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组胺刺激棕色和米色脂肪产热

冯月瑶¹, 张玉洁², 常永生^1,*

¹天津医科大学基础医学院生理与病理生理学系，天津 300070；²中国医学科学院基础医学研究所，北京协和医学院基础医学院，医学分子生物学国家重点实验室，北京 100005

摘要

β3-肾上腺素受体激动剂能够刺激棕色脂肪适应性产热，并能促进白色脂肪米色化。然而到目前为止，有哪些代谢产物参与介导β3-肾上腺素受体激动剂促进脂肪产热作用尚不清楚。本研究通过给予8周龄C57/BL6J雄性小鼠腹腔注射β3-肾上腺素受体激动剂CL316,243，分离提取小鼠脂肪组织进行RNA-Seq检测，结果显示组胺合成限速酶组氨酸脱羧酶(histidine decarboxylase, HDC)在脂肪中被CL316,243强烈诱导，因此推测HDC的代谢产物组胺可能参与了脂肪组织的产热过程。通过给予正常饮食与高脂饮食C57BL/6J小鼠静脉注射组胺，以明确组胺促进脂肪产热的生理作用和机制。结果显示，组胺可刺激正常饮食小鼠棕色脂肪和皮下白色脂肪中产热基因的表达，包括过氧化物酶体增殖物激活受体γ-辅活化因子-1α (peroxisome proliferator-activated receptor gamma coactivator-1α, PGC-1α)和解耦联蛋白1 (uncoupling protein 1, UCP1)。HE染色表明，组胺处理降低了脂肪细胞中脂滴的大小。此外，组胺还可以促进高脂饮食诱导的肥胖小鼠脂肪产热，改善糖耐量和脂肪肝表型。最后，我们通过脂肪原代前体细胞实验验证了组胺促进产热是细胞的自主特性。本研究结果表明，组胺可能参与介导了β3-肾上腺素受体激动剂促进脂肪的产热。

关键词： 组胺; 产热; 肥胖; UCP1; PGC-1α

分类号：R363

Histamine stimulates thermogenesis of brown and beige fat

FENG Yue-Yao¹, ZHANG Yu-Jie², CHANG Yong-Sheng^1,*

¹Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin 300070, China；²National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China

Abstract

β3-adrenergic agonists induce adaptive thermogenesis and promote beiging of white fat. However, it remains unclear which metabolites mediate the stimulatory effects of β3-adrenergic agonists on thermogenesis of brown and beige fat. In this study, adipose tissue was isolated from 8-week-old C57/BL6J male mice by intraperitoneal administration of β3-adrenergic agonist CL316,243 for RNA-Seq, which revealed that histidine decarboxylase, a key enzyme in histamine synthesis, was strongly induced in adipose by CL316,243. Therefore, we speculated that histamine might be involved in the process of thermogenesis in adipose tissue. We determined the physiological role and mechanism by which histamine promotes fat thermogenesis by intravenous administering histamine to C57BL/6J mice fed a normal or a high-fat diet. The results showed that intravenous injection of histamine into C57BL/6J mice fed a normal diet stimulated the expression of thermogenic genes, including peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) and uncoupling protein 1 (UCP1), in brown adipose tissue (BAT) and inguinal white adipose tissue (iWAT). H&E staining also suggested that histamine treatment decreased the size of lipid droplets in adipocytes. Moreover, histamine treatment also enhanced thermogenesis of fat in high-fat diet induced obese mice, and improved glucose intolerance and fatty liver phenotype. Finally, we demonstrated that the effects of histamine on the thermogenic program were cell autonomous. Our data suggest that histamine may mediate the effects of β3-adrenergic agonists on thermogenesis of fat.

Key words: Histamine; thermogenesis; obesity; UCP1; PGC-1α

收稿日期：2020-11-25　　录用日期：2021-02-26

通讯作者：常永生　　E-mail: changys@tmu.edu.cn

DOI: 10.13294/j.aps.2021.0039

引用本文：

冯月瑶, 张玉洁, 常永生. 组胺刺激棕色和米色脂肪产热[J]. 生理学报 2021; 73 (5): 821-827.

FENG Yue-Yao, ZHANG Yu-Jie, CHANG Yong-Sheng. Histamine stimulates thermogenesis of brown and beige fat. Acta Physiol Sin 2021; 73 (5): 821-827 (in Chinese with English abstract).