Maternal overnutrition negatively impacts the offspring's health leading to an increased risk of developing chronic diseases or metabolic syndrome in adulthood. What we eat affects the endocannabinoid system (eCS) activity, which in turn modulates lipogenesis and fatty acids utilization in hepatic, muscle, and adipose tissues. This study aimed to evaluate the transgenerational effect of maternal obesity on cannabinoid receptor 1 knock-out (CB1 KO) animals in combination with a postnatal obesogenic diet on the development of metabolic disturbances on their offspring. CB1 KO mice were fed a control diet (CD) or a high-fat diet (HFD; 33% more energy from fat) for 3 months. Offspring born to control and obese mothers were also fed with CD or HFD. We observed that pups born to an HFD-fed mother presented higher postnatal weight, lower hepatic fatty acid amide hydrolase activity, and increased blood cholesterol levels when compared to the offspring born to CD-fed mothers. When female mice born to HFD-fed CB1 KO mothers were exposed to an HFD, they gained more weight, presented elevated blood cholesterol levels, and more abdominal adipose tissue accumulation than control-fed adult offspring. The eCS is involved in several reproductive physiological processes. Interestingly, we showed that CB1 KO mice in gestational day 15 presented resistance to LPS-induced deleterious effects on pregnancy outcome, which was overcome when these mice were obese. Our results suggest that an HFD in CB1 receptor-deficient mice contributes to a “nutritional programming” of the offspring resulting in increased susceptibility to metabolic challenges both perinatally and during adulthood.

母亲营养过剩会对后代的健康产生负面影响，导致成年后患慢性疾病或代谢综合征的风险增加。我们吃的东西会影响内源性大麻素系统（eCS）的活性，进而调节肝脏、肌肉和脂肪组织中的脂肪生成和脂肪酸的利用。本研究旨在评估母亲肥胖对大麻素受体 1 敲除 (CB1 KO) 动物的跨代影响，并结合产后肥胖饮食对其后代代谢紊乱的发展。 CB1 KO 小鼠被喂食对照饮食 (CD) 或高脂肪饮食 (HFD；来自脂肪的能量增加 33%) 3 个月。对照组和肥胖母亲所生的后代也用 CD 或 HFD 喂养。我们观察到，与 CD 喂养的母亲所生的后代相比，HFD 喂养的母亲所生的幼崽出生后体重较高，肝脏脂肪酸酰胺水解酶活性较低，血液胆固醇水平升高。当高脂饮食喂养的 CB1 KO 母亲所生的雌性小鼠暴露于高脂饮食时，与对照喂养的成年后代相比，它们体重增加更多，血液胆固醇水平升高，腹部脂肪组织积累更多。 eCS 参与多种生殖生理过程。有趣的是，我们发现 CB1 KO 小鼠在妊娠第 15 天表现出对 LPS 诱导的对妊娠结局的有害影响的抵抗力，而当这些小鼠肥胖时，这种抵抗力就被克服了。我们的结果表明，CB1 受体缺陷小鼠的 HFD 有助于后代的“营养编程”，导致围产期和成年期对代谢挑战的敏感性增加。