Department of Pharmacology and Toxicology, School of Medicine Dayton, Wright State University, Ohio, United States.
Institut für Humangenetik Am Klinikum 1, Universitätsklinikum Jena, Jena, Germany.
Am J Physiol Endocrinol Metab. 2023 Nov 1;325(5):E581-E594. doi: 10.1152/ajpendo.00197.2023. Epub 2023 Oct 11.
Male mice lacking the Na-K-2Cl cotransporter () specifically in insulin-secreting β-cells () have reduced β-cell mass and mild β-cell secretory dysfunction associated with overweight, glucose intolerance, insulin resistance, and metabolic abnormalities. Here, we confirmed and extended previous results to female mice, which developed a similar metabolic syndrome-like phenotype as males, albeit milder. Notably, male and female mice developed overweight without consuming excess calories. Analysis of the feeding microstructure revealed that young lean male mice ate meals of higher caloric content and at a relatively lower frequency than normal mice, particularly during the night. In addition, overweight mice consumed significantly larger meals than lean mice. Therefore, the reduced satiation control of feeding precedes the onset of overweight and is worsened in older mice. However, the time spent between meals remained intact in lean and overweight mice, indicating conserved satiety responses to ad libitum feeding. Nevertheless, satiety was intensified during and after refeeding only in overweight males. In lean females, satiety responses to refeeding were delayed relative to age- and body weight-matched control mice but normalized in overweight mice. Since meal size did not change during refeeding, these data suggested that the satiety control of eating after fasting is impaired in lean mice before the onset of overweight and independently of their reduced satiation responses. Therefore, our results support the novel hypothesis that reduced satiation precedes the onset of overweight and the development of metabolic dysregulation. Obesity, defined as excess fat accumulation, increases the absolute risk for metabolic diseases. Although obesity is usually attributed to increased food intake, we demonstrate that body weight gain can be hastened without consuming excess calories. In fact, impaired meal termination control, i.e., satiation, is detectable before the development of overweight in an animal model that develops a metabolic syndrome-like phenotype.
雄性小鼠中特异性缺失钠钾 2 氯共转运蛋白（）的胰岛素分泌β细胞（）β细胞数量减少，β细胞分泌功能轻度障碍，同时伴有超重、葡萄糖耐量受损、胰岛素抵抗和代谢异常。在此，我们证实并扩展了之前的结果，表明雌性缺失的小鼠也会发展出类似的代谢综合征表型，尽管程度较轻。值得注意的是，雄性和雌性缺失的小鼠在不摄入过量卡路里的情况下就会超重。对进食微结构的分析表明，年轻健康的雄性缺失小鼠每餐的热量含量较高，且进食频率相对较低，尤其是在夜间。此外，超重的缺失小鼠每餐的进食量明显大于健康的缺失小鼠。因此，摄食饱腹感控制的减弱先于超重的发生，且在老年缺失小鼠中更为严重。然而，在健康和超重的缺失小鼠中，两次进食之间的时间保持不变，这表明对自由进食的饱腹感反应是保守的。然而，只有超重的雄性在重新进食期间和之后，饱腹感才会增强。在健康的雌性中，重新进食时的饱腹感反应相对于年龄和体重匹配的对照组小鼠延迟，但在超重的缺失小鼠中恢复正常。由于重新进食期间每餐的大小没有变化，这些数据表明，在超重发生之前，健康的缺失小鼠在禁食后重新进食时的进食控制受到损害，且与它们的饱腹感反应减弱无关。因此，我们的研究结果支持这样一种新假说，即饱腹感反应减弱先于超重的发生，并导致代谢失调。肥胖是指脂肪过度积累，会显著增加患代谢疾病的绝对风险。尽管肥胖通常归因于食物摄入量增加，但我们证明，在不摄入过量卡路里的情况下，体重也可以加速增加。事实上，在一种会发展出类似代谢综合征表型的动物模型中，在超重发生之前，就可以检测到进食结束控制（即饱腹感）受损。
