Abstract
Brown adipose tissue from mice living under conditions approaching human thermal and nutritional conditions (prolonged exposure to thermoneutral temperature and to an energy-rich (high-fat, high-sugar) diet) — referred to as “physiologically humanized” mice, displays morphological and molecular characteristics significantly different from those observed in young, chow-fed mice maintained at room temperature — referred to as “standard” mice. Here, we further examined brown fat from physiologically humanized and standard mice, as well as from mice exposed to thermoneutrality for a long time but not to an energy-rich diet - referred to here as “long-term thermoneutral” mice. Global transcriptome analysis of brown fat revealed that genes that were the most upregulated in brown fat of thermoneutral mice (both physiologically humanized and long-term thermoneutral) were those related to inflammatory processes, including genes expressed selectively in macrophages. Cellular and molecular analyses confirmed that brown fat from thermoneutral mice was heavily infiltrated by macrophages, predominantly organized into crown-like structures. However, despite this, the brown fat of thermoneutral mice retained full competence to attain the greatest possible recruitment state and became macrophage-depleted during the process of cold acclimation. Thus, profound macrophage accumulation does not influence the thermogenic recruitment competence of brown fat.
Highlights
Brown fat is a highly heterogeneous tissue characterized by extraordinary plasticity
To obtain an overview of the expression levels of the selected macrophage marker genes in the brown fat of the four groups of mice, the results presented in Figures 6B–E and in Figures 7B– E were visualized as a heatmap on the basis of hierarchical clustering (Figure 7F)
We demonstrate that prolonged exposure to thermoneutrality invokes abundant accumulation of macrophages in brown fat; neither an energy-rich diet nor increased age led to any significant effect on this accumulation
Summary
Brown fat is a highly heterogeneous tissue characterized by extraordinary plasticity. We recently demonstrated that brown adipose tissue from mice exposed to conditions approaching human thermal and nutritional conditions - prolonged exposure to thermoneutral temperature (approximately 30°C) and to an energy-rich (high-fat, high-sugar) diet - undergoes remarkable morphological, cellular and molecular remodeling [2]. The tissue displayed a distinct molecular signature: in comparison to brown fat of young mice housed under standard conditions (temperature of approximately 21°C and chow diet), the expression levels of genes related to thermogenesis were significantly decreased, the expression levels of genes proposed to discriminate between classical brown and brite/beige adipose depots (marker genes) [3,4,5,6] were altered to such a degree that their brown versus brite/beige discriminative power was principally lost and as many as about one quarter of all transcripts were expressed at significantly different levels
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