Selective remodelling of the adipose niche in obesity and weight loss

Antonio M. A. Miranda, Liam McAllan, Guianfranco Mazzei, Ivan Andrew, Iona Davies, Meryem Ertugrul, Julia Kenkre, Hiromi Kudo, Joana Carrelha, Bhavik Patel, Sophie Newton, Weihua Zhang, Alice Pollard, Amy Cross, Oliver McCallion, Mikyung Jang, Ka Lok Choi, Scarlett Brown, Yasmin Rasool, Marco Adamo, Mohamed Elkalaawy, Andrew Jenkinson, Borzoueh Mohammadi, Majid Hashemi, Robert Goldin, Laurence Game, Joanna Hester, Fadi Issa, Dylan G. Ryan, Patricia Ortega, Ahmed R. Ahmed, Rachel L. Batterham, John C. Chambers, Jaspal S. Kooner, Damir Baranasic, Michela Noseda, Tricia Tan and William R. Scott ()
Additional contact information
Antonio M. A. Miranda: Imperial College London
Liam McAllan: Imperial College London
Guianfranco Mazzei: Imperial College London
Ivan Andrew: Imperial College London
Iona Davies: Imperial College London
Meryem Ertugrul: Imperial College London
Julia Kenkre: Imperial College London
Hiromi Kudo: Imperial College London
Joana Carrelha: Imperial College London
Bhavik Patel: MRC Laboratory of Medical Sciences
Sophie Newton: Imperial College London
Weihua Zhang: Imperial College London
Alice Pollard: Imperial College London
Amy Cross: University of Oxford
Oliver McCallion: University of Oxford
Mikyung Jang: Imperial College London
Ka Lok Choi: Imperial College London
Scarlett Brown: Imperial College London
Yasmin Rasool: Imperial College London
Marco Adamo: University College London Hospitals
Mohamed Elkalaawy: University College London Hospitals
Andrew Jenkinson: University College London Hospitals
Borzoueh Mohammadi: University College London Hospitals
Majid Hashemi: University College London Hospitals
Robert Goldin: Imperial College Healthcare NHS Trust
Laurence Game: Imperial College London
Joanna Hester: University of Oxford
Fadi Issa: University of Oxford
Dylan G. Ryan: University of Cambridge
Patricia Ortega: Imperial College Healthcare NHS Trust
Ahmed R. Ahmed: Imperial College Healthcare NHS Trust
Rachel L. Batterham: University College London Hospitals
John C. Chambers: Imperial College Healthcare NHS Trust
Jaspal S. Kooner: Imperial College Healthcare NHS Trust
Damir Baranasic: Imperial College London
Michela Noseda: Imperial College London
Tricia Tan: Imperial College London
William R. Scott: Imperial College London

Nature, 2025, vol. 644, issue 8077, 769-779

Abstract: Abstract Weight loss significantly improves metabolic and cardiovascular health in people with obesity1–3. The remodelling of adipose tissue (AT) is central to these varied and important clinical effects4. However, surprisingly little is known about the underlying mechanisms, presenting a barrier to treatment advances. Here we report a spatially resolved single-nucleus atlas (comprising 171,247 cells from 70 people) investigating the cell types, molecular events and regulatory factors that reshape human AT, and thus metabolic health, in obesity and therapeutic weight loss. We discover selective vulnerability to senescence in metabolic, precursor and vascular cells and reveal that 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 AT dysfunction and its reversal by weight loss and are a key resource for mechanistic and therapeutic exploration.

Date: 2025
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DOI: 10.1038/s41586-025-09233-2

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