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

Grunewald, Zachary I., Lee, Sunhye, Kirkland, Rebecca, Ross, Matthew, de La Serre, Claire B.
Physiology & behavior 2019 v.199 pp. 282-291
antagonists, cannabinoid receptors, cannabinoids, chronic exposure, endotoxemia, endotoxins, food intake, inflammation, insulin, insulin resistance, laboratory animals, ligands, lipopolysaccharides, males, obesity, pumps, rats, therapeutics
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.