Distinct cellular and molecular mechanisms for β3 adrenergic receptor-induced beige adipocyte formation.
Distinct cellular and molecular mechanisms for β3 adrenergic receptor-induced beige adipocyte formation.
复制标题
DOI：
10.7554/elife.30329
复制
发表时间：
2017-10-11
期刊：
影响因子：
7.7
通讯作者：
Graff JM
中科院分区：
文献类型：
--
作者：
Jiang Y;Berry DC;Graff JM
米色/棕色脂肪细胞在白色脂肪组织（WAT）内被诱导，并且当被激活时，消耗葡萄糖和脂肪酸以产生热量。传统上，有两种刺激被用来触发beiging反应：低温和β3-肾上腺素能受体（Adrb 3）激动剂。这两个beiging触发器已被互换使用，但这两种刺激是否可能在细胞和分子水平上诱导beiging不同仍不清楚。在这里，我们发现冷诱导米色脂肪细胞的形成需要Adrb 1，而不是Adrb 3，激活。Adrb 1激活刺激WAT驻留血管周围（Acta 2+）细胞形成冷诱导的米色脂肪细胞。相反，Adrb 3激活刺激成熟的白色脂肪细胞转化为米色脂肪细胞。使用成熟脂肪细胞特异性Prdm 16缺失策略的必要性测试表明，脂肪细胞是产生Adrb 3诱导的米色脂肪细胞所必需的，并且是产生Adrb 3诱导的米色脂肪细胞的主要来源，但不是冷诱导的米色脂肪细胞。总的来说，我们确定低温和Adrb 3激动剂激活表达不同β-肾上腺素能受体的不同细胞群以诱导米色脂肪形成。一种称为白色脂肪的脂肪的过度积累与肥胖和代谢问题有关。白色脂肪细胞储存能量。白色脂肪组织还含有一些米色脂肪细胞，它们燃烧脂肪和糖来产生热量。寒冷的温度触发米色脂肪细胞的产生和活动，使身体保持温暖。肥胖的人往往有更少的米色脂肪和更多的白色脂肪。这促使科学家们测试增加一个人的米色脂肪细胞数量的治疗方法是否可以减少脂肪量并改善新陈代谢。为了开发增加米色脂肪的治疗方法，科学家们必须首先了解它来自哪里，以及寒冷和其他因素如何刺激它的生长。最近的研究表明，血管壁周围的平滑肌细胞会产生冷诱导的米色脂肪细胞。一种广泛使用的药物，打开β3肾上腺素能受体，这是在细胞膜中发现，也促进了米色脂肪细胞的创造。然而，目前还不清楚寒冷或这种药物是如何触发米色脂肪的产生的。现在，Jiang等人展示了靶向β3肾上腺素能受体的药物导致小鼠的白色脂肪细胞变成米色脂肪细胞。实验还表明，寒冷会打开平滑肌细胞上一种称为β1肾上腺素能受体的不同受体，使它们产生米色脂肪细胞。这表明身体中米色脂肪细胞的来源不止一个，并且增加米色脂肪细胞数量的不同策略的工作方式并不相同。需要更多的研究来了解暴露于寒冷或药物后产生的米色脂肪细胞是否以同样的方式表现，并对新陈代谢产生类似的影响。这可以帮助科学家确定这些策略中的一种是否可以更好地治疗肥胖或其他代谢紊乱。
Beige/brite adipocytes are induced within white adipose tissues (WAT) and, when activated, consume glucose and fatty acids to produce heat. Classically, two stimuli have been used to trigger a beiging response: cold temperatures and β3-adrenergic receptor (Adrb3) agonists. These two beiging triggers have been used interchangeably but whether these two stimuli may induce beiging differently at cellular and molecular levels remains unclear. Here, we found that cold-induced beige adipocyte formation requires Adrb1, not Adrb3, activation. Adrb1 activation stimulates WAT resident perivascular (Acta2+) cells to form cold-induced beige adipocytes. In contrast, Adrb3 activation stimulates mature white adipocytes to convert into beige adipocytes. Necessity tests, using mature adipocyte-specific Prdm16 deletion strategies, demonstrated that adipocytes are required and are predominant source to generate Adrb3-induced, but not cold-induced, beige adipocytes. Collectively, we identify that cold temperatures and Adrb3 agonists activate distinct cellular populations that express different β-adrenergic receptors to induce beige adipogenesis. Excess accumulation of a type of fat called white fat is associated with obesity and metabolic problems. White fat cells store energy. White fat tissue also contains some beige fat cells, which burn fats and sugars to produce heat. Cold temperatures trigger the production and activity of beige fat cells, which allows the body to stay warm. People with obesity tend to have less beige fat and more white fat. This has led scientists to test whether treatments that increase the number of beige fat cells a person has could reduce fat mass and improve metabolism. To develop treatments that increase beige fat, scientists must first understand where it comes from and how cold and other factors stimulate its growth. Recent studies have shown that smooth muscle cells, which surround blood vessel walls, make cold-induced beige fat cells. A widely used drug that turns on the β3 adrenergic receptor, which is found in the cell membrane, also boosts the creation of beige fat cells. Yet, it was not clear exactly how cold or this drug triggers the production of beige fat. Now, Jiang et al. show that drugs that target β3 adrenergic receptors cause white fat cells in mice to change into beige fat cells. The experiments also showed that cold turns on a different receptor called the β1 adrenergic receptor on smooth muscle cells causing them to make beige fat cells. This shows that there is more than one source for beige fat cells in the body and that different strategies for increasing beige fat cell numbers do not work the same way. More studies are needed to learn whether beige fat cells produced after exposure to cold or drugs behave in the same way and have similar affects on metabolism. This could help scientists determine if one of these strategies could make a better treatment for obesity or other metabolic disorders.