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Single Nucleus Transcriptomics Identifies Separate Classes of UCP1 and Futile Cycle Adipocytes [human snRNA-seq]

ABSTRACT: Adipose tissue can recruit catabolic adipocytes which utilize chemical energy to dissipate heat. This process occurs either by uncoupled respiration through uncoupling protein 1 (UCP1) or by utilizing ATP-dependent futile cycles (FCs). However, it remains unclear how these pathways coexist since both processes rely on the mitochondrial membrane potential. Utilizing single-nucleus RNA-sequencing to deconvolute the heterogeneity of subcutaneous adipose tissue in mice and humans, we identify at least 2 distinct subpopulations of beige adipocytes: FC-beige and UCP1-beige adipocytes. Importantly, we demonstrate that the FC-utilizing beige subpopulation is metabolically highly active and utilizes FCs to dissipate energy thus contributing to thermogenesis independent of UCP1. Furthermore, FC-beige adipocytes are important drivers of systemic energy homeostasis and linked to glucose metabolism and obesity resistance in humans. Taken together, our findings identify a noncanonical thermogenic adipocyte subpopulation, which could be an important regulator of energy homeostasis in mammals.

ORGANISM(S): Homo sapiens

PROVIDER: GSE184687 | GEO | 2024/07/30

REPOSITORIES: GEO

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Single Nucleus Transcriptomics Identifies Separate Classes of UCP1 and Futile Cycle Adipocytes [mouse snRNA-seq]

Project description:Adipose tissue can recruit catabolic adipocytes which utilize chemical energy to dissipate heat. This process occurs either by uncoupled respiration through uncoupling protein 1 (UCP1) or by utilizing ATP-dependent futile cycles (FCs). However, it remains unclear how these pathways coexist since both processes rely on the mitochondrial membrane potential. Utilizing single-nucleus RNA-sequencing to deconvolute the heterogeneity of subcutaneous adipose tissue in mice and humans, we identify at least 2 distinct subpopulations of beige adipocytes: FC-beige and UCP1-beige adipocytes. Importantly, we demonstrate that the FC-utilizing beige subpopulation is metabolically highly active and utilizes FCs to dissipate energy thus contributing to thermogenesis independent of UCP1. Furthermore, FC-beige adipocytes are important drivers of systemic energy homeostasis and linked to glucose metabolism and obesity resistance in humans. Taken together, our findings identify a noncanonical thermogenic adipocyte subpopulation, which could be an important regulator of energy homeostasis in mammals.

2024-07-30 | GSE184706 | GEO

Single Nucleus Transcriptomics Identifies Separate Classes of UCP1 and Futile Cycle Adipocytes [mouse snRNA-Seq Ucp1KO]

2024-07-30 | GSE270706 | GEO

TZD-induced beige fat activation

Project description:Beige fat cells dissipate energy through mitochondrial uncoupling protein UCP1 defending against obesity and can be activated by thermogenic stimuli in white adipose tissue. Here, we provide candidate molecules involved in beige fat activation induced the TZD, rosiglitazone.

2016-10-03 | GSE79031 | GEO

RNA-Sequencing of wild type and UCP1-null beige adipose tissue

Project description:Since brown adipose tissue (BAT) dissipates energy through UCP1, BAT has garnered attention as a therapeutic intervention for obesity and metabolic diseases including type 2 diabetes. As we better understand the roles of classical brown and beige adipocytes, increased beige fat mass in response to a variety of external/internal cues is associated with significant improvements in glucose and lipid homeostasis that may not be entirely mediated by UCP1. We aim to analyze transcriptome of wild type and UCP1-null beige adipocyte to identify the UCP1-independent function.

2017-10-28 | E-MTAB-4085 | biostudies-arrayexpress

Low-protein/high carbohydrate diet

Project description:Low-protein/high carbohydrate (LP/HC) diet promotes metabolic health and longevity in adult human and animal models. However, the complex molecular underpinnings of how LP/HC diet leads to metabolic benefits remain elusive. Through a multi-layered approach, here we observed that LP/HC diet promotes an energy-dissipating response consisting in the parallel recruitment of canonical and non-canonical (muscular) thermogenic systems in subcutaneous adipose tissue (sWAT). In particular, we measured Ucp1 induction in association with up-regulation of actomyosin components and several Serca (Serca1, Serca2a, Serca2b) ATPases. In beige adipocytes, we observed that AMPK activation is responsible for transducing the amino acid lowering in an enhanced fat catabolism, which sustains both Ucp1- and Serca-dependent energy dissipation. Limiting AMPK activation counteracts the expression of brown fat and muscular genes, including Ucp1 and Serca, as well as mitochondrial oxidative genes. We observed that mitochondrial reactive oxygen species are the upstream molecules controlling AMPK-mediated metabolic rewiring in amino acid-restricted beige adipocytes. Our findings delineate a novel metabolic phenotype of responses to amino acid shortage, which recapitulates some of the benefits of cool temperature in sWAT. In conclusion, this study highlights LP/HC diet as a valuable and practicable strategy to prevent metabolic diseases through the enhancement of mitochondrial oxidative metabolism and the recruitment of different energy dissipating routes in beige adipocytes.

2021-09-09 | PXD017786 | Pride

scATAC-seq of Inguinal Adipose Tissue of UCP1-KO and WT mice.

Project description:Single cell level analysis of transcriptional circuits regulating UCP1-indepednent theremogensis through Lgr6 in inguinal Adipose tissue. We previously identified an increase in Lgr6 gene expression in the beige adipocyte population of UCP1-KO mice and hypothesized its involvement in UCP1-independent thermogensis. Consistent with our previous data the scATAC-seq data reveals that chromatin accessibility at the Lgr6 loci is significantly higher in Ucp1- KO beige adipocytes as compared to WT and the promter is also more accessible in Ucp1- KO beige adipocytes. Other DNA-binding motifs involved in UCP-1 indepedent thermogensis were also analyzed and found to be upregulated in the KO model.

2021-05-15 | GSE174456 | GEO

Hyaluronan mediates cold-induced adipose tissue beiging

Project description:Adipose tissue beiging refers to a process through which beige adipocytes emerge in classical white adipose tissue depots. Beige adipocytes dissipate chemical energy and secrete adipokines like classical brown adipocytes to improve systemic metabolism, which offers benefits for people with obesity and metabolic diseases. Cold exposure and β3-adrenergic receptor (AR) agonist treatment are two commonly used stimuli for increasing beige adipocytes in mice, but their underlying biological processes are different. Transcriptional analysis of inguinal white adipose tissue (iWAT) has revealed that changes in extracellular matrix (ECM) pathway genes are specific to cold exposure. Hyaluronic acid (HA), a non-sulfated linear polysaccharide produced by nearly all cells, is one of the most common components of ECM. We found that cold exposure significantly increases iWAT HA levels while β3-AR agonist CL316,243 fails to do so. Increasing HA level in iWAT by Has2 overexpression significantly increases cold-induced adipose tissue beiging; in contrast, decreasing HA by Spam1 overexpression, which encodes a hyaluronidase that digests HA, significantly decreases cold-induced iWAT beiging. All of these data implicate a role of HA in promoting adipose tissue beiging that is unique to cold exposure. Given the failure of β3-AR agonists in clinical trials for obesity and metabolic diseases, increasing HA could serve as a new approach to recruiting more beige adipocytes to combat metabolic diseases.

2024-08-01 | GSE268781 | GEO

Ctnnb1/β-catenin inactivation in UCP1-positive adipocytes augments the browning of white adipose tissue

Project description:Canonical WNT pathway in mature adipocytes exacerbates obesity. In this study, we constructed UCP1-positive adipocytes-specific Ctnnb1 knockout mice (UBKO) and observed increased “browning” of white adipose tissue (WAT) following cold exposure or CL-316,243 administration compared to controls. UBKO mice also displayed increased energy expenditure. Furthermore, β-catenin (encoded by Ctnnb1) inhibited thermogenic genes expression in differentiated beige adipocytes and repressed Ucp1 expression at transcription level. Transcriptome analysis revealed UBKO mice treated with CL-316,243 had enhanced mitochondrial function and downregulated immunerelated genes in WAT. Improved glucose tolerance and insulin sensitivity were observed in 50-week-old UBKO mice. Public datasets indicated CTNNB1 expression inversely correlated with several thermogenic genes expression in human adipose/adipocytes, and positively correlated with body mass index (BMI) or waist-hip ratio (WHR). We proposed that intervention of β-catenin in adipocytes could be an effective strategy to enhance energy expenditure and improve age-related metabolic performance.

2023-03-31 | GSE227415 | GEO

Gene expression analysis in immortalized brown adipocyte cell line treated 18h with Z16078526

Project description:Strategies to increase energy expenditure are an attractive approach to reduce excess fat storage and body weight to improve metabolic health. In mammals, uncoupling protein-1 (UCP1) in brown and beige adipocytes uncouples fatty acid oxidation from ATP generation in mitochondria and promotes energy dissipation as heat. We set out to identify small molecules that enhance UCP1 levels and activity using a high-throughput screen of nearly 12,000 compounds in mouse brown adipocytes. We identified Z16078526 that increases Ucp1 and mitochondrial-related gene expression in mouse brown adipocytes.

2019-12-01 | GSE138264 | GEO

A non-cell autonomous mechanism of beige adipocyte renaissance in subcutaneous adipose tissue

Project description:Two types of UCP1 positive cells-brown and beige adipocytes exist in mammals. Beige adipocytes are very plastic, and can be dynamically regulated by environment.Beige adipocytes formed postnatally in subcutaneous inguinal white adipose tissue (iWAT) lost thermogenic gene expression and multilocular morphology at adult stage, but cold could restore their “beigeing” characteristics, a phenomenon termed as beige adipocyte renaissance. Our results showed that beige cell maintenance and renaissance in adult mice were regulated by cAMP and HDAC4 signaling in white adipocytes non-cell autonomously. Genetic modulations of various components of this cAMP-HDAC4 cascade (e.g. LKB1) led to persistent browning and reduced adiposity independent of thermogenesis. To further study the mechanisms of beige adipocytes maintenance, we performed RNA-seq with samples from inguinal white adipose tissues of WT, AdipoqCre LKB1 F/F, and AdipoqCre LKB1 F/F; HDAC4 F/F mice.Our studies will move the beige adipocyte field forward and attract clinical applications to target beige adipocyte renaissance.

2018-02-14 | GSE85335 | GEO

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