Masson Stewart W C, Simpson Rebecca C, Cutler Harry B, Carlos Patrick W, Marian Oana C, Yau Belinda, Potter Meg, Madsen Søren, Cooke Kristen C, Craw Niamh R, Fuller Oliver K, Harney Dylan J, Larance Mark, Cooney Gregory J, Morahan Grant, Shanahan Erin R, Kebede Melkam A, Hodgkins Christopher, Payne Richard J, Stöckli Jacqueline, James David E
School of Life and Environmental Sciences, Faculty of Science, The University of Sydney, Sydney, NSW, Australia.
Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia.
EMBO J. 2025 Sep 9. doi: 10.1038/s44318-025-00555-5.
Insulin resistance is a heritable risk factor for many chronic diseases; however, the genetic drivers remain elusive. In seeking these, we performed genetic mapping of insulin sensitivity in 670 chow-fed Diversity Outbred in Australia (DOz) mice and identified a genome-wide significant locus (QTL) on chromosome 8 encompassing 17 defensin genes. By taking a systems genetics approach, we identified alpha-defensin 26 (Defa26) as the causal gene in this region. To validate these findings, we synthesized Defa26 and performed diet supplementation experiments in two mouse strains with distinct endogenous Defa26 expression levels. In the strain with relatively lower endogenous expression (C57BL/6J) supplementation improved insulin sensitivity and reduced gut permeability, while in the strain with higher endogenous expression (A/J) it caused hypoinsulinemia, glucose intolerance and muscle wasting. Based on gut microbiome and plasma bile acid profiling this appeared to be the result of disrupted microbial bile acid metabolism. These data illustrate the danger of single strain over-reliance and provide the first evidence of a link between host-genetics and insulin sensitivity which is mediated by the microbiome.
胰岛素抵抗是许多慢性疾病的一种可遗传风险因素；然而，其遗传驱动因素仍不明确。为了寻找这些因素，我们对670只在澳大利亚以普通饲料喂养的多样性远交系（DOz）小鼠的胰岛素敏感性进行了基因定位，并在8号染色体上确定了一个全基因组显著位点（QTL），该位点包含17个防御素基因。通过采用系统遗传学方法，我们确定α-防御素26（Defa26）是该区域的因果基因。为了验证这些发现，我们合成了Defa26，并在两种内源性Defa26表达水平不同的小鼠品系中进行了饮食补充实验。在相对较低内源性表达的品系（C57BL/6J）中，补充Defa26可改善胰岛素敏感性并降低肠道通透性，而在较高内源性表达的品系（A/J）中，它会导致低胰岛素血症、葡萄糖不耐受和肌肉萎缩。基于肠道微生物群和血浆胆汁酸谱分析，这似乎是微生物胆汁酸代谢紊乱的结果。这些数据说明了过度依赖单一品系的危险性，并提供了宿主遗传学与由微生物群介导的胰岛素敏感性之间联系的首个证据。
