Oral Presentation ESA-SRB-ANZOS 2025 in conjunction with ENSA

Disrupting Polymerase Gamma Exonuclease in Adipose Tissue Protects Mice from Obesity and Related Complications (129310)

Moran Zhou 1 2 , Simon T Bond 1 2 3 , Christine Yang 1 , Aaron Jurrjens 1 , Darren C Henstridge 1 4 , Yingying Liu 1 , Lindsay E Wu 5 , Peter Miekle 1 2 , Brian G Drew 1 2 3
  1. Baker Heart & Diabetes Institute | University of Melbourne, Bentleigh East, VIC, Australia
  2. Baker Department of Cardiometabolic Health, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, VIC
  3. Central Clinical School, Monash University, Melbourne, VIC
  4. School of Health Sciences, University of Tasmania, Launceston, TAS
  5. School of Biomedical Sciences, University of New South Wales, Sydney, NSW

The risk of obesity-related complications such as diabetes, MASLD, cardiovascular disease and metabolic syndrome increases with mitochondrial dysfunction. Models of mitochondrial dysfunction such as polymerase gamma (PolG) mutator mice show lipodystrophy with lipotoxicity, despite reduced adiposity (Ross et al., 2025; Trifunovic et al., 2004). As the sole mitochondrial DNA (mtDNA) polymerase, PolG replicates, proofreads and repairs mtDNA. PolG mutation in PolG mutator mice impairs mtDNA maintenance, allowing mutations and deletions to accumulate. Subsequent mitochondrial dysfunction disturbs adipose metabolism, highlighting the necessity of mtDNA integrity. However, it is unknown whether adipose dysfunction in whole-body mitochondrial disorders mainly arises from mtDNA mutations in adipose tissue, or secondary to mutations of non-adipose tissues. Aiming to resolve this, we generated an adipose-specific exonuclease-deficient PolG mutator (PolG-AdipoQ) mouse model.

Here, we demonstrate that PolG-AdipoQ mice were resistant to weight gain with reduced fat mass and preserved lean mass compared to wildtype C57BL/6J mice when aged to 2 years. Moreover, PolG-AdipoQ mice fed a high fat diet (HFD) diet were resistant to adipocyte hypertrophy. Obesity resistance was likely due to increased energy expenditure from adipose browning, as Ucp1 was upregulated in PolG-AdipoQ mice. These mice also displayed elevated gene expression of Gdf15 and Fgf21 – mitokines of the mitochondrial integrated stress response – and were likely responsible for the enhanced thermogenesis. PolG-AdipoQ mice on HFD were also resistant to glucose intolerance, with increased physical activity and energy expenditure compared to wildtype mice. Lipidomic analyses further showed reduced triglyceride accumulation in the livers of PolG-AdipoQ mice fed HFD for 17 weeks. These results indicate that exonuclease-deficient PolG in adipose tissue protects against obesity and its metabolic complications. In conclusion, our findings suggest that mild mitochondrial stress in adipocytes may hormetically condition mitochondria and/or increase energy expenditure, preventing obesity in mice

  1. Ross, J.M., Kim, A., Berthod, K., Branca, R.M., Olin, M., Pichardo-Casas, I., Lehtiö, J., Björkhem, I., Sinclair, D.A., Olson, L., Coppotelli, G., 2025. Mitochondrial Dysfunction Induces Hepatic Lipid Accumulation and Inflammatory Responses in mtDNA Mutator Mice. https://doi.org/10.1101/2025.04.25.650453
  2. Trifunovic, A., Wredenberg, A., Falkenberg, M., Spelbrink, J.N., Rovio, A.T., Bruder, C.E., Bohlooly-Y, M., Gidlöf, S., Oldfors, A., Wibom, R., Törnell, J., Jacobs, H.T., Larsson, N.-G., 2004. Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature 429, 417–423. https://doi.org/10.1038/nature02517