Obese Adipose Tissue Extracellular Vesicles Activate Mitochondrial Fatty Acid β-oxidation to Drive Colonic Stemness

IF 7.1 1区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Cellular and Molecular Gastroenterology and Hepatology Pub Date : 2025-01-01 DOI:10.1016/j.jcmgh.2025.101504

Parsa S. Haque , Desiree Goodman , Thor Kuusivuori-Robinson , Christina Coughlan , Yaritza Delgado-Deida , Joseph C. Onyiah , Janos Zempleni , Arianne L. Theiss

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Abstract

Background & Aims

Patients with obesity and mouse models of obesity exhibit abnormalities in intestinal epithelial cells, including enhanced stemness. Adipose tissue (AT) is the largest endocrine organ secreting cytokines, hormones, and extracellular vesicles (EVs). Here, we characterized EV protein cargo from obese and non-obese AT and demonstrate the role of obese adipose-derived EVs in enhancing colonic stemness.

Methods

EVs were isolated from visceral AT from mice fed high-fat diet to induce obesity or control matched-diet. EV cargo was characterized by unbiased proteomics. Mouse colonoids were treated with EVs and analyzed for fatty acid β-oxidation (FAO), expression of stem marker genes, stem function, and β-catenin expression and acetylation. Mice deficient in adipocyte-specific Tsg101 expression were generated to alter adipocyte EV protein cargo, and colonic stemness was measured.

Results

EVs secreted from obese visceral AT (Ob EVs) were significantly enriched with acyl-CoA dehydrogenase long chain (ACADL), an initiator enzyme of FAO. Compared with non-obese EVs, colonoids treated with Ob EVs exhibited increased exogenous ACADL protein expression, FAO, growth, persistence of stem/progenitor function, and increased β-catenin protein expression and acetylation that was abolished by FAO inhibition. Mice deficient in adipocyte-specific Tsg101 expression exhibited Ob EVs with altered protein expression profiles and were protected from obesity-induced enhanced colonic stemness.

Conclusions

The contents of Ob EVs are poised to fuel FAO and to promote obesity-induced stemness in the colon. Alteration of metabolism is a key mechanism of adipose-to-intestinal tissue communication elicited by EVs, thereby influencing basal colonic stem cell homeostasis during obesity.

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肥胖脂肪组织细胞外囊泡激活线粒体脂肪酸β-氧化，驱动结肠干性。

背景和目的：肥胖患者和肥胖小鼠模型表现出肠上皮细胞异常，包括干性增强。脂肪组织是最大的内分泌器官，可分泌细胞因子、激素和细胞外囊泡（EVs）。在这里，我们分析了来自肥胖和非肥胖AT的EV蛋白货物，并证明了肥胖脂肪来源的EV在增强结肠干细胞中的作用。方法：从高脂饮食诱导肥胖或对照饮食的小鼠内脏AT中分离ev。EV货物的特征是无偏蛋白质组学。用ev处理小鼠结肠体，分析脂肪酸β-氧化（FAO）、茎标记基因表达、茎功能、β-catenin表达和乙酰化。产生脂肪细胞特异性Tsg101表达缺失的小鼠，改变脂肪细胞EV蛋白的载货量，并测量结肠干性。结果：肥胖内脏AT （Ob EVs）分泌的EVs显著富含FAO引发酶酰基辅酶a脱氢酶长链（ACADL）。与非肥胖EVs相比，Ob EVs处理的结肠体表现出外源ACADL蛋白表达、FAO、生长、茎/祖细胞功能的持久性增加，β-catenin蛋白表达和乙酰化增加，而FAO抑制了β-catenin蛋白的表达。缺乏脂肪细胞特异性Tsg101表达的小鼠表现出蛋白质表达谱改变的Ob ev，并保护其免受肥胖诱导的增强结肠干性。结论：Ob EVs的含量可能会促进肥胖诱导的结肠干枯。代谢的改变是EVs诱导脂肪与肠道组织沟通的关键机制，从而影响肥胖过程中结肠基底干细胞的稳态。

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来源期刊

Cellular and Molecular Gastroenterology and Hepatology Medicine-Gastroenterology

CiteScore

13.00

自引率

2.80%

发文量

246

审稿时长

42 days

期刊介绍： "Cell and Molecular Gastroenterology and Hepatology (CMGH)" is a journal dedicated to advancing the understanding of digestive biology through impactful research that spans the spectrum of normal gastrointestinal, hepatic, and pancreatic functions, as well as their pathologies. The journal's mission is to publish high-quality, hypothesis-driven studies that offer mechanistic novelty and are methodologically robust, covering a wide range of themes in gastroenterology, hepatology, and pancreatology. CMGH reports on the latest scientific advances in cell biology, immunology, physiology, microbiology, genetics, and neurobiology related to gastrointestinal, hepatobiliary, and pancreatic health and disease. The research published in CMGH is designed to address significant questions in the field, utilizing a variety of experimental approaches, including in vitro models, patient-derived tissues or cells, and animal models. This multifaceted approach enables the journal to contribute to both fundamental discoveries and their translation into clinical applications, ultimately aiming to improve patient care and treatment outcomes in digestive health.