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
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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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 1

Adipocyte CB1 deletion prevents DIO and metabolic dysregulation.

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Adipocyte CB1 deletion prevents DIO and metabolic dysregulation. (A) Bod...
(A) Body weight growth curves of Ati-CB1–KO (n = 21) and Ati-CB1–WT (n = 24) littermates on SD. Tamoxifen-induced recombination occurred for 5 days at 5 weeks of age (arrow). Tam, tamoxifen. (B) Body weight growth curves of Ati-CB1–WT (n = 22) and Ati-CB1–KO (n = 19) mice on HFD. Tam-induced recombination occurred for 5 days at 5 weeks of age (arrow). The switch from SD to HFD was at the beginning of week 7. (C) 3D visualization (ventral view) of skeleton (white) and total adipose tissue (red) from in vivo micro-CT images of Ati-CB1–WT and Ati-CB1–KO mice (19 weeks of age) on SD and HFD, respectively. (D) Quantification of total fat content (as percentage of total mouse volume) by in vivo micro-CT analysis in Ati-CB1–WT and Ati-CB1–KO mice on SD and HFD, respectively. (E) Comparison of body weight growth curves of Ati-CB1–KO (n = 19) mice and Total-CB1–KO (n = 8) mice on HFD. (F–L) Plasma profiles of Ati-CB1–WT (n = 4–9) and Ati-CB1–KO (n = 4–8) on both diet treatments (at 19 weeks of age). Data are shown as mean ± SEM. *P < 0.05; #P < 0.01; †P < 0.001. Two-way ANOVA (A, B, E); Student’s t test (D); 1-way ANOVA (F–L).