Copyright
©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
Metabolic and inflammatory functions of cannabinoid receptor type 1 are differentially modulated by adiponectin
Qiong Wei, Jong Han Lee, Chia-Shan Wu, Qun S Zang, Shaodong Guo, Hui-Chen Lu, Yuxiang Sun
Qiong Wei, Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, Jiangsu Province, China
Qiong Wei, Jong Han Lee, Chia-Shan Wu, Yuxiang Sun, Department of Pediatrics, USDA/ARS Children’s Nutrition Research Center, Baylor College of Medicine, Houston, TX 77030, United States
Jong Han Lee, Department of Marine Bioindustry, Hanseo University, Seosan 31962, South Korea
Chia-Shan Wu, Shaodong Guo, Yuxiang Sun, Department of Nutrition, Texas A and M University, College Station, TX 7743, United States
Qun S Zang, Department of Surgery, Stritch School of Medicine, Loyola University Chicago Health Science Campus, Maywood, IL 60153, United States
Hui-Chen Lu, Department of Psychological and Brain Sciences, Linda and Jack Gill Center of for Biomolecular Science, Bloomington, IN 47405, United States
Author contributions: Wei Q, Lee JH and Wu CS performed the experiments, analyzed the data and wrote the paper; Guo S and Zang QS consulted the study and proofread the paper; Lu HC provided the CB1 knockout mice, consulted in the study and proofread the paper; Sun Y designed the study and wrote the paper; all authors wrote, read and approved the final manuscript.
Supported by the NIH, No. DK118334 and No. AG064869; and the BrightFocus, No. A2019630S (to Sun Y).
Institutional review board statement: The study was reviewed and approved by the Institutional Review Board at Baylor College of Medicine.
Institutional animal care and use committee statement: All animal experiments conformed to the internationally accepted principles for the care and use of laboratory animals (Protocol AN-2770, The Institutional Animal Care and Use Committee at Baylor College of Medicine, Houston, TX, United States).
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
http://creativecommons.org/Licenses/by-nc/4.0/ Corresponding author: Yuxiang Sun, MD, PhD, Associate Professor, Department of Nutrition, Texas A and M University, 214C Cater-Mattil, 2253 TAMU College Station, TX 7743, United States.
yuxiang.sun@tamu.edu
Received: April 14, 2021
Peer-review started: April 14, 2021
First decision: May 12, 2021
Revised: June 7, 2021
Accepted: September 6, 2021
Article in press: September 6, 2021
Published online: October 15, 2021
Processing time: 181 Days and 12.5 Hours
BACKGROUND
Antagonists of cannabinoid type 1 receptor (CB1) have been shown to promote body weight loss and improve insulin sensitivity. Cannabinoids decrease adiponectin, and CB1 blocker increase adiponectin. However, the mediators of CB1 actions are not well defined.
AIM
To investigate whether the beneficial effects of CB1 inhibition are, at least in part, mediated by adiponectin.
METHODS
We compared metabolic and inflammatory phenotypes of wild-type (WT) mice, CB1-null (CB1-/-) and CB1/adiponectin double-knockout (DKO) mice. We assessed the insulin sensitivity using insulin tolerance test and glucose tolerance test, and inflammation using flow cytometry analysis of macrophages.
RESULTS
CB1-/- mice exhibited significantly reduced body weight and fat mass when compared to WT mice. While no significance was found in total daily food intake and locomotor activity, CB1-/- mice showed increased energy expenditure, enhanced thermogenesis in brown adipose tissue (BAT), and improved insulin sensitivity compared to WT mice. DKO showed no difference in body weight, adiposity, nor insulin sensitivity; only showed a modestly elevated thermogenesis in BAT compared to CB1-/- mice. The metabolic phenotype of DKO is largely similar to CB1-/- mice, suggesting that adiponectin is not a key mediator of the metabolic effects of CB1. Interestingly, CB1-/- mice showed reduced pro-inflammatory macrophage polarization in both peritoneal macrophages and adipose tissue macrophages compared to WT mice; in contrast, DKO mice exhibited increased pro-inflammatory macrophage polarization in these macrophages compared to CB1-/- mice, suggesting that adiponectin is an important mediator of the inflammatory effect of CB1.
CONCLUSION
Our findings reveal that CB1 functions through both adiponectin-dependent and adiponectin-independent mechanisms: CB1 regulates energy metabolism in an adiponectin-independent manner, and inflammation in an adiponectin-dependent manner. The differential effects of adiponectin on CB1-mediated metabolic and inflammatory functions should be taken into consideration in CB1 antagonist utilization.
Core Tip: Antagonists of cannabinoid type 1 receptor (CB1) have been shown to promote body weight loss and improve insulin sensitivity. Cannabinoids have been shown to regulate adiponectin. However, it is unclear whether adiponectin is a key mediator of the functions of CB1. We compared metabolic and inflammatory phenotypes of CB1-null vs CB1/adiponectin double-knockout mice. Our findings reveal that CB1 functions through both adiponectin-dependent and adiponectin-independent mechanisms: CB1 regulates energy metabolism in an adiponectin-independent manner, and inflammation in an adiponectin-dependent manner.
