Microglia mediate the early-life programming of adult glucose control.

IF 7.5 1区生物学 Q1 CELL BIOLOGY

Cell reports Pub Date : 2025-03-25 Epub Date: 2025-03-12 DOI:10.1016/j.celrep.2025.115409

Martin Valdearcos, Emily R McGrath, Stephen M Brown Mayfield, Melissa G Jacuinde, Andrew Folick, Rachel T Cheang, Ruoyu Li, Tomas P Bachor, Rachel N Lippert, Allison W Xu, Suneil K Koliwad

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引用次数: 0

Abstract

Glucose homeostasis is, in part, nutritionally programmed during early neonatal life, a critical window for synapse formation between hypothalamic glucoregulatory centers. Although microglia prune synapses throughout the brain, their role in refining hypothalamic glucoregulatory circuits remains unclear. Here, we show that the phagocytic activity of microglia in the mediobasal hypothalamus (MBH) is induced following birth, regresses upon weaning from maternal milk, and is exacerbated by feeding dams a high-fat diet while lactating. In addition to actively engulfing synapses, microglia are critical for refining perineuronal nets (PNNs) within the neonatal MBH. Remarkably, transiently depleting microglia before weaning (postnatal day [P]6-16) but not afterward (P21-31) induces glucose intolerance in adulthood due to impaired insulin responsiveness, which we link to PNN overabundance and reduced synaptic connectivity between hypothalamic glucoregulatory neurons and the pancreatic β cell compartment. Thus, microglia facilitate early-life synaptic plasticity in the MBH, including PNN refinement, to program hypothalamic circuits regulating adult glucose homeostasis.

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小胶质细胞介导成人血糖控制的早期规划。

葡萄糖稳态在一定程度上是在新生儿早期由营养程序控制的，这是下丘脑葡萄糖调节中心之间突触形成的关键窗口期。虽然小胶质细胞会修剪整个大脑的突触，但它们在完善下丘脑葡萄糖调节回路中的作用仍不清楚。在这里，我们发现小胶质细胞在下丘脑基底层（MBH）的吞噬活性是在出生后诱发的，在断奶后会恢复，并且在哺乳期给母体喂食高脂肪饮食会加剧这种活性。除了积极吞噬突触外，小胶质细胞对完善新生儿下丘脑周围神经元网（PNN）也至关重要。值得注意的是，在断奶前（出生后第 [P]6-16 天）而非断奶后（P21-31 天）瞬时消耗小胶质细胞可诱导成年期胰岛素反应受损导致的葡萄糖不耐受，我们将其与下丘脑葡萄糖调节神经元和胰腺 β 细胞区室之间的 PNN 过度丰富和突触连接减少联系起来。因此，小胶质细胞促进了 MBH 早期的突触可塑性，包括 PNN 的完善，从而对调节成人葡萄糖稳态的下丘脑回路进行编程。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell reports CELL BIOLOGY-

CiteScore

13.80

自引率

1.10%

发文量

1305

审稿时长

77 days

期刊介绍： Cell Reports publishes high-quality research across the life sciences and focuses on new biological insight as its primary criterion for publication. The journal offers three primary article types: Reports, which are shorter single-point articles, research articles, which are longer and provide deeper mechanistic insights, and resources, which highlight significant technical advances or major informational datasets that contribute to biological advances. Reviews covering recent literature in emerging and active fields are also accepted. The Cell Reports Portfolio includes gold open-access journals that cover life, medical, and physical sciences, and its mission is to make cutting-edge research and methodologies available to a wide readership. The journal's professional in-house editors work closely with authors, reviewers, and the scientific advisory board, which consists of current and future leaders in their respective fields. The advisory board guides the scope, content, and quality of the journal, but editorial decisions are independently made by the in-house scientific editors of Cell Reports.