Selective remodelling of the adipose niche in obesity and weight loss [Xenium]

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. Spatial transcriptomics was carried out in subcutaneous abdominal AT from 4 people with obesity before and after marked WL (paired samples), and in 4 healthy lean controls. All molecular phenotyping was carried out after overnight fast. AT samples were obtained intraoperatively from morbidly obese individuals (BMI>35kg/m2) undergoing laparoscopic bariatric surgery (gastric bypass or gastric sleeve) and healthy controls (BMI<26kg/m2) undergoing non-bariatric laparoscopic abdominal surgery. Subcutaneous AT was collected from abdominal surgical incision sites. Follow up subcutaneous AT samples were collected from the peri-umbilical region using needle biopsy at >5 months after weight loss intervention. Whole AT samples were snap frozen at collection and stored at -80C for future use. Participants were unrelated, between 20-70 years of age, from a multi-ethnic background, and free from systemic illnesses not related to obesity. People with treated T2D were excluded because of potential effects of hypoglycaemic medications on AT metabolism. All participants gave informed consent. The study complies with all relevant ethical regulations and was approved by the London – City Road and Hampstead Research Ethics Committee, United Kingdom (reference 13/LO/0477).