2. Academic Validation
  3. A shift in PKM2 oligomeric state instructs adipocyte inflammatory potential

A shift in PKM2 oligomeric state instructs adipocyte inflammatory potential

  • JCI Insight. 2025 Nov 24;10(22):e185914. doi: 10.1172/jci.insight.185914.
Michelle Sma Damen 1 2,  Pablo C Alarcon 1 2 3 4,  Calvin C Chan 1 2 3 5 6,  Traci E Stankiewicz 1 2,  Hak Chung 1 2,  Keisuke Sawada 1 2 3 5,  Cassidy J Ulanowicz 1 2 3,  John Eom 1 2,  Jarren R Oates 1 2 3,  Jennifer L Wayland 1 2 3 5,  Jessica R Doll 1 2,  Rajib Mukherjee 1 7 8,  Miki Watanabe-Chailland 1 4 9,  Lindsey Romick-Rosendale 1 4 9,  Sara Szabo 1 9,  Michael A Helmrath 1 6 10,  Joan Sanchez-Gurmaches 1 7 8,  Maria E Moreno-Fernandez 1 2,  Senad Divanovic 1 2 3 5 11
Affiliations

Affiliations

  • 1 Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
  • 2 Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
  • 3 Immunology Graduate Program, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
  • 4 NMR Metabolomics Core, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
  • 5 Medical Scientist Training Program, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
  • 6 Center for Stem Cell & Organoid Medicine (CuSTOM).
  • 7 Division of Endocrinology.
  • 8 Division of Developmental Biology.
  • 9 Division of Pathology.
  • 10 Division of Pediatric General and Thoracic Surgery, and.
  • 11 Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
PMID: 41277555 DOI: 10.1172/jci.insight.185914
Abstract

Processes that promote white adipocyte inflammatory function remain incompletely defined. Here, we demonstrated that type I interferon-dependent (IFN-I-dependent) skewing of adipocyte glycolysis, nicotinamide adenine dinucleotide (NAD+) utilization, and Pyruvate Kinase isozyme M2 (PKM2) function may contribute to increased systemic and tissue inflammation and disease severity in obesity. Notably, chemical and/or genetic inhibition of glycolysis, the NAD+ salvage pathway, or PKM2 restricted IFN-I-dependent increase in adipocyte inflammatory cytokine production. Further, genetic or small molecule targeting of PKM2 function in vivo was sufficient to reduce systemic and tissue inflammation and Metabolic Disease severity in obese mice, in an adipocyte PKM2-dependent manner. Further, white adipose tissue of individuals living with obesity and Metabolic Disease, compared with metabolically healthy individuals with obesity, showed an increase in expression of inflammatory and metabolic genes, while small molecule targeting of PKM2 function contributed to reduced IFN-I-driven inflammatory cytokine production by primary human adipocytes. Together, our findings invoke the IFN-I/PKM2 axis as a potential target for modulating adipocyte dysregulated inflammation.

Keywords

Adipose tissue; Cytokines; Immunology; Inflammation; Metabolism; Obesity.

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