Adipocyte cannabinoid receptor CB1 regulates energy homeostasis and alternatively activated macrophages.

Inigo Ruiz de Azua, Giacomo Mancini, Raj Kamal Srivastava, Alejandro Aparisi Rey, Pierre Cardinal, Laura Tedesco, Cristina Maria Zingaretti, Antonia Sassmann, Carmelo Quarta, Claudia Schwitter, Andrea Conrad, Nina Wettschureck, V. Kiran Vemuri, Alexandros Makriyannis, Jens Hartwig, Maria Mendez-Lago, Laura Bindila, Krisztina Monory, Antonio Giordano, Saverio Cinti, Giovanni Marsicano, Stefan Offermanns, Enzo Nisoli, Uberto Pagotto, Daniela Cota, Beat Lutz
Journal of Clinical Investigation. 2017-10-16; 127(11): 4148-4162
DOI: 10.1172/jci83626

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Ruiz de Azua I(1), Mancini G(1), Srivastava RK(1), Rey AA(1), Cardinal P(2)(3), Tedesco L(4), Zingaretti CM(5), Sassmann A(6), Quarta C(7)(8), Schwitter C(1), Conrad A(1), Wettschureck N(6), Vemuri VK(9), Makriyannis A(9), Hartwig J(10), Mendez-Lago M(10), Bindila L(1), Monory K(1), Giordano A(5), Cinti S(5), Marsicano G(2)(3), Offermanns S(6), Nisoli E(4), Pagotto U(8), Cota D(2)(3), Lutz B(1)(11).

Author information:
(1)Institute of Physiological Chemistry, University Medical Center of Johannes Gutenberg University of Mainz, Mainz, Germany.
(2)INSERM U1215, Neurocentre Magendie, Bordeaux, France.
(3)University of Bordeaux, Bordeaux, France.
(4)Center for Study and Research on Obesity, Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy.
(5)Department of Experimental and Clinical Medicine, Center of Obesity, University of Ancona (Politecnica delle Marche), Ancona, Italy.
(6)Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
(7)Helmholtz Diabetes Center (HDC) and German Center for Diabetes Research (DZD), Helmholtz Zentrum München, Neuherberg, Germany, and Division of Metabolic Diseases, Technische Universität München, Munich, Germany.
(8)Endocrinology Unit and Centro di Ricerca Biomedica Applicata, Department of Medical and Surgical Sciences, S. Orsola-Malpighi Hospital, Alma Mater University of Bologna, Bologna, Italy.
(9)Center for Drug Discovery, Departments of Pharmaceutical Sciences and Chemical Biology, Northeastern University, Boston, Massachusetts, USA.
(10)Institute of Molecular Biology (IMB), Mainz, Germany.
(11)German Resilience Center, University Medical Center of Johannes Gutenberg University of Mainz, Mainz, Germany.

Dysregulated adipocyte physiology leads to imbalanced energy storage, obesity, and associated diseases, imposing a costly burden on current health care. Cannabinoid receptor type-1 (CB1) plays a crucial role in controlling energy metabolism through central and peripheral mechanisms. In this work, adipocyte-specific inducible deletion of the CB1 gene (Ati-CB1-KO) was sufficient to protect adult mice from diet-induced obesity and associated metabolic alterations and to reverse the phenotype in already obese mice. Compared with controls, Ati-CB1-KO mice showed decreased body weight, reduced total adiposity, improved insulin sensitivity, enhanced energy expenditure, and fat depot-specific cellular remodeling toward lowered energy storage capacity and browning of white adipocytes. These changes were associated with an increase in alternatively activated macrophages concomitant with enhanced sympathetic tone in adipose tissue. Remarkably, these alterations preceded the appearance of differences in body weight, highlighting the causal relation between the loss of CB1 and the triggering of metabolic reprogramming in adipose tissues. Finally, the lean phenotype of Ati-CB1-KO mice and the increase in alternatively activated macrophages in adipose tissue were also present at thermoneutral conditions. Our data provide compelling evidence for a crosstalk among adipocytes, immune cells, and the sympathetic nervous system (SNS), wherein CB1 plays a key regulatory role.


Auteurs Bordeaux Neurocampus