Leptin resistance and desensitization of hypophagia during prolonged inflammatory challenge.

Acute exposure to bacterial lipopolysaccharide (LPS) is a potent inducer of immune response as well as hypophagia. Nevertheless, desensitization of responses to LPS occurs during long-term exposure to endotoxin. We induced endotoxin tolerance, injecting repeated (6LPS) LPS doses compared with single (1LPS) treatment. 1LPS, but not 6LPS group, showed decreased food intake and body weight, which was associated with an increased plasma leptin and higher mRNA expression of OB-Rb, MC4R, and SOCS3 in the hypothalamus. Hypophagia induced by 1LPS was associated with lower levels of 2-arachidonoylglycerol (2-AG), increased number of p-STAT3 neurons, and decreased AMP-activated protein kinase (AMPK) activity. Desensitization of hypophagia in the 6LPS group was related to high 2-AG, with no changes in p-STAT3 or increased p-AMPK. Leptin decreased food intake, body weight, 2-AG levels, and AMPK activity and enhanced p-STAT3 in control rats. However, leptin had no effects on 2-AG, p-STAT3, or p-AMPK in the 1LPS and 6LPS groups. Rats treated with HFD to induce leptin resistance showed neither hypophagia nor changes in p-STAT3 after 1LPS, suggesting that leptin and LPS recruit a common signaling pathway in the hypothalamus to modulate food intake reduction. Desensitization of hypophagia in response to repeated exposure to endotoxin is related to an inability of leptin to inhibit AMPK phosphorylation and 2-AG production and activate STAT3. SOCS3 is unlikely to underlie this resistance to leptin signaling in the endotoxin tolerance. The present model of prolonged inflammatory challenge may contribute to further investigations on mechanisms of leptin resistance.

Cannabinoids and capsaicin improve liver function following thioacetamide-induced acute injury in mice.

OBJECTIVES: We have shown the beneficial effects of cannabinoids in a murine model of hepatic encephalopathy following thioacetamide and now report their effects on the liver injury. METHODS: Fulminant hepatic failure (FHF) was induced by administration of 200 mg/kg thioacetamide to wild-type (WT) and CB2 Knockout (KO) mice. Twenty-four hours later, mice were injected with 2-arachidonoylglycerol (CB1, CB2, and TRPV1 agonist), HU308 (CB2 agonist), SR141716 A (CB1 receptor blocker), SR141716 A+2-AG, and SR144528 (CB2 receptor blocker), capsaicin and capsazepine (TRPV1 agonist and antagonist receptors). Mice were sacrificed 2 days after thioacetamide administration (day 3) and liver biochemistry and histopathology as well as evaluation of 2-arachidonoylglycerol levels were performed on liver tissue. RESULTS: Liver histopathology undertaken 48 h after thioacetamide showed evidence of necrosis and inflammation. SR141716 A, HU308, and 2-arachidonoylglycerol reduced inflammation and promoted regeneration 1 day after their administration. Liver enzymes increased after thioacetamide administration and were reversed after SR141716 A and 2-arachidonoylglycerol administered alone or combined, HU-308, but not SR144528. Thus, the beneficial effects mediated through CB2 receptors. However, CB2 KO mice still modulated liver function via the TRPV1 receptors. Capsaicin improved both liver pathology and function in WT thioacetamide-treated mice, while capsazepine impaired it. CONCLUSIONS: The similar pattern found between the effect of cannabinoids and their antagonists on brain and liver indicated that the therapeutic effect might be directed by the improvement in both organs through CB2 receptors and/or TRPV1 receptors. Modulation of these systems may have therapeutic potential.

2-Arachidonoylglycerol, an endogenous cannabinoid receptor agonist, in various rat tissues during the evolution of experimental cholestatic liver disease.

BACKGROUND/AIM: Changes in tissue levels of 2-arachidonoylglycerol (2-AG), an endocannabinoid, during the evolution of bile duct ligation (BDL) may indicate that endocannabinoids have a role in the hemodynamic changes that occur in this condition. METHODS: 2-AG levels, in various organs and vascular beds of BDL rats, 2 and 4 weeks post surgery, were determined. Untouched and sham-operated (SO) rats were used as controls. RESULTS: 2-AG content of a specific organ was not a static finding and depended on the rat's age, the time from the surgical procedure and the type of procedure. The most pronounced changes were observed in BDL rats 4 weeks post surgery. In these rats, hepatic, pulmonary, cardiac and renal medullary and papillary 2-AG levels were highest observed. No changes in splenic, aortic and renal cortical 2-AG levels were observed. In addition a stepwise increase in 2-AG levels from the cortex to the papilla was detected and was followed by a decrease in creatinine clearance. CONCLUSIONS: 2-AG probably has a role in the pathophysiologic changes in the liver, heart, lung and kidney that follows BDL.