Cell-Autonomous heterogeneity of nutrient uptake in white adipose tissue of rhesus macaques

Phenotypicdiversitymayplayanadaptiverolebyprovidinggradedbiological responses to fluctuations in environmental stimuli. We used single-cell imaging of the metabolizable fluorescent fatty acid analog 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY)-C₁₂ and fluorescent 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino]-2-deoxy-D-glucose (2-NBDG) to explore cellular heterogeneity in nutrient uptake in white adipose tissue (WAT) explants of rhesus macaques. Surprisingly, WAT displayed a striking cell size-independent mosaic pattern, in that adjacent adipocytes varied with respect to insulinstimulated BODIPY-C₁₂ and 2-NBDG uptake. Relative free fatty acid (FFA) transport activity correlated with the cellular levels of FFA transporter protein-1 and the scavenger receptor CD36 in individual adipocytes. In vitro incubation of WAT explants for 24 hours caused partial desynchronization of cellular responses, suggesting that adipocytes may slowly alter their differential nutrient uptake activity. In vitrodifferentiatedhumanadipocytesalsoexhibitedamosaicpatternofBODIPY-C₁₂uptake.WATfromanimals containing a homogeneous population of large adipocytes was nonmosaic, in that every adipocyte exhibited a similar level of BODIPY-C₁₂ fluorescence, suggesting that the development of obesity is associated with the loss of heterogeneity inWAT.Hence, for the first time,wedemonstrateanintrinsic heterogeneity in FFA and glucose transport activity in WAT.