The hypothalamus plays a crucial role in the progression of obesity and diabetes; however, its structural complexity and cellular heterogeneity impede targeted treatments. Here, we profiled the single-cell and spatial transcriptome of the hypothalamus in obese and sporadic type 2 diabetic macaques, revealing primate-specific distributions of clusters and genes as well as spatial region, cell-type-, and gene-feature-specific changes. The infundibular (INF) and paraventricular nuclei (PVN) are most susceptible to metabolic disruption, with the PVN being more sensitive to diabetes. In the INF, obesity results in reduced synaptic plasticity and energy sensing capability, whereas diabetes involves molecular reprogramming associated with impaired tanycytic barriers, activated microglia, and neuronal inflammatory response. In the PVN, cellular metabolism and neural activity are suppressed in diabetic macaques. Spatial transcriptomic data reveal microglia’s preference for the parenchyma over the third ventricle in diabetes. Our findings provide a comprehensive view of molecular changes associated with obesity and diabetes.

中文翻译：

---

猕猴下丘脑对肥胖和糖尿病的区域特异性转录组反应

下丘脑在肥胖和糖尿病的进展中起着至关重要的作用；然而，其结构复杂性和细胞异质性阻碍了靶向治疗。在这里，我们分析了肥胖和散发性 2 型糖尿病猕猴下丘脑的单细胞和空间转录组，揭示了灵长类特异性簇和基因的分布，以及空间区域、细胞类型和基因特征的特异性变化。漏斗部 (INF) 和室旁核 (PVN) 最容易受到代谢紊乱的影响，其中 PVN 对糖尿病更敏感。在INF中，肥胖导致突触可塑性和能量感知能力降低，而糖尿病涉及与受损的长细胞屏障、激活的小胶质细胞和神经元炎症反应相关的分子重编程。在糖尿病猕猴的 PVN 中，细胞代谢和神经活动受到抑制。空间转录组数据揭示了糖尿病中小胶质细胞对实质的偏好超过对第三脑室的偏好。我们的研究结果提供了与肥胖和糖尿病相关的分子变化的全面视图。