Sex-Specific Effect of a High-Energy Diet on Body Composition, Gut Microbiota, and Inflammatory Markers in Rats

<b>Background/Objectives</b>: A high-energy-density (HED) diet promotes body weight gain, fat accumulation, and gut dysbiosis, contributing to obesity. The aim of this study was to characterize the initial response to HED diet consumption, as well as identify any sex differences in body composition, systemic inflammation, gut microbiome, and fecal fat excretion in rats. <b>Methods</b>: Male and female Sprague-Dawley rats were fed a low-energy-density (LED) diet for 10 days and were then switched to an HED diet for four weeks. Food intake, body weight, and body composition were measured routinely. Serum samples were collected to measure inflammatory cytokines/chemokines. Fecal samples were collected for microbiome analysis and lipid content. <b>Results</b>: After the HED diet, all rats gained body weight and fat mass, with males exhibiting increased susceptibility to weight gain. Males displayed either a diet-induced obesity phenotype (DIO-P) or a diet-resistant (DR) phenotype, as characterized by their differential body weight gain. Males showed elevated TGF-β levels, while females exhibited increases in Interferon gamma-inducible protein 10 (IP-10), regulated on activation, normal T cell expressed and secreted (RANTES) protein, and basic fibroblast growth factor (FGFb). Changes in gut microbiota composition revealed a reduction in beneficial species, like <i>Bacteroides uniformis</i> and <i>Parabacteroides distasonis</i>, and an increase in species such as <i>Akkermansia muciniphila</i>. Sex differences in fat metabolism were shown in the greater fecal fat excretion observed in males. <b>Conclusions</b>: Our study demonstrates that short-term consumption of a high-energy diet elicits notable sex-specific differences in body weight, body composition, inflammatory markers, gut microbiota, and fat excretion in Sprague-Dawley rats. While we recognize that this study has a small sample size and a short-term intervention, our findings highlight the critical role of sex as a biological variable in diet-induced obesity research.