Sex specific pattern of adipose expansion, inflammation and dysfunction with short term high fat diet exposure

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Background While body mass index (BMI) and weight gain are commonly used indicators of metabolic disease risk, intrinsic features of adipose tissue function such as adipocyte hypertrophy and inflammation may serve as earlier and more accurate predictors of metabolic dysfunction. Sex specific responses in adipose function may lead to sex differences in how adiposity associates with metabolic disease. Objective This study aimed to determine the early sequence of events leading to adipose tissue dysfunction and metabolic inflammation in response to a high-fat diet (HFD), with a focus on sex-specific differences in adipose and immune responses during short-term high fat dietary exposure. Methods Male and female C57BL/6J mice were fed either a normal chow diet or HFD (60% fat) for 1, 2, 4, 6 weeks, or for 16 weeks, starting at 6 weeks of age. Adipose tissue mass, adipocyte size, glucose and insulin levels, inflammatory gene expression, and adipose tissue macrophage (ATM) populations were measured using immunohistochemistry, flow cytometry, gene expression, and metabolic assays. Serum and GWAT explant media proteomic evaluations were conducted using the Olink platform. Results HFD induced rapid adipose expansion in both sexes, but male mice exhibited greater weight gain, adipocyte hypertrophy, and insulin resistance over time. Males also demonstrated an earlier and more pronounced accumulation of pro-inflammatory CD11c + ATMs in gonadal adipose tissue, alongside increased inflammatory gene expression and inflammatory chemokines and cytokines. Female mice exhibited a delayed and less robust inflammatory response. Notably, metabolic dysfunction, including hyperinsulinemia, preceded inflammation, particularly in males. Conclusion Short term HFD induces sex-specific adipose tissue remodeling and metabolic dysfunction, with males showing earlier onset of both adipocyte hypertrophy and inflammation. These findings highlight the importance of sex as a biological variable in early metabolic disease development and suggest that insulin resistance may precede inflammation, which precedes metabolic dysfunction in the pathogenesis of adipose dysfunction.