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.
Keywords: adipose tissue; beige adipocytes; developmental biology; medicine; mouse; sympathetic nerves; whole tissue clearing; whole tissue imaging.
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.
© 2021, Chi et al.