Metabolic surgery mitigates early kidney injury in obese youth with diabetes by suppressing mTORC1/JAK/STAT signaling
Abhijit S. Naik, et al.
Abhijit S. Naik, et al.
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Clinical Research and Public Health Metabolism Nephrology

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

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 We performed paired analyses, including metabolic profiling, kidney volume assessment, histological evaluation, and single-cell RNA sequencing (scRNA-seq), on kidney biopsies from 5 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 After 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. scRNA-seq in proximal tubule (PT) and thick ascending limb cells indicated repression of glycolysis, gluconeogenesis, and tricarboxylic acid (TCA) 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. Janus kinase/signal transducer and activator of transcription (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 nonsurgical interventions against obesity- and diabetes-associated kidney disease.FUNDING University of Washington with the American Diabetes Association, University of Michigan with Chan Zuckerberg Initiative, and Breakthrough T1D.

Authors

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

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Figure 9

Integrated signaling pathways regulating intrarenal mTORC1 and JAK/STAT signaling in response to reduced insulin, relative energy stress, and reduced circulating ligands that activate the JAK/STAT pathway.

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Integrated signaling pathways regulating intrarenal mTORC1 and JAK/STAT ...
Reduced insulin availability leads to diminished activation of Ras and PI3K, subsequently decreasing signaling through the Raf/MEK/ERK/RSK and Akt branches. Both ERK/RSK and Akt negatively regulate the TSC1/2 complex. Reduced ERK/RSK and Akt signaling enhances TSC1/2 activity, which attenuates activation of Rheb-GTP and consequently inhibits mTORC1, thereby suppressing cell growth and proliferation. Under conditions of lowered blood glucose and relative energy stress (elevated AMP/ATP ratio) post-VSG, AMPK can be activated and inhibits mTORC1 directly, as well as indirectly via activation of TSC1/2. mTORC1 can inhibit AMPK in a reciprocal feedback loop. AMPK activation further promotes FOXO3, which drives transcriptional programs that enhance autophagy, mitophagy, apoptosis, and ROS defense while suppressing metabolic activity. Thus, mTORC1 and AMPK/FOXO3 pathways exhibit opposing responses to energy and growth factor signals, coordinating anabolic and stress-adaptive cellular programs. Additionally, reduced levels of circulating cytokines, interleukins, prolactin (PRL), and growth hormone (GH) result in decreased activation of their respective receptors and the downstream intrarenal JAK/STAT signaling cascade. The JAK/STAT pathway can also interface with the Ras/MAPK and PI3K/Akt pathways (dashed horizontal line), further modulating the integrated cellular response. BioRender. Naik, A. (2025) https://BioRender.com/6fif35r PI3K, phosphatidylinositol-3-kinase; Akt, v-akt murine thymoma viral oncogene homolog 1; Ras, rat sarcoma virus oncogene homolog; Raf, rapidly accelerated fibrosarcoma; MEK, mitogen-activated protein kinase; ERK, extracellular signal–regulated kinase; RSK, ribosomal S6 kinase; mTORC1, mechanistic target of rapamycin complex 1; TSC1/2, tuberous sclerosis complex 1 and 2; Rheb, ras homolog enriched in brain; AMPK, AMP-activated protein kinase; FOXO3, forkhead box O3; AMP/ATP, adenosine monophosphate/adenosine triphosphate.