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Moderate SIRT1 overexpression protects against brown adipose tissue inflammation
Molecular Metabolism ( IF 8.1 ) Pub Date : 2020-10-10 , DOI: 10.1016/j.molmet.2020.101097
Carmen Escalona-Garrido 1 , Patricia Vázquez 1 , Paula Mera 2 , Sebastián Zagmutt 3 , Ester García-Casarrubios 4 , Ana Montero-Pedrazuela 5 , Fernanda Rey-Stolle 6 , Ana Guadaño-Ferraz 5 , Francisco J Rupérez 6 , Dolors Serra 2 , Laura Herrero 2 , Maria Jesus Obregon 4 , Ángela M Valverde 1
Affiliation  

Objective

Metainflammation is a chronic low-grade inflammatory state induced by obesity and associated comorbidities, including peripheral insulin resistance. Brown adipose tissue (BAT), a therapeutic target against obesity, is an insulin target tissue sensitive to inflammation. Therefore, it is necessary to find strategies to protect BAT against the effects of inflammation in energy balance. In this study, we explored the impact of moderate sirtuin 1 (SIRT1) overexpression on insulin sensitivity and β-adrenergic responses in BAT and brown adipocytes (BA) under pro-inflammatory conditions.

Methods

The effect of inflammation on BAT functionality was studied in obese db/db mice and lean wild-type (WT) mice or mice with moderate overexpression of SIRT1 (SIRT1Tg+) injected with a low dose of bacterial lipopolysaccharide (LPS) to mimic endotoxemia. We also conducted studies on differentiated BA (BA-WT and BA-SIRT1Tg+) exposed to a macrophage-derived pro-inflammatory conditioned medium (CM) to evaluate the protection of SIRT1 overexpression in insulin signaling and glucose uptake, mitochondrial respiration, fatty acid oxidation (FAO), and norepinephrine (NE)-mediated-modulation of uncoupling protein-1 (UCP-1) expression.

Results

BAT from the db/db mice was susceptible to metabolic inflammation manifested by the activation of pro-inflammatory signaling cascades, increased pro-inflammatory gene expression, tissue-specific insulin resistance, and reduced UCP-1 expression. Impairment of insulin and noradrenergic responses were also found in the lean WT mice upon LPS injection. In contrast, BAT from the mice with moderate overexpression of SIRT1 (SIRT1Tg+) was protected against LPS-induced activation of pro-inflammatory signaling, insulin resistance, and defective thermogenic-related responses upon cold exposure. Importantly, the decline in triiodothyronine (T3) levels in the circulation and intra-BAT after exposure of the WT mice to LPS and cold was markedly attenuated in the SIRT1Tg+ mice. In vitro BA experiments in the two genotypes revealed that upon differentiation with a T3-enriched medium and subsequent exposure to a macrophage-derived pro-inflammatory CM, only BA-SIRT1Tg+ fully recovered insulin and noradrenergic responses.

Conclusions

This study has ascertained the benefit of the moderate overexpression of SIRT1 to confer protection against defective insulin and β-adrenergic responses caused by BAT inflammation. Our results have potential therapeutic value in combinatorial therapies for BAT-specific thyromimetics and SIRT1 activators to combat metainflammation in this tissue.



中文翻译:

中度 SIRT1 过表达可防止棕色脂肪组织炎症

客观的

Metainflammation 是一种慢性低度炎症状态,由肥胖和相关合并症(包括外周胰岛素抵抗)引起。棕色脂肪组织 (BAT) 是一种针对肥胖症的治疗靶标,是一种对炎症敏感的胰岛素靶标组织。因此,有必要找到保护 BAT 免受炎症对能量平衡影响的策略。在这项研究中,我们探讨了在促炎条件下中度 Sirtuin 1 (SIRT1) 过表达对 BAT 和棕色脂肪细胞 (BA) 中胰岛素敏感性和 β-肾上腺素能反应的影响。

方法

在肥胖db/db小鼠和瘦野生型 (WT) 小鼠或注射低剂量细菌脂多糖 (LPS) 以模拟内毒素血症的 SIRT1 (SIRT1 Tg+ )中度过度表达的小鼠中研究了炎症对 BAT 功能的影响。我们还对暴露于巨噬细胞衍生的促炎条件培养基 (CM) 的分化 BA(BA-WT 和 BA-SIRT1 Tg+)进行了研究,以评估 SIRT1 过表达对胰岛素信号传导和葡萄糖摄取、线粒体呼吸、脂肪酸的保护氧化 (FAO) 和去甲肾上腺素 (NE) 介导的解偶联蛋白 1 (UCP-1) 表达调节。

结果

来自db/db小鼠的BAT易受代谢炎症的影响,表现为促炎信号级联的激活、促炎基因表达增加、组织特异性胰岛素抵抗和 UCP-1 表达降低。在注射 LPS 后,瘦 WT 小鼠中也发现胰岛素和去甲肾上腺素能反应受损。相比之下,来自中度过度表达 SIRT1 (SIRT1 Tg+ )的小鼠的 BAT受到保护,不受 LPS 诱导的促炎信号激活、胰岛素抵抗和冷暴露时有缺陷的产热相关反应的影响。重要的是,在将 WT 小鼠暴露于 LPS 和寒冷后,循环和 BAT 内三碘甲腺原氨酸 (T 3 ) 水平的下降在SIRT1 中显着减弱Tg+小鼠。 体外在两个基因型BA实验揭示,在分化时具有T 3富集的介质和随后暴露于巨噬细胞衍生的促炎CM,只有BA-SIRT1的Tg +完全恢复胰岛素和去甲肾上腺素的反应。

结论

这项研究已经确定了 SIRT1 适度过表达的益处,以提供针对由 BAT 炎症引起的有缺陷的胰岛素和 β-肾上腺素能反应的保护作用。我们的结果在 BAT 特异性拟甲状腺素和 SIRT1 激活剂的组合疗法中具有潜在的治疗价值,以对抗该组织中的转移性炎症。

更新日期:2020-10-30
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