Dataset Information

Thermoneutrality-Induced Macrophage Accumulation in Brown Adipose Tissue Does Not Impair the Tissue's Competence for Cold-Induced Thermogenic Recruitment.

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.

SUBMITTER: Fischer AW

PROVIDER: S-EPMC7662517 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Thermoneutrality-Induced Macrophage Accumulation in Brown Adipose Tissue Does Not Impair the Tissue's Competence for Cold-Induced Thermogenic Recruitment.

Fischer Alexander W AW de Jong Jasper M A JMA Sass Frederike F Schlein Christian C Heeren Joerg J Petrovic Natasa N

Frontiers in endocrinology 20201030

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 physiologicall ...[more]

PMID: 33193086

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Project description:ObjectiveBrown adipose tissue (BAT) thermogenesis offers the potential to improve metabolic health in mice and humans. However, humans predominantly live under thermoneutral conditions, leading to BAT whitening, a reduction in BAT mitochondrial content and metabolic activity. Recent studies have established mitophagy as a major driver of mitochondrial degradation in the whitening of thermogenic brite/beige adipocytes, yet the pathways mediating mitochondrial breakdown in whitening of classical BAT remain largely elusive. The transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy belonging to the MiT family of transcription factors, is the only member of this family that is upregulated during whitening, pointing toward a role of TFEB in whitening-associated mitochondrial breakdown.MethodsWe generated brown adipocyte-specific TFEB knockout mice, and induced BAT whitening by thermoneutral housing. We characterized gene and protein expression patterns, BAT metabolic activity, systemic metabolism, and mitochondrial localization using in vivo and in vitro approaches.ResultsUnder low thermogenic activation conditions, deletion of TFEB preserves mitochondrial mass independently of mitochondriogenesis in BAT and primary brown adipocytes. However, this does not translate into elevated thermogenic capacity or protection from diet-induced obesity. Autophagosomal/lysosomal marker levels are altered in TFEB-deficient BAT and primary adipocytes, and lysosomal markers co-localize and co-purify with mitochondria in TFEB-deficient BAT, indicating trapping of mitochondria in late stages of mitophagy.ConclusionWe identify TFEB as a driver of BAT whitening, mediating mitochondrial degradation via the autophagosomal and lysosomal machinery. This study provides proof of concept that interfering with the mitochondrial degradation machinery can increase mitochondrial mass in classical BAT under human-relevant conditions. However, it must be considered that interfering with autophagy may result in accumulation of non-functional mitochondria. Future studies targeting earlier steps of mitophagy or target recognition are therefore warranted.

Dataset Information

Thermoneutrality-Induced Macrophage Accumulation in Brown Adipose Tissue Does Not Impair the Tissue's Competence for Cold-Induced Thermogenic Recruitment.

Publications

Thermoneutrality-Induced Macrophage Accumulation in Brown Adipose Tissue Does Not Impair the Tissue's Competence for Cold-Induced Thermogenic Recruitment.

Similar Datasets

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