Mitochondrial carrier SLC25A34 links clock, diet, and temperature control of adipocyte lipid cycling
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Illumina NovaSeq 6000
ORGANISM(S): Mus musculus
SUBMITTER: Single Cell Omics Platform CBMR
PROVIDER: E-MTAB-17580 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:RNA-seq was performed on brown adipose tissue from control and adipocyte-specific Rev-erbα/β double knockout mice (Ucp1-Cre; Nr1d1/2 fl/fl) across the circadian cycle under thermoneutral conditions (30°C).
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Project description:Brown adipose tissue (BAT) generates heat via uncoupled respiration, providing mammals with an evolutionary defense against environmental cold. Although the molecular pathways by which cold activates brown adipocytes are well understood, little is known about how BAT maintains its thermogenic capacity during adaptation to environmental warmth. Here, we identify the transcriptional repressor BCL6 as the switch for maintaining brown adipocyte cellular identity under warm conditions. Mice lacking BCL6 in their brown adipocytes display normal thermogenic responses when housed in a cool environment, but fail to maintain thermogenic fitness when housed under warm conditions. In a temperature-dependent manner, BCL6 suppresses apoptosis, fatty acid storage, and coupled respiration to maintain thermogenic competence in brown adipocytes. Enhancer analysis revealed that BCL6 reinforces brown-specific while opposing white-specific enhancers to maintain cellular identity. Thus, unlike other regulators, BCL6 is dispensable for differentiation and activation of brown adipocytes, but specifically required for their maintenance in warmth.
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Project description:Transcriptional effectors of white adipocyte-selective gene expression have not been described. TLE3 is a white-selective cofactor that acts reciprocally with the brown-selective cofactor Prdm16 to specify lipid storage and thermogenic gene programs. When expressed at elevated levels in brown fat, TLE3 counters Prdm16, suppressing brown-selective genes and inducing white-selective genes, resulting in impaired fatty acid oxidation and thermogenesis. To further test the functional consequences of the changes in BAT phenotype in aP2-TLE3 Tg mice, we challenged them with cold exposure at 4C. aP2-TLE3 Tg mice had an impaired ability to respond to cold exposure compared to littermate control mice, as evidenced by a marked drop in core body temperature. Transgenic mice expressing TLE3 from the aP2 enhancer and wild type mice were housed individually without food and bedding immediately before the start of experiments. Mice were allowed free access to water and placed at 4C for 5 hours while core body temperature was monitored every hour using a rectal probe. For microarray experiments of BAT, RNA was extracted and pooled from 4 mice in each group.
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Project description:Recent studies suggest that brown adipose tissue (BAT) plays a role in energy and glucose metabolism in humans. However, the physiological significance of human BAT in lipid metabolism remains unknown. To gain insight regarding the mechanisms of accelerated lipid metabolism in relation to the cold-activated BAT, we performed molecular (transcriptome) profiling of supraclavicular and subcutaneous abdominal adipose tissue samples collected from one subject during CE (cold exposure) and TN (thermoneutral) conditions.
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Project description:We have reported that cold temperature challenge results in a dramatic decrease in levels of the transcriptional repressor, Rev-erb alpha. Performing Rev-erb alpha ChIP-seq on brown adipose from wildtype animals kept at thermoneutrality or cold-challenged (and using Rev-erb alpha KO brown adipose as a control), we were able to globally determine the genomic regions undergoing Rev-erb alpha-dependent de-repression.
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Project description:Beyond its thermogenic potential, brown adipose tissue (BAT) performs important endocrine functions that regulate metabolism. However, the BAT microenvironment and the factors involved in BAT homeostasis and adaptation to cold remain poorly characterized. We therefore aimed to study secreted factors from active brown adipocytes that may be involved in adipocyte function and/or may orchestrate inter-cellular communications. For this, mRNA levels in mature adipocytes of brown, beige and white adipose depots from mice exposed to 21 days of cold were evaluated using RNA sequencing, and bioinformatic analysis was used to predict for potentially secreted factors. Cxcl12 was found to be the most cold-induced C-X-C chemokine in BAT, and Cxcl12 mRNA expression analysis by qPCR and fluorescence in-situ hybridization revealed its enrichment in brown adipocytes upon cold. Cold increased CXCL12 secretion from BAT, yet its level in plasma remained unchanged indicating a potential local action. Cxcl12 knockdown in mature brown adipocytes impaired thermogenesis, estimated by norepinephrine (NE)-induced Ucp1 gene expression, glycerol release and mitochondrial respiration despite unaltered β-adrenergic signaling, suggesting Cxcl12 regulates adipocyte function independently from the β-adrenergic pathway. Importantly, unaltered adipocyte characteristics upon Cxcl12 loss may indicate CXCL12 primarily regulates the NE-induced adipocyte activation. Furthermore, CXCL12 might exert inter-cellular crosstalk via its capacity to promote macrophage chemotaxis and neurite outgrowth. Here we present CXCL12 as a novel brown adipocyte, cold-induced secreted factor involved in adipocyte function and inter-cellular crosstalk within BAT.
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Project description:Brown adipose tissue (BAT) exhibits exceptional metabolic plasticity, rapidly increasing energy expenditure to sustain thermogenesis during cold exposure. This high metabolic activity imposes substantial demands on cellular systems, requiring robust adaptive mechanisms to maintain homeostasis and prevent cellular stress. Yet, the pathways that support and coordinate these adaptive responses in brown adipocytes remain incompletely understood. Here, we identify a cold- induced adaptive program in BAT characterized by the formation of endoplasmic reticulum- plasma membrane (ER-PM) contact sites and the activation of store-operated calcium entry (SOCE), which is essential for maintaining brown adipocyte health during thermogenic activation. Cold exposure enhances ER-PM contacts and upregulates the expression of STIM and Orai proteins, key mediators of SOCE. Loss of STIM in brown adipocytes disrupts intracellular Ca2+ homeostasis and induces aberrant aggregation of ER membranes. STIM deficiency also impairs cold-induced mitochondrial fission resulting in hyperfused mitochondria with reduced oxidative capacity, independently of UCP1 abundance. Importantly, mice lacking STIM in BAT exhibit impaired lipid oxidation, are cold intolerant and develop exacerbated peripheral insulin resistance when challenged with a high-fat diet. Together, these findings identify ER-PM remodeling and STIM-mediated SOCE as a central regulator that links organelle architecture to brown adipocyte function and contributes to whole-body metabolic homeostasis.
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Project description:Rodents are commonly housed below thermoneutrality (~20°C) 1. Under these conditions there is a substantial effect on rodent physiology including the hyperactivation of brown (BAT) and beige adipose tissue 2. Here, we raised animals from weaning, on an obesogenic diet at thermoneutrality (28°C) to closer mimic human physiology and determine the impact of a) moderate cold exposure (i.e. 20°C, a temperature reduction of ~8°C) or b) treatment with YM-178, a highly-selective, clinically used β3-adrenoreceptor agonist on classical BAT or subcutaneous inguinal (IWAT) beige depots. Under these conditions, uncoupling protein 1 mRNA was undetectable in IWAT in all groups. Maintenance at 20°C drove weight gain and a 125% increase in subcutaneous fat, an effect not seen with YM-178 administration thus suggesting a direct effect of ambient temperature in promoting weight gain and adiposity in obese rats. Using exploratory adipose tissue proteomics we reveal novel processes and pathways associated with cold-induced weight gain in BAT (i.e. histone deacetylation and glycosphingolipid biosynthesis) and IWAT (i.e. NAD+ binding and retinol metabolism). Conversely, YM-178 had minimal metabolic-related effects on BAT and drove a pro-inflammatory phenotype in IWAT. Exercise training elicits diverse effects on brown (BAT) and white adipose tissue (WAT) physiology in rodents housed below their thermoneutral zone (i.e. 28-32°C). In these conditions, BAT is chronically hyperactive and, unlike human residence, closer to thermoneutrality. Therefore, we set out to determine the effects of exercise training in obese animals at 28°C (i.e. thermoneutrality) on BAT and WAT in its basal (i.e. inactive) state. Sprague-Dawley rats (n=12) were housed at thermoneutrality from 3 weeks of age and fed a high-fat diet. At 12 weeks of age half these animals were randomised to 4-weeks of swim-training (1 hour/day, 5 days per week). Following a metabolic assessment interscapular and perivascular BAT and inguinal (I)WAT were taken for analysis of thermogenic genes and the proteome. Exercise attenuated weight gain but did not affect total fat mass or thermogenic gene expression. Proteomics revealed an impact of exercise training on2-oxoglutarate metabolic process, mitochondrial respiratory chain complex IV, carbon metabolism and oxidative phosphorylation. This was accompanied by an upregulation of multiple proteins involved in skeletal muscle physiology suggesting an adipocyte to myocyte switch in BAT. UCP1 mRNA was undetectable in IWAT with proteomics highlighting changes to DNA binding, the positive regulation of apoptosis, HIF-1 signalling and cytokine-cytokine receptor interaction.
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