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.
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.
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
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.
Project description:Most individuals do not maintain weight loss, and weight regain increases cardio-metabolic risk beyond that of obesity. Adipose inflammation directly contributes to insulin resistance; however, immune-related changes that occur with weight loss and weight regain are not well understood. Single cell RNA-sequencing was completed with CITE-sequencing and biological replicates to profile changes in murine immune subpopulations following obesity, weight loss, and weight cycling. Weight loss normalized glucose tolerance, however, type 2 immune cells did not repopulate adipose following weight loss. Many inflammatory populations persisted with weight loss and increased further following weight regain. Obesity drove T cell exhaustion and broad increases in antigen presentation, lipid handing, and inflammation that persisted with weight loss and weight cycling. This work provides critical groundwork for understanding the immunological causes of weight cycling-accelerated metabolic disease.