Selective remodelling of the adipose niche in obesity and weight loss [Xenium]
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ABSTRACT:
PROVIDER: PRJNA1256507 | ENA |
REPOSITORIES: ENA
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Project description:Weight loss significantly improves metabolic and cardiovascular health in people with obesity. Adipose tissue remodelling is central to these varied and important clinical effects. However surprisingly little is known about the underlying mechanisms, presenting a barrier to treatment advances. Here we report a spatially resolved single nucleus atlas (171,247 cells, 70 people) investigating the cell types, molecular events and regulatory factors that reshape human adipose tissues, and thus metabolic health, in obesity and therapeutic weight loss. We discover selective vulnerability to senescence in metabolic, precursor and vascular cells and reveal senescence is potently reversed by weight loss. We define gene regulatory mechanisms and tissue signals that may drive a degenerative cycle of senescence, tissue injury and metabolic dysfunction. We find that weight loss reduces adipocyte hypertrophy and biomechanical constraint pathways, activating global metabolic flux and bioenergetic substrate cycles that may mediate systemic improvements in metabolic health. In the immune compartment, we demonstrate that weight loss represses obesity-induced macrophage infiltration but does not completely reverse activation, leaving these cells primed to trigger potential weight regain and worsen metabolic dysfunction. Throughout, we map cells to tissue niches to understand the collective determinants of tissue injury and recovery. Overall, our complementary single nucleus and spatial datasets offer unprecedented insights into the basis of obese adipose tissue dysfunction and its reversal by weight loss, and a key resource for mechanistic and therapeutic exploration.
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Project description:Selective remodelling of the adipose niche in obesity and weight loss [snRNA-Seq]
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Project description:Weight loss significantly improves metabolic and cardiovascular health in people with obesity. Adipose tissue remodelling is central to these varied and important clinical effects. However surprisingly little is known about the underlying mechanisms, presenting a barrier to treatment advances. Here we report a spatially resolved single nucleus atlas (171,247 cells, 70 people) investigating the cell types, molecular events and regulatory factors that reshape human adipose tissues, and thus metabolic health, in obesity and therapeutic weight loss. We discover selective vulnerability to senescence in metabolic, precursor and vascular cells and reveal senescence is potently reversed by weight loss. We define gene regulatory mechanisms and tissue signals that may drive a degenerative cycle of senescence, tissue injury and metabolic dysfunction. We find that weight loss reduces adipocyte hypertrophy and biomechanical constraint pathways, activating global metabolic flux and bioenergetic substrate cycles that may mediate systemic improvements in metabolic health. In the immune compartment, we demonstrate that weight loss represses obesity-induced macrophage infiltration but does not completely reverse activation, leaving these cells primed to trigger potential weight regain and worsen metabolic dysfunction. Throughout, we map cells to tissue niches to understand the collective determinants of tissue injury and recovery. Overall, our complementary single nucleus and spatial datasets offer unprecedented insights into the basis of obese adipose tissue dysfunction and its reversal by weight loss, and a key resource for mechanistic and therapeutic exploration.
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Project description:Interactions between mutant cells and their environment play a key role in determining cancer susceptibility. However, our understanding of how the pre-cancerous microenvironment contributes to early tumorigenesis remains limited. Here, we show that newly emerging tumours at their most incipient stages shape their microenvironment in a critical process that determines their survival. Analysis of nascent squamous tumours in the upper gastrointestinal tract of the mouse reveals that the stress response of early tumour cells instructs the underlying mesenchyme to form a supportive “pre-cancerous niche”, which dictates the long-term outcome of epithelial lesions. Stimulated fibroblasts beneath emerging tumours activate a wound healing response that triggers a dramatic remodelling of the underlying extracellular matrix, resulting in the formation of a fibronectin-rich stromal scaffold that promotes tumour growth. Functional heterotypic 3D culture assays and in vivo grafting experiments, combining carcinogen-free healthy epithelium and tumour derived stroma, demonstrate that the pre-cancerous niche alone is sufficient to confer tumour properties to normal epithelial cells. We propose a model where both mutations and the stromal response to genetic stress together define the likelihood of early tumours to persist and progress towards more advanced disease stages.
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Project description:The hypothesis tested in the present study was The effect fo weight loss by dietary intervention with very low calorie diet on colorectal inflammatory genes and genepathways. The study results have shown that a 10% weight loss in obese women down-regulated inflammatory and cancer gene pathways. In addition there was downregulation of transcription factors known to play an important role in colorectal cancer. Total RNA obtained from colorectal mucosal biopsy samples
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Project description:The hypothesis tested in the present study was The effect fo weight loss by dietary intervention with very low calorie diet on colorectal inflammatory genes and genepathways. The study results have shown that a 10% weight loss in obese women down-regulated inflammatory and cancer gene pathways. In addition there was downregulation of transcription factors known to play an important role in colorectal cancer.
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