Abstract
Patients with obesity are susceptible to hypertension and diabetes. Over-activation of cannabinoid receptor 1 (CB1R) in adipose tissue is proposed in the pathophysiology of metabolic disorders, which led to the metabolic dysfunction of adipose tissue and deregulated production and secretion of adipokines. In the current study, we determined the impact of LH-21, a representative peripheral CB1R antagonist, on the obesity-accompanied hypertension and explored the modulatory action of LH-21 on the adipose tissue in genetically obese and diabetic KKAy mice. 3-week LH-21 treatment significantly decreased blood pressure with a concomitant reduction in body weight, white adipose tissue (WAT) mass, and a slight loss on food intake in KKAy mice. Meanwhile, glucose handling and dyslipidemia were also markedly ameliorated after treatment. Gene expression of pro-inflammatory cytokines in WAT and the aortae were both attenuated apparently by LH-21, as well the mRNA expression of adipokines (lipocalin-2, leptin) in WAT. Concomitant amelioration on the accumulation of lipocalin-2 was observed in both WAT and aortae. In corresponding with this, serum inflammatory related cytokines (tumor necrosis factor α, IL-6, and CXCL1), and lipocalin-2 and leptin were lowered notably. Thus according to current results, it can be concluded that the peripheral CB1R antagonist LH-21 is effective in managing the obesity-accompanied hypertension in KKAy mice. These metabolic benefits are closely associated with the regulation on the production and secretion of inflammatory cytokines and adipokines in the WAT, particularly alleviated circulating lipocalin-2 and its accumulation in aortae.
Highlights
Obesity, especially abdominal obesity, is closely associated with a variety of metabolic disorders hypertension, type 2 diabetes, and dyslipidemia
In the KKAy mice model, we investigated the antihypertension effect of LH-21 and explored the modulatory action of LH-21 to inflammatory cytokines and adipokines. 3-week sub-chronic treatment with 3 mg/kg LH-21 significantly reduced the body weight gain and improved glucose handling, and displayed apparent ability to counteract obesity-related high blood pressure and without affecting heart rate. These metabolic benefits are closely associated with its regulation on the production and secretion of inflammatory cytokines and adipokines from the white adipose tissue (WAT), besides the slight effect on food consumption (Figure S1 in Supplementary Material)
In agreement with previous studies on the high-fat diet-induced obese rat and the genetic obese Zucker rat [12, 13], here we found that only the higher dose of LH-21 (3 mg/kg) showed clear anti-obesity action, apparent decrease on body weight occurred after about 1-week administration
Summary
Especially abdominal obesity, is closely associated with a variety of metabolic disorders hypertension, type 2 diabetes, and dyslipidemia. The second generation of peripheral CB1R-targeted neutral antagonist or inverse agonist with limited access to the central nervous system is holding great promise to be the blockbuster for obesity therapy. Recent studies indicated that the beneficial actions of CB1R blockage in decreasing body fat and improving insulin resistant were in close association with the improvement on the concentrations of local and systemic adipokines. Such as rimonabant (SR141716) was demonstrated to be able to increase level of serum adiponectin, decrease serum tumor necrosis factor α (TNFα) and leptin content, as well as upregulate the expression of adiponectin in adipose tissue [9, 10]. Whether peripheral CB1R-targeted antagonist is effective in managing the obesity-accompanied hypertension is unknown
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