Rapid Remodeling of Human White Adipose Tissue Following Bariatric Surgery

SUMMARY Bariatric surgery induces profound weight loss and improvement of obesity-associated metabolic dysfunction. Recent studies have shown that adipose tissue undergoes remodeling after weight loss, characterized by a reduction in proinflammatory immune cells, increased vascularization, and a shift in the adipocyte transcriptome, but these studies focused on time points long after surgery. We performed single nucleus RNA-seq (snRNA-seq) in subcutaneous white adipose tissue (SAT) samples from subjects with obesity undergoing bariatric surgery, collected at baseline and at one, six, and twelve months after surgery. We identify profound remodeling of SAT within the first month after surgery, characterized by a surge in lipid-associated macrophages and sharp reductions in specific populations of adipocytes, adipose stromal and progenitor cells (ASPCs), and endothelial cells. Transcriptional profiles strongly suggest that some adipocytes undergo apoptosis soon after surgery, while new adipocytes are generated by de novo differentiation. Mechanistically, the data are consistent with a model whereby coordinated early loss of a hedgehog signaling axis between endothelial cells and an anti-adipogenic population of ASPCs known as adipose regulatory cells (Aregs; ASPCPTCH2) enables a transient burst of adipogenesis to occur. Interestingly, very few of these early features seen in human subjects are represented in a mouse model of surgical weight loss. Competing Interest Statement EDR is on the Scientific Advisory Board of Source Bio, Inc. RJS has received research support from Fractyl, AstraZeneca, Congruence Therapeutics, Eli Lilly, Diasome, and Amgen. RJS has served as a paid consultant for Novo Nordisk, Eli Lilly, CinRx, Crinetics, Amgen, Helicore, Gallant, General Medicines, Abbvie, Protagonist Therapeutics, Aardvark, Zealand, Alveus and Nuanced Health. RJS holds equity in Nuanced Health, Coronation Bio, Eccogene, Fractyl, and Rewind. JJL and LLJ are employees of Novartis. Footnotes Lead Contact: Evan Rosen (erosen{at}bidmc.harvard.edu) Figure 1 and Supplemental Figure 2 revised to reflect correct cell type color coding.