Adipocyte cannabinoid receptor CB1 regulates energy homeostasis and alternatively activated macrophages.
Journal of Clinical Investigation. 2017-10-16; 127(11): 4148-4162
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1. J Clin Invest. 2017 Nov 1;127(11):4148-4162. doi: 10.1172/JCI83626. Epub 2017 Oct
Adipocyte cannabinoid receptor CB1 regulates energy homeostasis and alternatively
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
(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
PMID: 29035280 [Indexed for MEDLINE]