Peña-Villalobos Isaac, Casanova-Maldonado Ignacio, Lois Pablo, Sabat Pablo, Palma Verónica
Departamento de Ciencias Ecológicas, Facultad de Ciencias, Universidad de Chile, Santiago, Chile.
Laboratorio de Células troncales y Biología del Desarrollo, Departamento de Biología, Facultad de Ciencias, Universidad de Chile, Santiago, Chile.
Front Physiol. 2019 Jan 8;9:1821. doi: 10.3389/fphys.2018.01821. eCollection 2018.
Several studies have evaluated plastic changes in the morphology of the digestive tract in rodents subjected to caloric restriction or restricted availability. Nevertheless, studies that link these morphological responses to physiological consequences are scarce. In order to investigate short-term plastic responses in the intestine, we acclimated adult (BALB/c) males for 20 days to four distinctive treatments: two caloric regimens ( and 60% of calorie ingestion) and two levels of periodicity of the regimens (continuous and stochastic treatment). At the end of the treatment we analyzed the cell proliferation and cell death dynamics of small intestinal crypts in these animals. In addition, we measured organ masses and lengths, hydrolytic digestive enzyme activities, and energy output from feces. Finally, in order to explore the metabolic changes generated by these dietary conditions we assessed the catabolic activity (i.e., enzymes) of the liver. Our results show that individuals acclimated to a continuous and 60% regimen presented longer intestines in comparison to the other treatments. Indeed, their intestines grew with a rate of 0.22 cm/day, generating a significant caloric reduction in the content of their feces. Besides, both mass and intestinal lengths were predicted strongly by the stabilization coefficient of BrdU+ proliferating cells per crypt, the latter correlating positively with the activity of n-aminopeptidases. Interestingly, by using pharmacological inhibition of the kinase mammalian target of rapamycin complex 1 (mTORC1) by Rapamycin, we were able to recapitulate similar changes in the proliferation dynamics of intestinal stem cells. Based on our results, we propose that the impact of caloric restriction on macroscopic variation in morphology and functional changes in digestive n-aminopeptidases occurs through synchronization in the proliferation rate of stem and/or progenitor cells located in the small intestinal crypts and requires mTORC1 as a key mediator. Hence, we suggest that an excessive stem and progenitor activity could result in increased crypts branching and might therefore underlie the reported intestinal tissue expansion in response to short-term caloric restriction. Summarizing, we demonstrate for the first time that short-term caloric restriction induces changes in the level of cell proliferation dynamics explaining in part digestive tract plasticity in adaptive performance.
多项研究评估了热量限制或食物供应受限的啮齿动物消化道形态的可塑性变化。然而，将这些形态学反应与生理后果联系起来的研究却很少。为了研究肠道的短期可塑性反应，我们将成年（BALB/c）雄性小鼠适应20天，采用四种不同的处理方式：两种热量摄入方案（正常热量摄入和60%热量摄入）以及两种方案的周期性水平（连续处理和随机处理）。在处理结束时，我们分析了这些动物小肠隐窝中的细胞增殖和细胞死亡动态。此外，我们测量了器官质量和长度、水解消化酶活性以及粪便中的能量输出。最后，为了探究这些饮食条件所产生的代谢变化，我们评估了肝脏的分解代谢活性（即酶）。我们的结果表明，与其他处理相比，适应连续60%热量摄入方案的个体小肠更长。事实上，它们的小肠以每天0.22厘米的速度生长，导致粪便中的热量显著减少。此外，每个隐窝中BrdU+增殖细胞的稳定系数强烈预测了质量和小肠长度，后者与n-氨基肽酶的活性呈正相关。有趣的是，通过雷帕霉素对激酶哺乳动物雷帕霉素靶蛋白复合物1（mTORC1）进行药理学抑制，我们能够在肠道干细胞增殖动态中重现类似的变化。基于我们的结果，我们提出热量限制对形态学宏观变化和消化n-氨基肽酶功能变化的影响是通过位于小肠隐窝中的干细胞和/或祖细胞增殖速率的同步发生的，并且需要mTORC1作为关键介质。因此，我们认为过度的干细胞和祖细胞活性可能导致隐窝分支增加，因此可能是报道的短期热量限制引起肠道组织扩张的基础。总之，我们首次证明短期热量限制会诱导细胞增殖动态水平的变化，这部分解释了适应性表现中消化道的可塑性。
