Nck2 Regulates Adiposity and Adiposity-Related Metabolic Disorders in Mice and Human
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE63510 | GEO | 2016/07/01
SECONDARY ACCESSION(S): PRJNA268103
REPOSITORIES: GEO
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Project description:Obesity is linked to the development of metabolic disorders. Expansion of white adipose tissue (WAT) from hypertrophy of pre-existing adipocytes and/or differentiation of precursors into new mature adipocytes contributes to obesity. We found that Nck2 expression is largely restricted to WAT, raising the hypothesis that it may play a unique function in that tissue. Using mice lacking Nck2, we found that Nck2 regulates adipocyte hypertrophy thus contributing to increased adiposity and progressive glucose intolerance, insulin resistance and hepatic steatosis. These findings were recapitulated in humans such that Nck2 expression in omental WAT was inversely correlated with the degree of obesity. Mechanistically, Nck2 deficiency promoted the induction of an adipocyte differentiation program and signaling by the PERK-eIF2α-ATF4 pathway in agreement with a role for the unfolded protein response in adipogenesis. These findings uncover Nck2 as a novel regulator of adipogenesis and that perturbation in its functionality contributes to adiposity-related metabolic disorders. Differential gene expression profile between epididymal white adipose tissue of Nck2-/- and Nck2+/+ mice by RNA sequencing (Illumina HiSEq 2000)
2016-07-01 | E-GEOD-63510 | biostudies-arrayexpress
Project description:White adipose tissue (WAT) is a key regulator of systemic energy metabolism, and impaired WAT plasticity characterized by enlargement of preexisting adipocytes associates with WAT dysfunction, obesity and metabolic complications. However, the mechanisms that retain proper adipose tissue plasticity required for metabolic fitness are unclear. Here, we comprehensively showed that adipocyte-specific DNA methylation, manifested in enhancers and CTCF sites, directs distal enhancer-mediated transcriptomic features required to conserve metabolic functions of white adipocytes. Particularly, genetic ablation of adipocyte Dnmt1, the major methylation writer, led to increased adiposity characterized by increased adipocyte hypertrophy along with reduced expansion of adipocyte precursors (APs). These effects of Dnmt1 deficiency provoked systemic hyperlipidemia and impaired energy metabolism both in lean and obese mice. Mechanistically, Dnmt1 deficiency abrogated mitochondrial bioenergetics by inhibiting mitochondrial fission and promoted aberrant lipid metabolism in adipocytes, rendering adipocyte hypertrophy and WAT dysfunction. Dnmt1-dependent DNA methylation prevented aberrant CTCF binding and, in turn, sustained the proper chromosome architecture to permit interactions between enhancer and dynamin-related protein gene Drp1 in adipocytes. Also, adipose DNMT1 expression inversely correlated with adiposity and markers of metabolic health, but positively correlated with AP-specific markers in obese human subjects. Thus, these findings support strategies utilizing Dnmt1 action on mitochondrial bioenergetics in adipocytes to combat obesity and related metabolic pathology.
2021-03-24 | GSE158944 | GEO
Project description:Obesity is a pandemic health problem with poor solutions, especially for targeted treatment. Here we develop a polycation-based nanomedicine to selectively target visceral adiposity, the more metabolically detrimental and manipulation-resistant fat. We demonstrated that the polycationic polymer polyamidoamine (PAMAM) generation 3 (P-G3) was specifically enriched in the visceral fat due to its high charge density when delivered intraperitoneally. Moreover, P-G3 treatment of obese mice inhibited visceral adiposity, increased energy expenditure, prevented obesity, and alleviated the associated metabolic dysfunctions. In vitro adipogenesis models and single-cell RNA sequencing (scRNA-seq) revealed that P-G3 paradoxically uncouples the defining function of adipocyte - lipid synthesis and storage - from adipocyte development to create unique “dwarf” adipocytes that possess normal adipocyte functions but are deficient in hypertrophic growth at least through synergistically modulating NAD and mTOR pathways. The visceral fat distribution of P-G3 was further enhanced by modifying P-G3 with cholesterol to form lipophilic nanoparticles, which were also effective in treating obesity. Our study highlights an unexpected strategy to tackle visceral adiposity and champions a new direction of exploring cationic nanomaterials for treating metabolic diseases.
2022-09-19 | GSE209819 | GEO
Project description:White adipose tissue (WAT) plays a central role in lipid storage and systemic energy, lipid, and glucose homeostasis. Understanding the intricacies of adipocyte formation could inform therapies for obesity and metabolic disorders. We have identified the POZ/BTB and AT Hook Containing Zinc Finger 1 (PATZ1) protein as an adipogenic transcription factor through an unbiased high-throughput cDNA screen for transcriptional modulators of adipogenesis. PATZ1 is expressed by both human and mouse adipocyte precursor cells (APCs) and adipocytes, and in cell models, PATZ1 expression promotes adipogenesis through a mechanism dependent on protein-protein interaction and DNA binding. Both adipocyte-specific and APC-specific ablation of PATZ1 in mice leads to decreased fat mass and hypertrophied adipocytes. Genome-wide PATZ1 DNA binding analyses using ChIP-Seq suggest PATZ1 facilitates adipogenesis through interactions with transcription factor machinery at the promoter regions of critical early adipogenic factors and histone modifiers. Purification of the PATZ1 complex showed that General Transcription Factor 2I (GTF2I) associates with PATZ1 in a differentiation-dependent manner. Downregulation of GTF2I levels during adipogenesis markedly augments PATZ1 adipogenic function, suggesting a repressive interaction between GTF2I and PATZ1. These findings identify PATZ1 as a regulator of both adiposity and adipocyte differentiation programs and advance our understanding of the complex transcriptional mechanisms underlying adipose tissue development and homeostasis.
2024-07-29 | GSE273320 | GEO
Project description:White adipose tissue (WAT) plays a central role in lipid storage and systemic energy, lipid, and glucose homeostasis. Understanding the intricacies of adipocyte formation could inform therapies for obesity and metabolic disorders. We have identified the POZ/BTB and AT Hook Containing Zinc Finger 1 (PATZ1) protein as an adipogenic transcription factor through an unbiased high-throughput cDNA screen for transcriptional modulators of adipogenesis. PATZ1 is expressed by both human and mouse adipocyte precursor cells (APCs) and adipocytes, and in cell models, PATZ1 expression promotes adipogenesis through a mechanism dependent on protein-protein interaction and DNA binding. Both adipocyte-specific and APC-specific ablation of PATZ1 in mice leads to decreased fat mass and hypertrophied adipocytes. Genome-wide PATZ1 DNA binding analyses using ChIP-Seq suggest PATZ1 facilitates adipogenesis through interactions with transcription factor machinery at the promoter regions of critical early adipogenic factors and histone modifiers. Purification of the PATZ1 complex showed that General Transcription Factor 2I (GTF2I) associates with PATZ1 in a differentiation-dependent manner. Downregulation of GTF2I levels during adipogenesis markedly augments PATZ1 adipogenic function, suggesting a repressive interaction between GTF2I and PATZ1. These findings identify PATZ1 as a regulator of both adiposity and adipocyte differentiation programs and advance our understanding of the complex transcriptional mechanisms underlying adipose tissue development and homeostasis.
2024-07-29 | GSE273319 | GEO
Project description:White adipose tissue (WAT) plays a central role in lipid storage and systemic energy, lipid, and glucose homeostasis. Understanding the intricacies of adipocyte formation could inform therapies for obesity and metabolic disorders. We have identified the POZ/BTB and AT Hook Containing Zinc Finger 1 (PATZ1) protein as an adipogenic transcription factor through an unbiased high-throughput cDNA screen for transcriptional modulators of adipogenesis. PATZ1 is expressed by both human and mouse adipocyte precursor cells (APCs) and adipocytes, and in cell models, PATZ1 expression promotes adipogenesis through a mechanism dependent on protein-protein interaction and DNA binding. Both adipocyte-specific and APC-specific ablation of PATZ1 in mice leads to decreased fat mass and hypertrophied adipocytes. Genome-wide PATZ1 DNA binding analyses using ChIP-Seq suggest PATZ1 facilitates adipogenesis through interactions with transcription factor machinery at the promoter regions of critical early adipogenic factors and histone modifiers. Purification of the PATZ1 complex showed that General Transcription Factor 2I (GTF2I) associates with PATZ1 in a differentiation-dependent manner. Downregulation of GTF2I levels during adipogenesis markedly augments PATZ1 adipogenic function, suggesting a repressive interaction between GTF2I and PATZ1. These findings identify PATZ1 as a regulator of both adiposity and adipocyte differentiation programs and advance our understanding of the complex transcriptional mechanisms underlying adipose tissue development and homeostasis.
2024-07-29 | GSE273318 | GEO
Project description:White adipose tissue (WAT) plays a central role in lipid storage and systemic energy, lipid, and glucose homeostasis. Understanding the intricacies of adipocyte formation could inform therapies for obesity and metabolic disorders. We have identified the POZ/BTB and AT Hook Containing Zinc Finger 1 (PATZ1) protein as an adipogenic transcription factor through an unbiased high-throughput cDNA screen for transcriptional modulators of adipogenesis. PATZ1 is expressed by both human and mouse adipocyte precursor cells (APCs) and adipocytes, and in cell models, PATZ1 expression promotes adipogenesis through a mechanism dependent on protein-protein interaction and DNA binding. Both adipocyte-specific and APC-specific ablation of PATZ1 in mice leads to decreased fat mass and hypertrophied adipocytes. Genome-wide PATZ1 DNA binding analyses using ChIP-Seq suggest PATZ1 facilitates adipogenesis through interactions with transcription factor machinery at the promoter regions of critical early adipogenic factors and histone modifiers. Purification of the PATZ1 complex showed that General Transcription Factor 2I (GTF2I) associates with PATZ1 in a differentiation-dependent manner. Downregulation of GTF2I levels during adipogenesis markedly augments PATZ1 adipogenic function, suggesting a repressive interaction between GTF2I and PATZ1. These findings identify PATZ1 as a regulator of both adiposity and adipocyte differentiation programs and advance our understanding of the complex transcriptional mechanisms underlying adipose tissue development and homeostasis.
2024-07-29 | GSE273317 | GEO
Project description:Aims: Adipocytes are critical cornerstones of energy metabolism. While obesity-induced adipocyte dysfunction is associated with insulin resistance and systemic metabolic disturbances, adipogenesis, the formation of new adipocytes and healthy adipose tissue expansion are associated with metabolic benefits. Understanding the molecular mechanisms governing adipogenesis is of great clinical potential to efficiently restore metabolic health in obesity. Here we investigate the role of Heart and neural crest derivatives-expressed protein 2 (HAND2) in adipogenesis. Methods: Human white adipose tissue (WAT) were collected in a cross-sectional study of 318 individuals. In vitro, for mechanistic experiments we used primary adipocytes from human and mice as well as human multipotent adipose derived stem (hMADS) cells. Gene silencing was performed using siRNA or genetic inactivation in primary adipocytes from LoxP mouse models with Cre-encoding mRNA. Adipogenesis efficiency was measured by OilRedO staining, qPCR and microarray. A combinatorial RNASeq approach was used to identify gene clusters regulated by HAND2. In vivo, we created a conditional adipocyte Hand2 deletion mouse model using Cre under control of the Adipoq promoter (HAND2AdipoqCRE). Results: We found that HAND2 is an obesity-linked white adipocyte transcription factor regulated by glucocorticoids that was required but insufficient for adipocyte differentiation in vitro. In a large cohort of humans with obesity, WAT HAND2 expression was correlated to body-mass-index (BMI). The HAND2 gene was enriched in white adipocytes compared to brown, induced early in differentiation and responded to DEX, a typical glucocorticoid receptor (GR, encoded by NR3C1) agonist. Silencing of NR3C1 in hMADS or deletion of GR in a transgenic conditional mouse model results in diminished HAND2 expression, establishing that adipocyte HAND2 is regulated by GCs via GR in vitro and in vivo. Furthermore, we identified gene clusters indirectly regulated by the GR-HAND2 pathway. Interestingly, silencing of HAND2 impaired adipocyte differentiation in hMADS and primary mouse adipocytes. However, a conditional adipocyte Hand2 deletion mouse model using Cre under control of the Adipoq promoter did not mirror these effects on adipose tissue differentiation, indicating that Hand2 was required at stages prior to Adipoq expression. Conclusion: In summary, our study identifies HAND2 as a novel obesity-linked adipocyte transcription factor, highlighting new mechanisms of GR-dependent adipogenesis in human and mice.
2021-02-26 | GSE148699 | GEO
Project description:Obesity has become a global health problem. Brown adipose tissue (BAT), specialized for energy expenditure through thermogenesis, potently counteracts obesity. Recently, BAT is also identified in human adults. We found that Lgr4 homozygous mutant (Lgr4m/m) mice display reduced adiposity and exhibit brown-like adipocytes in their WAT depots with higher expression of uncoupling protein 1 (Ucp1). Furthermore, Lgr4 ablation potentiates brown adipocyte differentiation from stromal vascular fraction (SVF) of epididymal WAT (eWAT) in vitro. We used microarrays to emxamine the gene expression profiles of the brown-like adipocytes differentiated from SVF of wild-type and Lgr4 mutant mice. We identified distinct gene expression profiles of these two groups. To demonstrate Lgr4 ablation can potentiate the differentiation of SVF from eWAT toward brown-like adipocytes in vitro, we isolated SVF from epididymal white adipose tissue (eWAT) of wild-type (WT) and Lgr4 mutant mice. We then plated SVF cells in 12-well plate, and differentiated them to brown adipocytes, followed by RNA extraction and hybridization with Affymetrix microarrays.
2013-11-07 | E-GEOD-47760 | biostudies-arrayexpress
Project description:Obesity has become a global health problem. Brown adipose tissue (BAT), specialized for energy expenditure through thermogenesis, potently counteracts obesity. Recently, BAT is also identified in human adults. We found that Lgr4 homozygous mutant (Lgr4m/m) mice display reduced adiposity and exhibit brown-like adipocytes in their WAT depots with higher expression of uncoupling protein 1 (Ucp1). Furthermore, Lgr4 ablation potentiates brown adipocyte differentiation from stromal vascular fraction (SVF) of epididymal WAT (eWAT) in vitro. We used microarrays to emxamine the gene expression profiles of the brown-like adipocytes differentiated from SVF of wild-type and Lgr4 mutant mice. We identified distinct gene expression profiles of these two groups.
2013-11-07 | GSE47760 | GEO