Maternal high-fat diet impairs leptin signaling and up-regulates type-1 cannabinoid receptor with sex-specific epigenetic changes in the hypothalamus of newborn rats
Maternal high-fat diet impairs leptin signaling and up-regulates type-1 cannabinoid receptor with sex-specific epigenetic changes in the hypothalamus of newborn rats
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DOI：
10.1016/j.psyneuen.2019.02.004
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发表时间：
2019-05-01
影响因子：
3.7
通讯作者：
Trevenzoli, Isis H.
中科院分区：
文献类型：
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作者：
Almeida, Mariana M.;Dias-Rocha, Camilla P.;Trevenzoli, Isis H.
母体营养不平衡触发发育适应，涉及与成人慢性病相关的早期表观遗传机制。母体高脂饮食可促进断奶和成年雄性大鼠后代肥胖和下丘脑瘦素抵抗。瘦素抵抗与内源性大麻素系统（ECS）的过度激活有关。ECS主要由源自n-6脂肪酸的内源性大麻素和大麻素受体（由Curl编码的CB 1和由Cnr 2编码的CB 2）组成。下丘脑中的CB 1激活刺激进食和对脂肪的食欲，而CB 2激活似乎起免疫调节作用。我们证明，母亲的HF饮食增加下丘脑CB 1的男性后代，而增加CB 2的女性后代出生时，肥胖的发展之前。然而，这些变化背后的分子机制仍然未被探索。我们假设母体HF饮食将下调出生时后代下丘脑中的瘦素信号传导并上调Cnrl mRNA水平，这与表观遗传标记物和性类固醇信号传导的性别特异性变化相关。为了验证我们的假设，我们使用了从交配前8周直到分娩接受对照饮食（C，9%脂肪）或等热量高脂肪饮食（HF，28%脂肪）的雌性大鼠。在出生时收集C和HF雄性和雌性后代的血液、下丘脑和尸体用于生化和分子分析。母亲的HF饮食下调转录因子STAT 3在下丘脑的男性和女性的后代，但只在男性和女性后代中的磷酸化STAT 3的减少，诱导hypoleptinemia。由于瘦素通过STAT 3通路抑制中枢ECS，我们的研究结果表明，瘦素通路的障碍可能有助于增加Cnr 1 mRNA水平在下丘脑的两性后代。此外，母亲HF饮食增加了雄性后代中Cnrl启动子的组蛋白乙酰化百分比，并增加了与Cnrl启动子的雄激素受体结合，这可能有助于新生HF后代中Cnrl的更高表达。母体HF饮食增加了雄性后代的血浆n6与n3脂肪酸比率，这是代谢性疾病的重要危险因素，可能表明内源性大麻素信号过度激活。因此，虽然母亲HF饮食方案在成年后代的性别（肥胖，食欲过旺和更高的脂肪偏好）相似的表型，在这里，我们表明，涉及瘦素信号，ECS，表观遗传标记和性激素信号的分子机制进行了修改之前，肥胖的发展和新生儿男性和女性后代之间的差异。这些观察结果可能为抗肥胖治疗提供性别特异性靶点的分子见解。
Maternal nutritional imbalances trigger developmental adaptations involving early epigenetic mechanisms associated with adult chronic disease. Maternal high-fat (HF) diet promotes obesity and hypothalamic leptin resistance in male rat offspring at weaning and adulthood. Leptin resistance is associated with over activation of the endocannabinoid system (ECS). The ECS mainly consists of endocannabinoids derived from n-6 fatty acids and cannabinoid receptors (CB1 coded by Curl and CB2 coded by Cnr2). The CB1 activation in hypothalamus stimulates feeding and appetite for fat while CB2 activation seems to play an immunomodulatory role. We demonstrated that maternal HF diet increases hypothalamic CB1 in male offspring while increases CB2 in female offspring at birth, prior to obesity development. However, the molecular mechanisms behind these changes remain unexplored. We hypothesized that maternal HF diet would down-regulate leptin signaling and up-regulate Cnrl mRNA levels in the hypothalamus of the offspring at birth, associated with sex-specific changes in epigenetic markers and sex steroid signaling. To test our hypothesis, we used progenitor female rats that received control diet (C, 9% fat) or isocaloric high-fat diet (HF, 28% fat) from 8 weeks before mating until delivery. Blood, hypothalamus and carcass from C and HF male and female offspring were collected for biochemical and molecular analyses at birth. Maternal HF diet down-regulated the transcriptional factor STAT3 in the hypothalamus of male and female offspring, but induced hypoleptinemia only in males and decreased phosphorylated STAT3 only in female offspring. Because leptin acts through STAT3 pathway to inhibit central ECS, our results suggest that leptin pathway impairment might contribute to increased levels of Cnr1 mRNA in hypothalamus of both sex offspring. Besides, maternal HF diet increased the histone acetylation percentage of Cnrl promoter in male offspring and increased the androgen receptor binding to the Cnrl promoter, which can contribute to higher expression of Cnr1 in newborn HF offspring. Maternal HF diet increased plasma n6 to n3 fatty acid ratio in male offspring, which is an important risk factor to metabolic diseases and might indicate an over activation of endocannabinoid signaling. Thus, although maternal HF diet programs a similar phenotype in adult offspring of both sexes (obesity, hyperphagia and higher preference for fat), here we showed that molecular mechanisms involving leptin signaling, ECS, epigenetic markers and sex hormone signaling were modified prior to obesity development and can differ between newborn male and female offspring. These observations may provide molecular insights into sex-specific targets for anti-obesity therapies.