Objective

Obesity-induced insulin resistance is closely associated with chronic subclinical inflammation in white adipose tissue. However, the mechanistic involvement of adipocyte-derived inflammation under these disease conditions remains unclear. Our aim was to investigate the relative inflammation-related contributions of adipocytes and macrophages to insulin sensitivity.

Methods

RIDα/β is an adenoviral protein complex that inhibits several inflammatory pathways, including TLR4, TNFα, and IL1β signaling. We generated novel mouse models with adipocyte-specific and macrophage-specific doxycycline (dox)-inducible RIDα/β-transgenic mice (RID^ad and RID^mac mice, respectively).

Results

RIDα/β induction significantly reduced LPS-stimulated inflammatory markers, such as Tnf, Il1b, and Saa3 in adipose tissues. Surprisingly, RID^ad mice had elevated levels of postprandial glucose and insulin and exhibited glucose intolerance and insulin resistance, even under chow-fed conditions. Moreover, the RID^ad mice displayed further insulin resistance under obesogenic (high-fat diet, HFD) conditions despite reduced weight gain. In addition, under pre-existing obese and inflamed conditions on an HFD, subsequent induction of RIDα/β in RID^ad mice reduced body weight gain, further exacerbating glucose tolerance, enhancing insulin resistance and fatty liver, and reducing adiponectin levels. This occurred despite effective suppression of the inflammatory pathways (including TNFα and IL1β). In contrast, RID^mac mice, upon HFD feeding, displayed similar weight gain, comparable adiponectin levels, and insulin sensitivity, suggesting that the inflammatory properties of macrophages did not exert a negative impact on metabolic readouts. RIDα/β expression and the ensuing suppression of inflammation in adipocytes enhanced adipose tissue fibrosis and reduced vascularization.

Conclusion

Our novel findings further corroborate our previous observations suggesting that suppressing adipocyte inflammation impairs adipose tissue function and promotes insulin resistance, despite beneficial effects on weight gain.

中文翻译：

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抑制脂肪细胞炎症可促进小鼠的胰岛素抵抗。

目的

肥胖引起的胰岛素抵抗与白色脂肪组织中的慢性亚临床炎症密切相关。然而，在这些疾病条件下脂肪细胞源性炎症的机制涉及尚不清楚。我们的目的是研究脂肪细胞和巨噬细胞对胰岛素敏感性的相对炎症相关贡献。

方法

RIDα/β是一种腺病毒蛋白复合物，可抑制多种炎症途径，包括TLR4，TNFα和IL1β信号传导。我们生成了具有脂肪细胞特异性和巨噬细胞特异性强力霉素（dox）诱导的RIDα/β转基因小鼠（分别为RID ^ad和RID ^mac小鼠）的新型小鼠模型。

结果

RIDα/β诱导显着减少脂肪组织中LPS刺激的炎症标记，例如Tnf，Il1b和Saa3。出乎意料的是，RID ^ad小鼠即使在高脂饮食条件下，餐后葡萄糖和胰岛素水平也升高，并表现出葡萄糖耐量和胰岛素抵抗。此外，尽管体重减轻，RID ^ad小鼠在致肥胖（高脂饮食，HFD）条件下仍表现出进一步的胰岛素抵抗。此外，在HFD先前存在肥胖和发炎的情况下，随后在RID ^ad中诱导RIDα/β小鼠减少体重增加，进一步加剧葡萄糖耐量，增强胰岛素抵抗和脂肪肝，并降低脂联素水平。尽管有效抑制了炎症途径（包括TNFα和IL1β），但仍发生了这种情况。相比之下，RID ^mac小鼠在喂食HFD后显示出相似的体重增加，可比的脂联素水平和胰岛素敏感性，这表明巨噬细胞的炎症特性并未对代谢读数产生负面影响。RIDα/β的表达以及随之而来的脂肪细胞炎症抑制作用增强了脂肪组织纤维化并减少了血管生成。

结论

我们的新发现进一步证实了我们先前的发现，即尽管对体重增加有有益作用，但抑制脂肪细胞炎症会损害脂肪组织功能并促进胰岛素抵抗。