Cannabinoid receptor type-1 partially mediates metabolic endotoxemia-induced inflammation and insulin resistance.

Circulating levels of bacterial lipopolysaccharide (LPS) or endotoxin are chronically elevated in obesity (metabolic endotoxemia), resulting in low-grade inflammation. Metabolic endotoxemia has been identified as a triggering factor for obesity-associated metabolic complications such as insulin resistance. Furthermore, LPS has been shown to modulate endocannabinoid synthesis and notably to induce cannabinoid receptor type-1 (CB1) ligand synthesis. CB1 activation promotes inflammation, increases food intake and impairs insulin signaling. Therefore, we hypothesized that LPS acts through a CB1-dependent mechanism to aggravate inflammation and promote insulin resistance. Male Wistar rats fed a chow diet were implanted with mini-osmotic pumps delivering a low dose of LPS (n = 20; 12.5 μg/kg body weight (BW)/hr.) or saline (n = 10) continuously for six weeks. LPS-treated rats were injected daily with a CB1 antagonist (Rimonabant, SR141716A; 3 mg/kg, intraperitoneal (ip); LPS + CB1x; n = 10) or vehicle (1 mL/kg, LPS; n = 10). Control and LPS rats' food intake was matched to the LPS + CB1x group level. Despite no significant differences in body weight among groups, chronic exposure to low-level LPS altered hepatic endocannabinoid signaling, increased inflammation, and impaired insulin sensitivity and insulin clearance (P < 0.05). CB1 inhibition significantly attenuated LPS signaling (P < 0.05), which attenuated LPS-induced metabolic alterations. Therefore, we concluded that CB1 contributes to LPS-mediated inflammation and insulin resistance, suggesting that blocking CB1 signaling may have therapeutic benefits in reducing inflammation-induced metabolic abnormalities.