尽管丧失了 H3K27 乙酰转移酶 p300 或 CBP,但生热脂肪组织仍能维持。

IF 4.2 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM American journal of physiology. Endocrinology and metabolism Pub Date : 2024-10-01 Epub Date: 2024-08-14 DOI:10.1152/ajpendo.00120.2024
Daniel Gamu, Makenna S Cameron, William T Gibson
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引用次数: 0

摘要

棕色和米色脂肪组织专门用于产热,对小鼠的能量平衡非常重要。越来越多的证据表明,染色质修饰酶是生热脂肪细胞发育、维持和发挥作用不可或缺的因素。p300 和 CREB 结合蛋白(CBP)是组蛋白乙酰转移酶(HAT),负责写入转录激活标记 H3K27ac。尽管它们具有同源性,但 p300 和 CBP 确实具有独特的组织和环境依赖性作用,这些作用尚未在棕色和米色脂肪细胞中进行专门研究。我们利用 Ucp1-Cre 介导的小鼠基因敲除技术评估了产热脂肪对 p300 或 CBP 的需求,以确定它们的缺失是否会影响组织发育、对饮食诱发肥胖的易感性以及对通过 b3-agonism 进行药物诱导的反应。尽管成功敲除了HAT,但棕色脂肪组织的质量和生热标志物的表达并没有受到HAT缺失的影响。因此,基因敲除小鼠在饮食诱发肥胖和葡萄糖不耐受方面的发展程度与基因缺失对照组相当。此外,b3-肾上腺素能激动剂 CL-316243 对白色脂肪组织的 "棕色化 "作用在基因敲除小鼠中基本保持不变。虽然 p300 和 CBP 在其他组织中的作用并不重叠,但我们的研究结果表明,它们在产热脂肪中是不可或缺的,这可能是由于它们之间的功能补偿作用。
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Maintenance of thermogenic adipose tissues despite loss of the H3K27 acetyltransferases p300 or CBP.

Brown and beige adipose tissues are specialized for thermogenesis and are important for energy balance in mice. Mounting evidence suggests that chromatin-modifying enzymes are integral for the development, maintenance, and functioning of thermogenic adipocytes. p300 and cAMP-response element binding protein (CREB)-binding protein (CBP) are histone acetyltransferases (HATs) responsible for writing the transcriptionally activating mark H3K27ac. Despite their homology, p300 and CBP do have unique tissue- and context-dependent roles, which have yet to be examined in brown and beige adipocytes specifically. We assessed the requirement of p300 or CBP in thermogenic fat using uncoupling protein 1 (Ucp1)-Cre-mediated knockdown in mice to determine whether their loss impacted tissue development, susceptibility to diet-induced obesity, and response to pharmacological induction via β3-agonism. Despite successful knockdown, brown adipose tissue mass and expression of thermogenic markers were unaffected by loss of either HAT. As such, knockout mice developed a comparable degree of diet-induced obesity and glucose intolerance to that of floxed controls. Furthermore, "browning" of white adipose tissue by the β3-adrenergic agonist CL-316,243 remained largely intact in knockout mice. Although p300 and CBP have nonoverlapping roles in other tissues, our results indicate that they are individually dispensable within thermogenic fats specifically, possibly due to functional compensation by one another.NEW & NOTEWORTHY The role of transcriptionally activating H3K27ac epigenetic mark has yet to be examined in mouse thermogenic fats specifically, which we achieved here via Ucp1-Cre-driven knockdown of the histone acetyltransferases (HAT) p300 or CBP under several metabolic contexts. Despite successful knockdown of either HAT, brown adipose tissue was maintained at room temperature. As such, knockout mice were indistinguishable to controls when fed an obesogenic diet or when given a β3-adrenergic receptor agonist to induce browning of white fat. Unlike other tissues, thermogenic fats are resilient to p300 or CBP ablation, likely due to sufficient functional overlap between them.

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来源期刊
CiteScore
9.80
自引率
0.00%
发文量
98
审稿时长
1 months
期刊介绍: The American Journal of Physiology-Endocrinology and Metabolism publishes original, mechanistic studies on the physiology of endocrine and metabolic systems. Physiological, cellular, and molecular studies in whole animals or humans will be considered. Specific themes include, but are not limited to, mechanisms of hormone and growth factor action; hormonal and nutritional regulation of metabolism, inflammation, microbiome and energy balance; integrative organ cross talk; paracrine and autocrine control of endocrine cells; function and activation of hormone receptors; endocrine or metabolic control of channels, transporters, and membrane function; temporal analysis of hormone secretion and metabolism; and mathematical/kinetic modeling of metabolism. Novel molecular, immunological, or biophysical studies of hormone action are also welcome.
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