Early postnatal interactions between beige adipocytes and sympathetic neurites regulate innervation of subcutaneous fat.
Early postnatal interactions between beige adipocytes and sympathetic neurites regulate innervation of subcutaneous fat.
复制标题
出生后早期，米色脂肪细胞和交感神经突起之间的相互作用调节皮下脂肪的神经支配。
DOI：
10.7554/elife.64693
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发表时间：
2021-02-16
期刊：
影响因子：
7.7
通讯作者：
Cohen P
中科院分区：
文献类型：
--
作者：
Chi J;Lin Z;Barr W;Crane A;Zhu XG;Cohen P
虽然已发现米色脂肪细胞与小鼠腹股沟皮下白色脂肪（iWAT）中致密的交感神经突起相关，但人们对这种模式何时以及如何建立知之甚少。在这里，我们应用全组织成像来检查iWAT中交感神经支配的发展。我们发现，实质神经突起积极生长之间出生后第6天（P6）和P28，与出生后早期米色脂肪形成重叠。脂肪细胞中Prdm16的组成性缺失导致出生后早期米色脂肪细胞和交感神经密度在此窗口内显著减少。使用可诱导的脂肪细胞特异性Prdm16敲除模型，我们发现Prdm16是在早期发育过程中指导交感神经生长所必需的。然而，在成年动物中删除Prdm16并不影响iWAT中的交感神经结构。总之，这些研究结果强调，米色的脂肪细胞交感神经突通信是至关重要的，建立交感神经结构在出生后早期，但可能是其维护在成熟的动物。哺乳动物有两种类型的脂肪组织：主要储存能量的白色脂肪，以及棕色和米色脂肪，也被称为产热脂肪，燃烧能量产生热量。在人类中，棕色脂肪与有效的抗肥胖和抗糖尿病作用有关。更好地了解这种类型的脂肪是如何发展和发挥作用的，可能会导致治疗这些疾病的治疗策略。成年人的棕色脂肪类似于啮齿动物诱导的棕色脂肪，也称为米色脂肪。在成年小鼠中，米色脂肪细胞需要环境刺激才能形成。寒冷可以通过激活被称为交感神经系统的神经系统的一部分而导致米色脂肪细胞的产生。为了使这种冷诱导的米色脂肪细胞的形成发生，来自交感神经系统的神经必须首先支配脂肪组织。米色脂肪细胞本身对建立这种神经支配很重要，但人们还不清楚这种情况何时以及如何发生。为了研究米色脂肪细胞在建立神经支配中的作用，Chi等人使用了转基因小鼠，当用一种名为强力霉素的抗生素治疗时，这些小鼠的米色脂肪细胞被去除。如果没有经过基因改造的小鼠用强力霉素治疗，它们在出生后不久就产生了米色的脂肪细胞，这些细胞很快就被交感神经系统密集地支配。然而，如果突变小鼠在出生时接受多西环素治疗，这些小鼠在治疗期间无法制造米色脂肪细胞，即使长大后也无法形成密集的神经支配。这些结果表明，出生后不久形成的米色脂肪细胞是建立交感神经系统神经支配所必需的。但是，随着老鼠年龄的增长，米色脂肪细胞是否需要维持这种神经支配呢？为了验证这一点，Chi等人在神经支配完全建立后将它们移除。这些小鼠维持了它们的神经支配，表明米色脂肪细胞似乎只在神经支配的建立过程中才需要。了解交感神经系统如何建立与脂肪的联系，使寒冷能够刺激米色脂肪的形成，是寻找糖尿病或肥胖症等疾病新疗法的第一步。探索交感神经系统和米色脂肪细胞之间相互作用的时间可能会在这个方向上提供治疗目标。
While beige adipocytes have been found to associate with dense sympathetic neurites in mouse inguinal subcutaneous white fat (iWAT), little is known about when and how this patterning is established. Here, we applied whole-tissue imaging to examine the development of sympathetic innervation in iWAT. We found that parenchymal neurites actively grow between postnatal day 6 (P6) and P28, overlapping with early postnatal beige adipogenesis. Constitutive deletion of Prdm16 in adipocytes led to a significant reduction in early postnatal beige adipocytes and sympathetic density within this window. Using an inducible, adipocyte-specific Prdm16 knockout model, we found that Prdm16 is required for guiding sympathetic growth during early development. Deleting Prdm16 in adult animals, however, did not affect sympathetic structure in iWAT. Together, these findings highlight that beige adipocyte-sympathetic neurite communication is crucial to establish sympathetic structure during the early postnatal period but may be dispensable for its maintenance in mature animals. Mammals have two types of fatty tissue: white fat that mainly stores energy, and brown and beige fat, also known as thermogenic fat, which burns energy to generate heat. In humans, brown fat is associated with potent anti-obesity and anti-diabetes effects. A better understanding of how this type of fat develops and functions could lead to therapeutic strategies to treat these conditions. Adult human brown fat is similar to rodent inducible brown fat, also known as beige fat. In adult mice, beige fat cells need stimulation from the environment to form. Cold can lead to the generation of beige fat cells by activating a part of the nervous system known as the sympathetic nervous system. In order for this cold-induced formation of beige fat cells to take place, nerves from the sympathetic nervous system must first innervate the fatty tissue. Beige fat cells themselves are important for establishing this innervation, but it was not well understood when and how this occurs. To study the role of beige fat cells in the establishment of nerve innervation, Chi et al. used genetically modified mice whose beige fat cells are removed when they are treated with an antibiotic called doxycycline. If mice that had not been genetically modified were treated with doxycycline, they developed beige fat cells soon after birth, and these cells shortly became densely innervated by the sympathetic nervous system. However, if the mutant mice were treated with doxycycline around birth, these mice could not make beige fat cells during the treatment and failed to develop dense innervation even when they grew older. These results showed that beige fat cells that form soon after birth are necessary to establish sympathetic nervous system innervation. But are beige fat cells required to maintain this innervation as the mice grow older? To test this, Chi et al. removed them after the innervation was fully established. These mice maintained their innervation, showing that beige fat cells appear to only be required during the establishment of innervation. Understanding how the sympathetic nervous system establishes its connection to fat so cold can stimulate beige fat formation is a first step to finding new treatments for conditions such as diabetes or obesity. Exploring the timing that underlies the interactions between the sympathetic nervous system and beige fat cells may provide therapeutic targets in this direction.