Metabolic surgery mitigates early kidney injury in obese youth with diabetes by suppressing mTORC1/JAK–STAT signaling

Background Youth with type 2 diabetes (T2D) and severe obesity face high risk of diabetic kidney disease, which metabolic bariatric surgery (MBS) can mitigate. This study explores structural and molecular changes in kidneys after vertical sleeve gastrectomy (VSG), a form of MBS. Methods Paired analyses, including metabolic profiling, kidney volume assessment, histological evaluation, and single-cell RNA sequencing (scRNAseq) on kidney biopsies from five youth with T2D and obesity pre- and 12 months post-VSG in the IMPROVE-T2D (Impact of Metabolic surgery on Pancreatic, Renal and cardiOVascular hEalth in youth with T2D) cohort. Circulating proteomics with kidney transcriptomics, were linked using data from an independent cohort of youth with obesity, with or without T2D, undergoing MBS in Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS, n=64). Results Post-VSG, participants lost weight and had improvements in insulin sensitivity and metabolic parameters. Kidney changes included reduced renal hyperfiltration, total kidney volume, mesangial matrix area, and microalbuminuria. scRNAseq in proximal tubule (PT) and thick ascending limb cells indicated repression of glycolysis, gluconeogenesis, and tricarboxylic acid cycle genes, with upregulation of AMP-activated protein kinase (AMPK) and Forkhead box O3 (FOXO3). Decreased metabolic signaling aligned with reduced ribosomal phosphorylated S6K (pS6K), suggesting attenuated mTORC1 activity. JAK-STAT pathway activation in PT was diminished, correlating with lower circulating ligands from Teen-LABS proteomic data. Conclusion MBS/VSG prompts kidney molecular adaptations, providing potential targets for non-surgical interventions against obesity- and diabetes-associated kidney disease.

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Journal
Journal of Clinical Investigation
Published
2026-02-03
DOI
https://doi.org/10.1172/jci198545
Primary Topic
Chronic Kidney Disease and Diabetes
Type
article
Field-Weighted Citation Impact
0.00

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article

Metabolic surgery mitigates early kidney injury in obese youth with diabetes by suppressing mTORC1/JAK–STAT signaling

Ye Ji Choi, Hailey E Hampson, Phoom Narongkiatikhun, FADHL ALAKWAA et al.
Journal of Clinical Investigation
Chronic Kidney Disease and Diabetes
article

Metabolic surgery mitigates early kidney injury in obese youth with diabetes by suppressing mTORC1/JAK–STAT signaling

Ye Ji Choi, Hailey E Hampson, Phoom Narongkiatikhun, FADHL ALAKWAA, Cathy Smith, Abhijit Naik, Ken Inoki, Yusuke Okabayashi, Swayam Prakash Srivastava, Francesca Annese, Jesse A. Goodrich, Kalie L. Tommerdahl, Patricia Ladd, Tyler Dobbs, Jeffrey A. Beamish, Melanie Green Cree, Edgar A. Otto, Megan Kelsey, Justin R. Ryder, Matthias Kretzler, Kareem Al-Fagih, Kristen J. Nadeau, Phillip J. McCown, Laura Pyle, Jeffrey B. Hodgin, Victor G. Puelles, Jenna Ferrence-Salo, Thomas H. Inge, John Hartman, Pottumarthi Prasad, Jennifer A. Schaub, Frank C. Brosius, Daniël H. van Raalte, Viji Nair, Petter Bjornstad, Sean Eddy, Shota Yoshida, Robert G. Nelson, Long Yuan, Subramaniam Pennathur
article en

Abstract

Background Youth with type 2 diabetes (T2D) and severe obesity face high risk of diabetic kidney disease, which metabolic bariatric surgery (MBS) can mitigate. This study explores structural and molecular changes in kidneys after vertical sleeve gastrectomy (VSG), a form of MBS. Methods Paired analyses, including metabolic profiling, kidney volume assessment, histological evaluation, and single-cell RNA sequencing (scRNAseq) on kidney biopsies from five youth with T2D and obesity pre- and 12 months post-VSG in the IMPROVE-T2D (Impact of Metabolic surgery on Pancreatic, Renal and cardiOVascular hEalth in youth with T2D) cohort. Circulating proteomics with kidney transcriptomics, were linked using data from an independent cohort of youth with obesity, with or without T2D, undergoing MBS in Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS, n=64). Results Post-VSG, participants lost weight and had improvements in insulin sensitivity and metabolic parameters. Kidney changes included reduced renal hyperfiltration, total kidney volume, mesangial matrix area, and microalbuminuria. scRNAseq in proximal tubule (PT) and thick ascending limb cells indicated repression of glycolysis, gluconeogenesis, and tricarboxylic acid cycle genes, with upregulation of AMP-activated protein kinase (AMPK) and Forkhead box O3 (FOXO3). Decreased metabolic signaling aligned with reduced ribosomal phosphorylated S6K (pS6K), suggesting attenuated mTORC1 activity. JAK-STAT pathway activation in PT was diminished, correlating with lower circulating ligands from Teen-LABS proteomic data. Conclusion MBS/VSG prompts kidney molecular adaptations, providing potential targets for non-surgical interventions against obesity- and diabetes-associated kidney disease.

Journal of Clinical Investigation
University of Southern California (US), NorthShore University HealthSystem (US), Johns Hopkins University (US), Universität Hamburg (DE), University of Washington (US), University of Michigan (US), Johns Hopkins Medicine (US), University Medical Center Hamburg-Eppendorf (DE), Lurie Children's Hospital (US), Amsterdam University Medical Centers (NL), University of Colorado Anschutz Medical Campus (US), University of Bari Aldo Moro (IT), University of Amsterdam (NL)
American Diabetes Association, American Heart Association, amfAR, The Foundation for AIDS Research, American Society of Nephrology, Amgen, Bristol-Myers Squibb, Eli Lilly and Company, AstraZeneca, Sanofi, Life Technologies Corporation, Boettcher Foundation, Gilead Sciences, Nephcure Foundation, Alexion Pharmaceuticals, University of Washington, A. Alfred Taubman Medical Research Institute, Regeneron Pharmaceuticals, Seattle Children's Research Institute, Children’s Hospital of Wisconsin Research Institute, Horizon Pharma, Georgia Clinical and Translational Science Alliance, Moderna, Angion, European Commission, Novo Nordisk, National Institutes of Health, Genentech, Anschutz Medical Campus, University of Colorado, National Heart, Lung, and Blood Institute, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Advancing Translational Sciences
Good health and well-being
Openalex Percentile: Top 65%
Chronic Kidney Disease and Diabetes
DOIOpen Access PDFOpenAlex
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