Cell-Autonomous Heterogeneity of Nutrient Uptake in White Adipose Tissue of Rhesus Macaques

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Abstract

Phenotypic diversity may play an adaptive role by providing graded biological 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 insulin-stimulated 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 vitro-differentiated human adipocytes also exhibited a mosaic pattern of BODIPY-C12 uptake. WAT from animals 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 in WAT. Hence, for the first time, we demonstrate an intrinsic heterogeneity in FFA and glucose transport activity in WAT.

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