Metabolic dysfunction-associated fatty liver disease (MAFLD) represents a growing cause of mortality and morbidity and encompasses a spectrum of liver pathologies. Although dozens of preclinical models have been developed to recapitulate stages of MAFLD, few achieve fibrosis using an experimental design that mimics human pathogenesis. We sought to clarify whether the combination of thermoneutral (T_N) housing and consumption of a classical Western diet (WD) would accelerate the onset and progression of MAFLD. Male and female C57Bl/6J mice were fed a nutrient-matched low-fat control or Western diet (WD) for 16 wk. Mice were housed with littermates at either standard temperature (T_S; 22°C) or thermoneutral-like conditions (T_N; ∼29°C). Male, but not female, mice housed at T_N and fed a WD were significantly heavier than T_S-housed control animals. WD-fed mice housed under T_N conditions had lower levels of circulating glucose compared with T_S mice; however, there were select but minimal differences in other circulating markers. Although WD-fed T_N males had higher liver enzyme and higher liver triglyceride levels, no differences in markers of liver injury or hepatic lipid accumulation were observed in females. Housing temperature had little effect on histopathological scoring of MAFLD progression in males; however, although female mice retained a level of protection, WD-T_N conditions trended toward a worsened hepatic phenotype, which was associated with higher macrophage transcript expression and content. Our results indicate that interventions coupling T_N housing and WD-induced MAFLD should be longer than 16 wk to accelerate hepatic steatosis and increase inflammation in both sexes of mice.NEW & NOTEWORTHY Mouse models leading to accelerated fatty liver onset are a useful translational tool. Here we show that coupling thermoneutral-like housing and Western diet feeding in mice for 16 wk does not lead to significant disease progression in either sex, though the molecular phenotype indicates priming of immune-related and fibrotic pathways.

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