Thermoneutrality Accelerates a Distinctive Metabolic Dysfunction–Associated Steatohepatitis Phenotype in a Diet-Induced Male Mouse Model With Similarities to Human Disease

@article{leke2026thermoneutrality,
  title = {{Thermoneutrality Accelerates a Distinctive Metabolic Dysfunction–Associated Steatohepatitis Phenotype in a Diet-Induced Male Mouse Model With Similarities to Human Disease}},
  author = {Renata Leke and Jennifer Y. Tan and Stephanie Ling and Misha Siddiqui and Dorota Kakol-Palm and Anna Lindblom and Anne-Christine Andréasson and Giovanni Pellegrini and Magnus Söderberg and Natalie Van Zuydam and David Baker and Kristina Wallenius and Daniel Lindén and Bader Zarrouki},
  journal = {Cellular and Molecular Gastroenterology and Hepatology},
  year = {2026},
  month = aug,
  doi = {10.1016/j.jcmgh.2026.101866},
  url = {https://doi.org/10.1016/j.jcmgh.2026.101866},
  note = {CC BY-NC-ND 4.0},
}

TY  - JOUR
TI  - Thermoneutrality Accelerates a Distinctive Metabolic Dysfunction–Associated Steatohepatitis Phenotype in a Diet-Induced Male Mouse Model With Similarities to Human Disease
AU  - Renata Leke
AU  - Jennifer Y. Tan
AU  - Stephanie Ling
AU  - Misha Siddiqui
AU  - Dorota Kakol-Palm
AU  - Anna Lindblom
AU  - Anne-Christine Andréasson
AU  - Giovanni Pellegrini
AU  - Magnus Söderberg
AU  - Natalie Van Zuydam
AU  - David Baker
AU  - Kristina Wallenius
AU  - Daniel Lindén
AU  - Bader Zarrouki
PY  - 2026
DA  - 2026/08/27
JO  - Cellular and Molecular Gastroenterology and Hepatology
DO  - 10.1016/j.jcmgh.2026.101866
UR  - https://doi.org/10.1016/j.jcmgh.2026.101866
AB  - Background & Aims: Metabolic dysfunction–associated steatohepatitis is a prevalent chronic liver disease characterized by steatosis, inflammation, and hepatocyte damage, with or without fibrosis. Robust preclinical models that represent the clinical features of metabolic dysfunction–associated steatohepatitis are critical for drug development. We aimed to examine the effects of 2 widely used Western-type diets and thermoneutral housing on the induction of metabolic dysfunction–associated steatohepatitis and liver fibrosis in mice.  Methods: Male mice were fed either a Gubra-Amylin metabolic dysfunction–associated steatohepatitis or Western non–trans fat diet and were housed at standard room temperature (21 °C) for a period of 25, 33, or 46 weeks or at thermoneutrality (30 °C) for 25 weeks. Liver histology, transcriptome profiling, and in situ imaging cytometry were applied to analyze the differences between the models.  Results: Liver inflammation and hepatocyte damage were increased by housing mice at thermoneutrality. Remarkably, mice housed at thermoneutrality developed liver fibrosis after 25 weeks of diet feeding, reaching a degree of extracellular matrix deposition equivalent to the levels that required 46 weeks of diet feeding at standard temperature. Thermoneutral housing enhanced the expression of genes related to extracellular matrix organization and inflammatory pathways, demonstrating higher similarity to human metabolic dysfunction–associated steatohepatitis. This model was also characterized by distinctive hepatic immune cell infiltration and greater cell–cell interactions, compared with housing at standard temperatures.  Conclusions: Housing diet-induced metabolic dysfunction–associated steatohepatitis mice at thermoneutrality accelerated fibrosis onset and induced increased disease severity. Phenotypically and transcriptionally, this mouse model showed greater similarity to human metabolic dysfunction–associated steatohepatitis. In addition, mice with metabolic dysfunction–associated steatohepatitis at thermoneutrality developed a distinct and enhanced hepatic innate and adaptive immune response.
SN  - 2352-345X
ER  -