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Cannabinoid Receptor Type‐1 Regulates Inflammation and Insulin Resistance in Metabolic Endotoxemia
Author(s) -
Grunewald Zachary Ian
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.lb631
Subject(s) - insulin resistance , medicine , endocrinology , endocannabinoid system , insulin , inflammation , cannabinoid receptor , adiponectin , antagonist , lipopolysaccharide , diet induced obese , type 2 diabetes , receptor , diabetes mellitus
Background Circulating endotoxin, or lipopolysaccharide (LPS), is a suggested trigger of obesity‐associated inflammation and insulin resistance. In rodents, chronic low‐level administration of LPS induces weight gain, inflammation and insulin resistance, inducing metabolic endotoxemia. Additionally, obesity is associated with over‐activation of the endocannabinoid system, promoting insulin resistance. Interestingly, LPS has been shown to regulate endocannabinoid synthesis. We hypothesized that metabolic endotoxemia promotes inflammation and insulin resistance via a cannabinoid receptor type‐1 (CB1R) dependent pathway. Methods 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/hr) or saline (n=10) continuously for 6 weeks (42 days). 10 rats receiving LPS were injected with a CB1R antagonist (SR141716, ip 3μg/g) daily. Rats were pair‐fed to the level of the LPS + CB1R antagonist group (CB1Rx) to control for differences in body weight. Glucose tolerance (OGTT, 2g/kg) and insulin sensitivity (ITT, 0.75u/kg) were measured after 5 weeks of treatment. Insulin was given 1 hour prior to sacrifice (n=5/group). RT‐PCR, ELISA assays, and western blot was used to determine experimental outcomes. Results After 6 weeks, pair‐feeding was successful to control for body weight and energy intake differences. LPS administration was sufficient to alter insulin sensitivity. However, alterations to both glucose and insulin sensitivity were further exacerbated in the CB1Rx group. Circulating LPS binding protein was elevated in the CB1Rx group only. Serum adiponectin was reduced in both groups receiving LPS infusion compared to control. Liver, visceral and periaortic adipose tissue, and muscle exhibited a pro‐inflammatory phenotype in LPS and LPS + CB1Rx treated animals. Liver total AKT/PKB was reduced in the CB1Rx group only. p‐AKT (T308) was reduced in the LPS treated group and further reduced in the CB1Rx group. Insulin degrading enzyme was partially attenuated with CB1Rx treatment compared to LPS treatment alone. Conclusions Our findings oppose our hypothesis that LPS induces inflammation and insulin resistance via a CB1R dependent pathway. Rather, inhibition of CB1R further exacerbates the inflammatory and insulin resistant state induced by chronic low‐level LPS administration. Moreover, our findings suggest that CB1R may play a role in regulating the pro‐inflammatory and insulin resistant phenotype associated with obesity. Thus, these findings suggest that CB1R inhibition may not be a beneficial strategy towards the treatment of obesity‐associated inflammation and insulin resistance. Support or Funding Information Funding for this project came from 1) UGA Junior Faculty Research Grant for Claire de La Serre, 2) Kappa Omicron Nu Eileen C. Maddex Master's Fellowship for Zachary I. Grunewald