of Enzymology, Research Centre for Natural Sciences, Centre of Excellence of the Hungarian Academy of Sciences, 1117 Budapest, Hungary
László Hunyady
Department of Physiology, Semmelweis University Medical School, 1094 Budapest, Hungary; Institute of Enzymology, Research Centre for Natural Sciences, Centre of Excellence of the Hungarian Academy of Sciences, 1117 Budapest, Hungary
Asuka Inoue
Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan
Viktória Bea Horváth
Department of Physiology, Semmelweis University Medical School, 1094 Budapest, Hungary
András Spät
Department of Physiology, Semmelweis University Medical School, 1094 Budapest, Hungary
Joseph Tam
Obesity and Metabolism Laboratory, The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel
George Kunos
Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA; Corresponding author
Summary: 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.
