Gene-Environment Interactions in the Regulation of Obesity and Metabolic Disorders

Abstract

Background: Obesity and type 2 diabetes arise from gene-environment interactions. Matrix metalloproteinase 28 (MMP28) is an immune-modulating extracellular matrix protease. Previous studies have shown that Mmp28-/- mice reared under specific pathogen-free (SPF) conditions develop obesity, hepatic steatosis, and metabolic dysfunction, including elevated fasting blood glucose. Transferring SPF-housed Mmp28-/- mice to a conventional mouse room (CMR, low-barrier, richer microbial exposure) for 5 weeks partially reversed these metabolic abnormalities. In the present study, we aimed to investigate whether the development of obesity, hepatic steatosis, and metabolic dysfunction can be prevented by raising and maintaining the Mmp28-/- mice in CMR from birth. Methods: Male and female Mmp28-/- and wild-type (WT) C57BL/6J mice were reared in either SPF or CMR facilities on an identical chow diet. Phenotyping at about 30 weeks of age included body weight, food intake, indirect calorimetry for energy expenditure (EE), open field activity, fasting blood glucose and glucose tolerance tests, tail-cuff blood pressure, and liver histology. Hepatic bulk RNA-seq assessed differential gene expression by genotype, housing, and their interaction, followed by gene set enrichment analysis. Results: As previously found, in SPF, Mmp28-/- mice developed increased adiposity, impaired glucose tolerance with elevated fasting glycaemia, reduced EE, and hepatic steatosis versus WT. By contrast, Mmp28-/- mice housed from birth in CMR remained lean, normoglycemic and largely free of fatty liver, with higher EE and activity, resembling WT mice. Blood pressure showed a genotype-environment interaction where Mmp28-/- mice showed higher systolic and diastolic values in CMR than SPF-housed Mmp28-/- mice, whereas WT mice tended to show the opposite trends. Liver transcriptomics revealed genes involved in fatty acid β-oxidation and

mitochondrial catabolism were downregulated in SPF-housed Mmp28-/- mice, while genes related to inflammation and lipogenesis were upregulated. These transcriptomic changes are consistent with the observed obesity and metabolic dysfunction in these mice. Housing Mmp28-/- mice in CMR prevented these transcriptomic alterations, resulting in profiles comparable to those of WT mice. Taken together, these findings indicate that housing exerts a dominant effect on the metabolic and transcriptomic phenotypes of Mmp28-/- mice. Conclusions: The metabolic consequences of Mmp28 deletion are strongly influenced by the housing environment. Lifelong CMR exposure prevented obesity, glucose dysregulation and hepatic steatosis observed under SPF conditions. These effects may involve environment-driven immune and metabolic adaptations, with a possible contribution of microbiota-related mechanisms inferred from previous studies, although these were not directly assessed in this study. Overall, these findings highlight the critical role of environmental context in metabolic genetics and support microbiome-targeted or environment-mimetic strategies to mitigate obesity risk in genetically susceptible individuals.