Metabolic and inflammatory functions of cannabinoid receptor type 1 are differentially modulated by adiponectin

Figure 1 Cannabinoid type 1 receptor-null mice have reduced adiposity and improved insulin sensitivity. Wild-type (WT) and cannabinoid type 1 receptor-null (CB1^-/-) male mice at 4 mo of age. A: Body weight and body composition; B: Daily food intake; C: Locomotor activity; D: Energy expenditure adjusted by body weight or lean mass; E: Insulin tolerance tests; F: Glucose tolerance tests at 5 mo of age. n = 5-7. ^aP < 0.05, ^bP < 0.001, WT vs CB1^-/-.

Figure 2 Cannabinoid type 1 receptor-null mice have similar adiposity and insulin sensitivity compared to double-knockout mice. Cannabinoid type 1 receptor-null (CB1^-/-) and double-knockout (DKO) male mice at 4 mo of age. A: Body weight and body composition; B: Daily food intake; C: Locomotor activity; D: Energy expenditure adjusted by body weight or lean mass; E: Insulin tolerance tests; F: Glucose tolerance tests at 5 mo of age. n = 5-7. ^aP < 0.05, CB1^-/- vs DKO.

Figure 3 Double-knockout mice have similar expression of thermogenic genes compare to cannabinoid type 1 receptor-null mice. Wild-type (WT) and cannabinoid type 1 receptor-null (CB1^-/-) male mice at 8 mo of age. A: Brown adipose tissue (BAT) weight and percentage of BAT depot; B: Quantitative real-time RT-PCR analysis of gene expression in BAT. Cannabinoid type 1 receptor-null (CB1^-/-) and double-knockout (DKO) male mice at 8 mo of age. C: BAT weight and percentage of BAT depot; D: Quantitative real-time RT-PCR analysis of gene expression in BAT. n = 6-8. ^aP < 0.05, ^bP < 0.001, WT vs CB1^-/- or CB1^-/- vs DKO.

Figure 4 Cannabinoid type 1 receptor-null mice have reduced peritoneal and adipose tissue inflammation. Wild-type (WT) and cannabinoid type 1 receptor-null (CB1^-/-) male mice at 8 mo of age. A: Flow cytometry analysis of M1 and M2 in peritoneal macrophages; B: Percentage of epididymal fat depot; C: Flow cytometry analysis of M1 and M2 in epididymal fat; D: Pro-inflammatory cytokines expression in epididymal fat. n = 6-8. ^aP < 0.05, ^bP<0.001, WT vs CB1^-/- mice.

Figure 5 Double-knockout mice have increased peritoneal and adipose tissue inflammation compared to cannabinoid type 1 receptor-null mice. Cannabinoid type 1 receptor-null (CB1^-/-) and double-knockout (DKO) male mice at 7 mo of age. A: Flow cytometry analysis of M1 and M2 macrophages of peritoneal macrophages; B: Epididymal weight and percentage of epididymal depot; C: Flow cytometry analysis of M1 and M2 in stromal vascular fraction of epididymal fat; D: Pro-inflammatory cytokines expression of epididymal fat. n = 6-7. ^aP < 0.05, ^bP < 0.001, CB1^-/- vs DKO mice.

Figure 6 Schematic diagram of summary. Cannabinoid type 1 receptor (CB1) utilizes differential mechanisms in control of metabolism and inflammation. A: CB1 decreases thermogenesis in BAT through sympathetic nerve activity to reduce energy expenditure and adiposity. So the effect of CB1 on metabolism is adiponectin-independent; B: CB1 suppresses adiponectin in adipose tissue, which diminishes the anti-inflammatory effect of adiponectin, thus promoting macrophage pro-inflammatory polarization. So the effect of CB1 on inflammation is adiponectin-dependent. Thus, CB1 utilizes differential mechanisms in control of metabolism and inflammation: its effect on metabolism is adiponectin-independent while effects on inflammation are adiponectin-dependent. Thus, adiponectin is not required for CB1-mediated metabolism, but is required for CB1-mediated inflammation.