Leptin production capacity determines food intake and susceptibility to obesity-induced diabetes in Oikawa-Nagao Diabetes-Prone and Diabetes-Resistant mice
Leptin production capacity determines food intake and susceptibility to obesity-induced diabetes in Oikawa-Nagao Diabetes-Prone and Diabetes-Resistant mice
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DOI：
10.1007/s00125-020-05191-8
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发表时间：
2020-06-19
期刊：
影响因子：
8.2
通讯作者：
Oikawa, Shinichi
中科院分区：
文献类型：
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作者：
Asai, Akira;Nagao, Mototsugu;Oikawa, Shinichi
目标/假设 暴饮暴食导致的肥胖在 2 型糖尿病的发生中起着关键作用。然而，人们对于在肥胖发生之前如何确定个体膳食量差异仍知之甚少。在这里，我们研究了新建立的 Oikawa-Nagao 糖尿病易发 (ON-DP) 和糖尿病抵抗 (ON-DR) 小鼠自发食物摄入量的潜在机制。方法比较高脂饲料喂养下ON-DP和ON-DR小鼠5周龄至10周龄的食物摄入量和代谢表型。 5周龄时评估了两个小鼠系之间瘦素状态的差异。还进行了脂肪组织外植体培养以评估体外瘦素生产能力。结果与 ON-DR 小鼠相比，ON-DP 小鼠表现出自发性过度喂养。通过与 ON-DR 小鼠配对喂养，ON-DP 小鼠的过度体重增加和脂肪积累被完全抑制到 ON-DR 小鼠的水平。 ON-DP 小鼠的葡萄糖耐量恶化在配对喂养条件下也得到改善。虽然比较 5 周龄时的两个小鼠系时，体重和脂肪组织质量没有差异，但 ON-DP 小鼠的血浆瘦素浓度和脂肪组织瘦素基因表达水平较低。根据外周瘦素状态，与没有明显瘦素抵抗的 ON-DR 小鼠相比，ON-DP 小鼠在下丘脑弓状核中表现出较低的厌食性瘦素信号传导。外植体培养研究表明，ON-DP 小鼠的脂肪组织瘦素生成能力较低。与 ON-DR 小鼠相比，ON-DP 小鼠脂肪细胞瘦素基因启动子区域的 DNA 甲基化水平也更高。结论/解释 结果表明，遗传性较低的瘦素产生能力在 ON-DP 小鼠过度喂养引起的肥胖和随后的葡萄糖耐量恶化中起着关键作用。脂肪细胞中瘦素的产生能力，尤其是在肥胖发生之前，可能具有诊断潜力，可以预测个体因暴饮暴食而导致的肥胖风险以及未来发生 2 型糖尿病的风险。
Aims/hypothesis Obesity caused by overeating plays a pivotal role in the development of type 2 diabetes. However, it remains poorly understood how individual meal size differences are determined before the development of obesity. Here, we investigated the underlying mechanisms in determining spontaneous food intake in newly established Oikawa-Nagao Diabetes-Prone (ON-DP) and Diabetes-Resistant (ON-DR) mice. Methods Food intake and metabolic phenotypes of ON-DP and ON-DR mice under high-fat-diet feeding were compared from 5 weeks to 10 weeks of age. Differences in leptin status at 5 weeks of age were assessed between the two mouse lines. Adipose tissue explant culture was also performed to evaluate leptin production capacity in vitro. Results ON-DP mice showed spontaneous overfeeding compared with ON-DR mice. Excessive body weight gain and fat accumulation in ON-DP mice were completely suppressed to the levels seen in ON-DR mice by pair-feeding with ON-DR mice. Deterioration of glucose tolerance in ON-DP mice was also ameliorated under the pair-feeding conditions. While no differences were seen in body weight and adipose tissue mass when comparing the two mouse lines at 5 weeks of age, the ON-DP mice had lower plasma leptin concentrations and adipose tissue leptin gene expression levels. In accordance with peripheral leptin status, ON-DP mice displayed lower anorexigenic leptin signalling in the hypothalamic arcuate nucleus when compared with ON-DR mice without apparent leptin resistance. Explant culture studies revealed that ON-DP mice had lower leptin production capacity in adipose tissue. ON-DP mice also displayed higher DNA methylation levels in the leptin gene promoter region of adipocytes when compared with ON-DR mice. Conclusions/interpretation The results suggest that heritable lower leptin production capacity plays a critical role in overfeeding-induced obesity and subsequent deterioration of glucose tolerance in ON-DP mice. Leptin production capacity in adipocytes, especially before the development of obesity, may have diagnostic potential for predicting individual risk of obesity caused by overeating and future onset of type 2 diabetes.