Early postnatal interactions between beige adipocytes and sympathetic neurites regulate innervation of subcutaneous fat

Abstract

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.

Eosinophils regulate intra-adipose axonal plasticity

“…The sympathetic neurites are established in iWAT during development ( 47 ); however, the precise cellular mechanism for the developmental innervation remains unclear. NGF functions as a critical neurotrophic factor for the sympathetic arborizations across multiple tissues and organs ( 30 , 48 ).…”

Global Adipose Tissue Remodeling During the First Month of Postnatal Life in Mice

“…The extent of this transient remodeling is different by mouse strain and ambient temperature, as comprehensively reviewed below. Our understanding of its exact temporal sequence is limited by the choice of time points studied with low resolution in the past: peak browning has been varyingly detected at day 20 (12)(13)(14)(15), several days earlier (16) or later (17,18).…”

“…Sympathetic innervation development and postnatal browning of white adipose tissue have recently been debated to be causally linked (55) or not (17). In any case, from postnatal day 6 onwards, sympathetic innervation and number of beige cells concomitantly increase in iWAT of C57BL6/J mice, until a peak around day 12-16 (16). Importantly, the hormone leptin constitutes the key driver of sympathetic innervation, potentially offering an experimental route to influence postnatal browning in iWAT.…”

“…Possibly, increased fat content is the consequence of a developmental bout of increased de novo lipogenesis, a powerful, cold-stimulated process in mature BAT ( 44 , 45 ). Similarly, white adipose tissue experiences a distinct postnatal phase of strong sympathetic neurite innervation independent of ambient temperature ( 16 , 17 ). This may be accompanied by a transient increase in sympathetic tone during the establishment of ligand-receptor connections, in turn underlying an apparent browning.…”

Exercise Training Remodels Inguinal White Adipose Tissue Through Adaptations in Innervation, Vascularization and the Extracellular Matrix

“…Prdm16 is a transcriptional regulator that creates a complex with Gtf2ird1 and Ehmt1 to repress expression of pro-fibrotic genes (Hasegawa et al, 2018). Gtf2ird1 is an essential component of this complex and plays a role in inhibiting fibrosis and promoting sympathetic neurite density in scWAT (Hasegawa et al, 2018;Chi et al, 2018bChi et al, , 2021. We studied both Adipo-cre PRDM16 knockout (PRDM16KO) and wild type mice following 11 days of voluntary wheel running and found no difference in running distance between genotypes (Figure 6A).…”