Effects of the CB1 Receptor Antagonists AM6545 and AM4113 on Insulin Resistance in a High-Fructose High-Salt Rat Model of Metabolic Syndrome

Abstract

Background and Objectives: Insulin resistance (IR) is a serious condition leading to development of diabetes and cardiovascular complications. Hyper-activation of cannabinoid receptors-1 (CB1) has been linked to the development of metabolic disorders such as IR. Therefore, the effect of blocking CB1 on the development of IR was investigated in the present study. Materials and Methods: A 12-week high-fructose/high-salt feeding model of metabolic syndrome was used to induce IR in male Wistar rats. For this purpose, two different CB1-antagonists were synthesized and administered to the rats during the final four weeks of the study, AM6545, the peripheral neutral antagonist and AM4113, the central neutral antagonist. Results: High-fructose/salt feeding for 12 weeks led to development of IR while both AM6545 and AM4113, administered in the last 4 weeks, significantly inhibited IR. This was correlated with increased animal body weight wherein both AM6545 and AM4113 decreased body weight in IR animals but with loss of IR/body weight correlation. While IR animals showed significant elevations in serum cholesterol and triglycerides with no direct correlation with IR, both AM6545 and AM4113 inhibited these elevations, with direct IR/cholesterol correlation in case of AM6545. IR animals had elevated serum uric acid, which was reduced by both AM6545 and AM4113. In addition, IR animals had decreased adiponectin levels and elevated liver TNFα content with strong IR/adiponectin and IR/TNFα correlations. AM6545 inhibited the decreased adiponectin and the increased TNFα levels and retained the strong IR/adiponectin correlation. However, AM4113 inhibited the decreased adiponectin and the increased TNFα levels, but with loss of IR/adiponectin and IR/TNFα correlations. Conclusions: Both CB1 neutral antagonists alleviated IR peripherally, and exerted similar effects on rats with metabolic syndrome. They also displayed anti-dyslipidemic, anti-hyperurecemic and anti-inflammatory effects. Overall, these results should assist in the development of CB1 neutral antagonists with improved safety profiles for managing metabolic disorders.

Interference with TGFβ1-Mediated Inflammation and Fibrosis Underlies Reno-Protective Effects of the CB1 Receptor Neutral Antagonists AM6545 and AM4113 in a Rat Model of Metabolic Syndrome

“…The increased risk of developing kidney disease in MetS has been well documented [ 6 , 7 , 8 ]. We have recently demonstrated that eight weeks of high-fructose and high-salt loading in Wistar rats was sufficient to induce a state of MetS manifested by obesity, hyperinsulinemia, hyperuricemia and dyslipidemia [ 28 ]. Furthermore, we have demonstrated that pre-treatment of these animals with either AM6545 or AM4113 caused an alleviation of the developed metabolic syndrome.…”

“…We have demonstrated that the area under the curve of the oral glucose tolerance test following an oral challenge of glucose was higher in the metabolic syndrome group relative to the controls. Effects on blood glucose levels were ameliorated after either AM6545 or AM4113 administration [ 28 ]. Moreover, studies by members of our group have shown that both AM6545 and AM4113 reduce food intake in rodents and thus can be useful in the treatment of obesity [ 22 , 29 ].…”

“…Several reports have demonstrated that dyslipidemia, including high triglycerides and high serum cholesterol levels, may contribute to kidney disease [ 41 , 42 ]. In our previous study, CB1 blockade with both antagonists produced a marked decrease in serum cholesterol and triglycerides, serum insulin, body weight, serum uric acid and liver TNFα together with increased adiponectin levels in the same MetS rat model [ 28 ]. Therefore, these beneficial effects could indirectly be preserving renal function.…”

“…479–16). The same animals used in our previous published work were used in the current study [ 28 ].…”

“…Rats were placed randomly into six groups ( n = 8/group), as previously described in our published work [ 28 ]. Briefly, the first control group (C) was fed a standard rodent food with freely accessible water for eight weeks.…”