Woolcott Orison O, Richey Joyce M, Kabir Morvarid, Chow Robert H, Iyer Malini S, Kirkman Erlinda L, Stefanovski Darko, Lottati Maya, Kim Stella P, Harrison L Nicole, Ionut Viorica, Zheng Dan, Hsu Isabel R, Catalano Karyn J, Chiu Jenny D, Bradshaw Heather, Wu Qiang, Kolka Cathryn M, Bergman Richard N
Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
PLoS One. 2015 Apr 9;10(4):e0123558. doi: 10.1371/journal.pone.0123558. eCollection 2015.
Obesity has been associated with elevated plasma anandamide levels. In addition, anandamide has been shown to stimulate insulin secretion in vitro, suggesting that anandamide might be linked to hyperinsulinemia.
To determine whether high-fat diet-induced insulin resistance increases anandamide levels and potentiates the insulinotropic effect of anandamide in isolated pancreatic islets.
Dogs were fed a high-fat diet (n = 9) for 22 weeks. Abdominal fat depot was quantified by MRI. Insulin sensitivity was assessed by the euglycemic-hyperinsulinemic clamp. Fasting plasma endocannabinoid levels were analyzed by liquid chromatography-mass spectrometry. All metabolic assessments were performed before and after fat diet regimen. At the end of the study, pancreatic islets were isolated prior to euthanasia to test the in vitro effect of anandamide on islet hormones. mRNA expression of cannabinoid receptors was determined in intact islets. The findings in vitro were compared with those from animals fed a control diet (n = 7).
Prolonged fat feeding increased abdominal fat content by 81.3±21.6% (mean±S.E.M, P<0.01). In vivo insulin sensitivity decreased by 31.3±12.1% (P<0.05), concomitant with a decrease in plasma 2-arachidonoyl glycerol (from 39.1±5.2 to 15.7±2.0 nmol/L) but not anandamide, oleoyl ethanolamide, linoleoyl ethanolamide, or palmitoyl ethanolamide. In control-diet animals (body weight: 28.8±1.0 kg), islets incubated with anandamide had a higher basal and glucose-stimulated insulin secretion as compared with no treatment. Islets from fat-fed animals (34.5±1.3 kg; P<0.05 versus control) did not exhibit further potentiation of anandamide-induced insulin secretion as compared with control-diet animals. Glucagon but not somatostatin secretion in vitro was also increased in response to anandamide, but there was no difference between groups (P = 0.705). No differences in gene expression of CB1R or CB2R between groups were found.
In canines, high-fat diet-induced insulin resistance does not alter plasma anandamide levels or further potentiate the insulinotropic effect of anandamide in vitro.
肥胖与血浆花生四烯酸乙醇胺水平升高有关。此外，花生四烯酸乙醇胺已被证明在体外可刺激胰岛素分泌，这表明花生四烯酸乙醇胺可能与高胰岛素血症有关。
确定高脂饮食诱导的胰岛素抵抗是否会增加花生四烯酸乙醇胺水平，并增强其对离体胰岛的促胰岛素分泌作用。
给犬喂食高脂饮食（n = 9）22周。通过磁共振成像对腹部脂肪储存进行定量。通过正常血糖-高胰岛素钳夹技术评估胰岛素敏感性。通过液相色谱-质谱分析法分析空腹血浆内源性大麻素水平。所有代谢评估均在高脂饮食方案前后进行。在研究结束时，在安乐死之前分离胰腺胰岛，以测试花生四烯酸乙醇胺对胰岛激素的体外作用。在完整胰岛中测定大麻素受体的mRNA表达。将体外研究结果与喂食对照饮食的动物（n = 7）的结果进行比较。
长期喂食脂肪使腹部脂肪含量增加了81.3±21.6%（平均值±标准误，P<0.01）。体内胰岛素敏感性降低了31.3±12.1%（P<0.05），同时血浆2-花生四烯酰甘油水平降低（从39.1±5.2降至15.7±2.0 nmol/L），但花生四烯酸乙醇胺、油酰乙醇胺、亚油酰乙醇胺或棕榈酰乙醇胺水平未降低。在喂食对照饮食的动物（体重：28.8±1.0 kg）中，与未处理相比，用花生四烯酸乙醇胺孵育的胰岛具有更高的基础和葡萄糖刺激的胰岛素分泌。与喂食对照饮食的动物相比，喂食脂肪的动物（34.5±1.3 kg；与对照相比P<0.05）的胰岛未表现出花生四烯酸乙醇胺诱导的胰岛素分泌的进一步增强。体外，对花生四烯酸乙醇胺的反应中胰高血糖素分泌增加，但生长抑素分泌未增加，且两组之间无差异（P = 0.705）。两组之间CB1R或CB2R的基因表达无差异。
在犬类中，高脂饮食诱导的胰岛素抵抗不会改变血浆花生四烯酸乙醇胺水平，也不会在体外进一步增强花生四烯酸乙醇胺的促胰岛素分泌作用。
