Adipocyte cannabinoid receptor CB1 regulates energy homeostasis and alternatively activated macrophages
Inigo Ruiz de Azua, … , Daniela Cota, Beat Lutz
Inigo Ruiz de Azua, … , Daniela Cota, Beat Lutz
Published October 16, 2017
Citation Information: J Clin Invest. 2017;127(11):4148-4162. https://doi.org/10.1172/JCI83626.
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Research Article Genetics Metabolism

Adipocyte cannabinoid receptor CB1 regulates energy homeostasis and alternatively activated macrophages

Abstract

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.

Authors

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

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Figure 4

CB1 deletion in adipocytes promotes alternatively activated macrophages and remodeling of adipose tissue preceding body weight changes.

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CB1 deletion in adipocytes promotes alternatively activated macrophages...
(A) Body weight of 7-week-old SD-fed Ati-CB1–WT (n = 13) and Ati-CB1–KO mice (n = 10) 2 weeks after tamoxifen-induced CB1 deletion in adipocytes. (B) Relative CB1 mRNA levels are strongly decreased in EF, SF, and BAT from 7-week-old Ati-CB1–KO (n = 9–12) mice as compared with WT controls (n = 8–9) on SD. (C) Representative images of EF, SF, and BAT from Ati-CB1–WT and Ati-CB1–KO on SD. H&E staining. Scale bar: 100 μm. (D) Quantification of adipocyte cell size (arbitrary units) in EF from Ati-CB1–WT (n = 3) and Ati-CB1–KO (n = 3). (E) Gene expression analysis (relative units) in EF of markers of adipocyte differentiation (Pparg, Cebpa) and lipogenesis (Fasn, Acaca) and of adipokines (Lep, Adipoq) (n = 9). (F) Gene expression analysis (relative units) of alternatively activated macrophages (Mrc1, Clec10a) in EF (n = 9). (G) Protein analysis of markers for alternatively activated macrophages (CD206 and CD301) was monitored by flow cytometry in EF from Ati-CB1–WT (n = 13) and Ati-CB1–KO (n = 13) on SD. (H) Gene expression (relative units) of catecholamine-synthesizing enzymes (Th, Dbh, Ddc) in whole EF from Ati-CB1–WT (n = 3–8) and Ati-CB1–KO (n = 5–13) on SD. (I) Tissue NE levels in EF from Ati-CB1–WT (n = 8) and Ati-CB1–KO (n = 8) mice on SD. (J) Gene expression analysis (relative units) of thermogenic markers (Cox8b, Ucp1, Ppargc1a) in SF (n = 8–12). (K) Gene expression analysis (relative units) of thermogenic markers (Cox4i2, Ucp1) in BAT from Ati-CB1–WT (n = 8) and Ati-CB1–KO (n = 12) mice on SD. Data are shown as mean ± SEM. *P < 0.05; #P < 0.01; †P < 0.001 vs. WT, Student’s t test.