Recent developments in natural products for white adipose tissue browning.

✅ 全文

天然产物诱导白色脂肪组织褐变的研究进展

作者 Ma Peng; He Ping; Xu Chun-Yang; Hou Bi-Yu; Qiang Gui-Fen; DU Guan-Hua 期刊 Chinese Journal Of Natural Medicines 发表日期 2020 卷/期/页码 Vol. 18(11) ISSN 1875-5364 DOI 10.1016/S1875-5364(20)60021-8 类型原创研究 (Original Research)

📄 英文摘要 English Abstract

Excess accumulation of white adipose tissue (WAT) causes obesity which is an imbalance between energy intake and energy expenditure. Obesity is a serious concern because it has been the leading causes of death worldwide, including diabetes, stroke, heart disease and cancer. Therefore, uncovering the mechanism of obesity and discovering anti-obesity drugs are crucial to prevent obesity and its complications. Browning, inducing white adipose tissue to brown or beige (brite) fat which is brown-like fat emerging in WAT, becomes an appealing therapeutic strategy for obesity and metabolic disorders. Due to lack of efficacy or intolerable side-effects, the clinical trials that promote brown adipose tissue (BAT) thermogenesis and browning of WAT have not been successful in humans. Obviously, more specific means still need to be developed to activate browning of white adipose tissue. In this review, we summarized seven kinds of natural products (alkaloids, flavonoids, terpenoids, long chain fatty acids, phenolic acids, else and extract) promoting white adipose tissue browning which can ameliorate the metabolic disorders, including obesity, dislipidemia, insulin resistance and diabetes. Since natural products are important drug sources and the browning property plays a significant role in not only obesity treatment but also in type 2 diabetes (T2DM) improvement, natural products of inducing browning may be an irreplaceable drug discovery orientation for obesity, diabetes and even other metabolic disorders.

📄 中文摘要 Chinese Abstract

中文

白色脂肪组织（WAT）的过度积累导致肥胖，这是能量摄入与能量消耗之间的失衡。肥胖是一个严重的问题，因为它一直是全球死亡的主要原因，包括糖尿病、中风、心脏病和癌症。因此，揭示肥胖的机制并发现抗肥胖药物对于预防肥胖及其并发症至关重要。褐变，即诱导白色脂肪组织转变为棕色或米色（brite）脂肪——这是一种在WAT中出现的类棕色脂肪——已成为治疗肥胖和代谢紊乱的一种有吸引力的治疗策略。由于缺乏疗效或无法耐受的副作用，促进棕色脂肪组织（BAT）产热和白色脂肪组织褐变的临床试验在人类中尚未成功。显然，仍需要开发更特异性的方法来激活白色脂肪组织的褐变。

📋 英文结构化总结 English Structured Summary

全文整理

Background:

Methods:

N/A - Review article

Results:

In this review, we summarized seven kinds of natural products (alkaloids, flavonoids, terpenoids, long chain fatty acids, phenolic acids, else and extract) promoting white adipose tissue browning which can ameliorate the metabolic disorders, including obesity, dislipidemia, insulin resistance and diabetes. Since natural products are important drug sources and the browning property plays a significant role in not only obesity treatment but also in type 2 diabetes (T2DM) improvement, natural products of inducing browning may be an irreplaceable drug discovery orientation for obesity, diabetes and even other metabolic disorders.

Data Summary:

The review categorizes natural products into seven distinct classes based on their chemical properties: alkaloids, flavonoids, terpenoids, long chain fatty acids, phenolic acids, other compounds, and extracts. These compounds were identified for their ability to promote the browning of white adipose tissue, specifically by upregulating thermogenic markers such as uncoupling protein-1 (UCP1), PR domain containing-16 (PRDM-16), peroxisome proliferator-activated receptor-γ coactivator 1-α (PGC1α), and cell death inducing DFFA like effector a (CIDEA).

Conclusions:

Inducing WAT into beige fat is a therapeutic strategy for combating obesity, especially since the volume of BAT in adult humans is much less than WAT. Natural products have been exhibiting a great deal of diverse pharmacological activities and serve as an irreplaceable drug discovery source. The browning property of these natural products plays a significant role in not only obesity treatment but also in type 2 diabetes (T2DM) improvement.

Practical Significance:

Natural products that induce browning may be an irreplaceable drug discovery orientation for obesity, diabetes, and other metabolic disorders, providing a crucial alternative to synthetic chemicals which have faced challenges in clinical trials due to lack of efficacy or intolerable side-effects.

📋 中文结构化总结 Chinese Structured Summary

中文

背景:

方法:

不适用——综述文章

结果:

在本综述中，我们总结了七类促进白色脂肪组织褐变的天然产物（生物碱、黄酮类、萜类、长链脂肪酸、酚酸类、其他及提取物），这些产物可改善代谢紊乱，包括肥胖、血脂异常、胰岛素抵抗和糖尿病。由于天然产物是重要的药物来源，且褐变特性不仅在肥胖治疗中发挥重要作用，还在2型糖尿病（T2DM）的改善中具有重要意义，诱导褐变的天然产物可能是肥胖、糖尿病甚至其他代谢紊乱药物发现中不可替代的方向。

数据总结:

本综述根据化学性质将天然产物分为七类：生物碱、黄酮类、萜类、长链脂肪酸、酚酸类、其他化合物和提取物。这些化合物因其促进白色脂肪组织褐变的能力而被鉴定，具体通过上调产热标志物如解偶联蛋白-1（UCP1）、PR结构域包含蛋白-16（PRDM-16）、过氧化物酶体增殖物激活受体-γ共激活因子1-α（PGC1α）和细胞死亡诱导DFFA样效应因子a（CIDEA）来实现。

结论:

将白色脂肪组织诱导为米色脂肪是对抗肥胖的一种治疗策略，特别是因为成年人体内棕色脂肪组织的体积远小于白色脂肪组织。天然产物已展现出多种多样的药理活性，并作为不可替代的药物发现来源。这些天然产物的褐变特性不仅在肥胖治疗中发挥重要作用，还在2型糖尿病（T2DM）的改善中具有重要意义。

实际意义:

诱导褐变的天然产物可能是肥胖、糖尿病和其他代谢紊乱药物发现中不可替代的方向，为合成化学品提供了重要的替代选择，而合成化学品在临床试验中因缺乏疗效或无法耐受的副作用而面临挑战。

📖 英文全文 English Full Text

Available online at www.sciencedirect.com Chinese Journal of Natural Medicines 2020, 18(11): 803-817 doi: 10.1016/S1875-5364(20)60021-8 •Special topic•

Recent developments in natural products for white adipose tissue browning MA Peng1, HE Ping1, XU Chun-Yang2, HOU Bi-Yu1, QIANG Gui-Fen1*, DU Guan-Hua1* 1

State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College and Beijing Key Laboratory of Drug Target and Screening Research, Beijing 100050, China; 2 Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing 100026, China Available online 20 Nov., 2020

[ABSTRACT] Excess accumulation of white adipose tissue (WAT) causes obesity which is an imbalance between energy intake and energy expenditure. Obesity is a serious concern because it has been the leading causes of death worldwide, including diabetes, stroke, heart disease and cancer. Therefore, uncovering the mechanism of obesity and discovering anti-obesity drugs are crucial to prevent obesity and its complications. Browning, inducing white adipose tissue to brown or beige (brite) fat which is brown-like fat emerging in WAT, becomes an appealing therapeutic strategy for obesity and metabolic disorders. Due to lack of efficacy or intolerable side-effects, the clinical trials that promote brown adipose tissue (BAT) thermogenesis and browning of WAT have not been successful in humans. Obviously, more specific means still need to be developed to activate browning of white adipose tissue. In this review, we summarized seven kinds of natural products (alkaloids, flavonoids, terpenoids, long chain fatty acids, phenolic acids, else and extract) promoting white adipose tissue browning which can ameliorate the metabolic disorders, including obesity, dislipidemia, insulin resistance and diabetes. Since natural products are important drug sources and the browning property plays a significant role in not only obesity treatment but also in type 2 diabetes (T2DM) improvement, natural products of inducing browning may be an irreplaceable drug discovery orientation for obesity, diabetes and even other metabolic disorders. [KEY WORDS] Natural products; Browning; Brown adipose tissue; White adipose tissue; Obesity

Introduction Obesity is a serious concern as it induces metabolic disorders associated with high morbidity and mortality, including diabetes, hyperlipidemia, heart disease, stroke and cancer, which makes it a pathological condition worldwide. It is reported that the amount of obese people in over 70 countries has been doubled over the past 25 years [1] . Uncovering the mechanism of obesity and exploring the therapeutic strategy are crucial to prevent obesity and its complications. White adipose tissue, including subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT), plays a central role in energy storage and endocrine function [2] . However, [Received on] 21-Feb.-2020 [Research funding] This work was supported by the National Natural Science Foundation of China (No. 81770847), the Drug Innovation Major Project (No. 2018ZX09711001-003-005), CAMS Innovation Fund for Medical Sciences (No. 2017-I2M-1-010). [*Corresponding author] E-mail: qianggf@imm.ac.cn (QIANG GuiFen); dugh@imm.ac.cn (DU Guan-Hua) These authors have no conflict of interest to declare.

brown adipose tissue (BAT) is characterized by the energy expenditure and adipose thermogenesis with unique marker of uncoupling protein-1 (UCP1). BAT can be activated then “burned” under stimulus of exercise, cold exposure or norepinephrine [3] . In addition, inducing WAT to beige (brite) fat which is brown-like fat appearing in WAT becomes a hot research spot of metabolic disorders with the upregulated UCP1 expression in WAT, as well as other thermogenic markers, such as PR domain containing-16 (PRDM-16), peroxisome proliferator-activated receptor-γ coactivator 1-α (PGC1α) and cell death inducing DFFA like effector a (CIDEA) [4]. In recent years, piles of agents with activating adipose tissue burning have been discovered from synthetic chemicals and natural products. They either mediate WAT into beige fat or promote BAT combustion. However, since the volume of BAT in adult humans is much less than WAT, and white fat (particularly visceral fat) is positively associated with metabolic disorders, inducing WAT into BAT becomes a therapeutic strategy of combating obesity [5] . As an irreplaceable drug discovery source, natural products have been exhibiting a great deal of diverse pharmacological activities, like

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