Heterogeneity in the perirenal region of humans suggests presence of dormant brown adipose tissue that contains brown fat precursor cells

Naja Z. Jespersen, Amir Feizi, Eline S. Andersen, Sarah Heywood, Helle B. Hattel, Søren Daugaard, Lone Peijs, Per Bagi, Bo Feldt-Rasmussen, Heidi S. Schultz, Ninna S. Hansen, Rikke Krogh-Madsen, Bente K. Pedersen, Natasa Petrovic, Søren Nielsen, Camilla Scheele

Perirenal fat surrounds the kidney as well as the adrenal gland, which secretes epinephrine and norepinephrine in response to sympathetic activation. Jespersen, Feizi, et al. hypothesized that multilocular brown adipose tissue (BAT) would accumulate close to the adrenal gland and aimed to characterize the molecular differences between this fat compared to perirenal fat more distant from sources of norepinephrine. They demonstrate that most of the perirenal fat in adult humans consists of dormant BAT, while small amounts of adipocytes with a multilocular morphology and gene expression signature of active BAT, are present near regions where sympathetic activity is expected to be high.

Objective: Increasing the amounts of functionally competent brown adipose tissue (BAT) in adult humans has the potential to restore dysfunctional metabolism and counteract obesity. In this study, we aimed to characterize the human perirenal fat depot, and we hypothesized that there would be regional, within-depot differences in the adipose signature depending on local sympathetic activity.

Methods: We characterized fat specimens from four different perirenal regions of adult kidney donors, through a combination of qPCR mapping, immunohistochemical staining, RNA-sequencing, and pre-adipocyte isolation. Candidate gene signatures, separated by adipocyte morphology, were recapitulated in a murine model of unilocular brown fat induced by thermoneutrality and high fat diet.

Results: We identified widespread amounts of dormant brown adipose tissue throughout the perirenal depot, which was contrasted by multilocular BAT, primarily found near the adrenal gland. Dormant BAT was characterized by a unilocular morphology and a distinct gene expression profile, which partly overlapped with that of subcutaneous white adipose tissue (WAT). Brown fat precursor cells, which differentiated into functional brown adipocytes were present in the entire perirenal fat depot, regardless of state. We identified SPARC as a candidate adipokine contributing to a dormant BAT state, and CLSTN3 as a novel marker for multilocular BAT.

Conclusions: We propose that perirenal adipose tissue in adult humans consists mainly of dormant BAT and provide a data set for future research on factors which can reactivate dormant BAT into active BAT, a potential strategy for combatting obesity and metabolic disease.