Structure of sympathetic input to interscapular brown adipose tissue in the mouse

Abstract

Interscapular brown adipose tissue (iBAT) is under sympathetic and sensory nerve control. We recently identified the stellate and thoracic sympathetic chain ganglia T1‐T5 as the main origins of sympathetic input to iBAT in adult male and female mice. Previous studies reported that iBAT receives sympathetic innervation from five intercostal nerves; even though intercostal nerves (which originate from ventral rami) are typically known to provide innervation to lateral, ventral body tissues. Furthermore, we were unable to find literature with detailed anatomical studies. Here, we used a reporter mouse model that expresses tdTomato in tyrosine hydroxylase expressing neurons (TH‐tomato mice) in all sympathetic nerve fibers to facilitate dissection and imaging of sympathetic nerves to iBAT. Our data clarifies that iBAT receives sympathetic input via dorsal rami, which combine sensory and sympathetic fibers. This is consistent with the role of dorsal rami to innervate dorsal body structures, while intercostal nerves (traveling along the ribs) provide innervation to lateral and ventral body structures in mammals. Furthermore, we performed whole mount and paraffin embedded anatomical studies of TH (as surrogate for sympathetic nerves) to understand the anatomy and structure of sympathetic iBAT innervation. We found that fine sympathetic nerve fibers branch off the dorsal rami emanating from T1‐T4 to enter the BAT pad, and from there further branch to form axonal varicosities. Meanwhile, the dorsal rami continue to innervate vasculature and skin. We further established a novel tool to quantify axonal varicosities across entire adipose tissue depots using the IMARIS spot detection tool. This allowed us to visualize the extensive variation of axonal varicose density within the entire iBAT depot with dense varicosities adjacent to brown adipocytes, but sparse varicosities adjacent to white adipocytes. We also analyzed the axonal varicosities in inguinal white adipose tissue and found denser varicosities associated with beige islands that were significantly increased after 7day cold exposure (10°C). Finally, we use UCP1‐reporter mice and whole mount iBAT staining of TH to verify that dense axonal varicosities overlap with UCP1‐positive tissue, while UCP1‐negative tissue shows sparse axonal varicosities. The dynamic and anatomically distinct regulation of sympathetic axonal varicose density is likely due to distinct neurotrophic interaction of brown and white adipocytes with sympathetic neurons. Our data clarify the structure of sympathetic innervation to the iBAT in the mouse and highlights the benefits to study endorgans like entire adipose depots in an anatomically defined manner.Support or Funding InformationGrant support: NIH 4OT2 OD23864‐01