Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA.
Mol Metab. 2018 Aug;14:130-138. doi: 10.1016/j.molmet.2018.06.001. Epub 2018 Jun 6.
To date, early developmental ablation of leptin receptor (LepRb) expression from circumscribed populations of hypothalamic neurons (e.g., arcuate nucleus (ARC) Pomc- or Agrp-expressing cells) has only minimally affected energy balance. In contrast, removal of LepRb from at least two large populations (expressing vGat or Nos1) spanning multiple hypothalamic regions produced profound obesity and metabolic dysfunction. Thus, we tested the notion that the total number of leptin-responsive hypothalamic neurons (rather than specific subsets of cells with a particular molecular or anatomical signature) subjected to early LepRb deletion might determine energy balance.
We generated new mouse lines deleted for LepRb in ARC Ghrh neurons or in Htr2c neurons (representing roughly half of all hypothalamic LepRb neurons, distributed across many nuclei). We compared the phenotypes of these mice to previously-reported models lacking LepRb in Pomc, Agrp, vGat or Nos1 cells.
The early developmental deletion of LepRb from vGat or Nos1 neurons produced dramatic obesity, but deletion of LepRb from Pomc, Agrp, Ghrh, or Htr2c neurons minimally altered energy balance.
Although early developmental deletion of LepRb from known populations of ARC neurons fails to substantially alter body weight, the minimal phenotype of mice lacking LepRb in Htr2c cells suggests that the phenotype that results from early developmental LepRb deficiency depends not simply upon the total number of leptin-responsive hypothalamic LepRb cells. Rather, specific populations of LepRb neurons must play particularly important roles in body energy homeostasis; these as yet unidentified LepRb cells likely reside in the DMH.
迄今为止，早期发育性切除特定下丘脑神经元（如弓状核（ARC）中的 POMC 或 Agrp 表达细胞）中的瘦素受体（LepRb）表达，对能量平衡的影响极小。相比之下，从至少两个大的种群（表达 vGat 或 Nos1）中去除 LepRb，跨越多个下丘脑区域，会导致严重肥胖和代谢功能障碍。因此，我们测试了这样一种观点，即接受早期 LepRb 缺失的瘦素反应性下丘脑神经元的总数（而不是具有特定分子或解剖特征的特定细胞亚群）可能决定能量平衡。
我们生成了新的小鼠品系，其中 ARC Ghrh 神经元或 Htr2c 神经元中的 LepRb 缺失（代表所有下丘脑 LepRb 神经元的大约一半，分布在许多核中）。我们将这些小鼠的表型与先前报道的缺乏 Pomc、Agrp、vGat 或 Nos1 细胞中 LepRb 的模型进行了比较。
早期发育性地从 vGat 或 Nos1 神经元中删除 LepRb 会导致明显肥胖，但从 Pomc、Agrp、Ghrh 或 Htr2c 神经元中删除 LepRb 对能量平衡的影响很小。
尽管从已知的 ARC 神经元群体中早期发育性地删除 LepRb 不能显著改变体重，但缺乏 Htr2c 细胞中 LepRb 的小鼠的最小表型表明，早期发育性 LepRb 缺乏导致的表型不仅取决于瘦素反应性下丘脑 LepRb 细胞的总数。相反，特定的 LepRb 神经元群体必须在身体能量稳态中发挥特别重要的作用；这些尚未确定的 LepRb 细胞可能位于 DMH 中。
