Adipose tissue macrophages (ATMs) are involved in the development of insulin resistance in obesity. We have recently shown that myeloid cell–specific reduction of HMG-CoA reductase (Hmgcrm−/m−), which is the rate-limiting enzyme in cholesterol biosynthesis, protects against atherosclerosis by inhibiting macrophage migration in mice. We hypothesized that ATMs are harder to accumulate in Hmgcrm−/m− mice than in control Hmgcrfl/fl mice in the setting of obesity. To test this hypothesis, we fed Hmgcrm−/m− and Hmgcrfl/fl mice a high-fat diet (HFD) for 24 weeks and compared plasma glucose metabolism as well as insulin signaling and histology between the two groups. Myeloid cell–specific reduction of Hmgcr improved glucose tolerance and insulin sensitivity without altering body weight in the HFD-induced obese mice. The improvement was due to a decrease in the number of ATMs. The ATMs were reduced by decreased recruitment of macrophages as a result of their impaired chemotactic activity. These changes were associated with decreased expression of proinflammatory cytokines in adipose tissues. Myeloid cell–specific reduction of Hmgcr also attenuated hepatic steatosis. In conclusion, reducing myeloid HMGCR may be a promising strategy to improve insulin resistance and hepatic steatosis in obesity.

中文翻译：

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髓系 HMG-CoA（3-羟基-3-甲基戊二酰辅酶 A）还原酶确定饮食诱导的肥胖小鼠的脂肪组织炎症、胰岛素抵抗和肝脂肪变性。

脂肪组织巨噬细胞 (ATM) 参与肥胖胰岛素抵抗的发展。我们最近表明，骨髓细胞特异性降低 HMG-CoA 还原酶 (Hmgcrm-/m-) 是胆固醇生物合成的限速酶，通过抑制小鼠巨噬细胞迁移来预防动脉粥样硬化。我们假设在肥胖的情况下，ATM 在 Hmgcrm-/m- 小鼠中比在对照 Hmgcrfl/fl 小鼠中更难积累。为了验证这一假设，我们给 Hmgcrm-/m- 和 Hmgcrfl/fl 小鼠喂食高脂肪饮食 (HFD) 24 周，并比较了两组之间的血浆葡萄糖代谢以及胰岛素信号传导和组织学。Hmgcr 的骨髓细胞特异性降低改善了 HFD 诱导的肥胖小鼠的葡萄糖耐量和胰岛素敏感性，而不会改变体重。改善是由于自动柜员机数量减少。由于趋化活性受损，巨噬细胞募集减少，ATM 减少。这些变化与脂肪组织中促炎细胞因子的表达降低有关。Hmgcr 的骨髓细胞特异性降低也减轻了肝脂肪变性。总之，减少髓系 HMGCR 可能是改善肥胖患者胰岛素抵抗和肝脂肪变性的一种有前景的策略。