ABSTRACT: Biological sex impacts on the prevalence, incidence, and severity of metabolic disorders associated to obesity, particularly type 2 diabetes. To elucidate the influence of sex on metabolic diseases during obesity progression, we conducted a comprehensive metabolic and transcriptomic analysis aiming to unravel the dynamics of metabolic adaptations to an obesogenic diet in both female and male mice.Males fed high-fat diet (HFD) displayed a progressive increase in glucose intolerance, fasting hyperglycemia, hyperinsulinemia, and impaired glucose-dependent insulin secretion, concomitant with increased adiposity and liver steatosis. Interestingly, females displayed a comparable increase in relative adiposity, but exhibited milder glucose intolerance, hyperglycemia, and lower insulin levels, which remained responsive to glucose even at advanced stages.These phenotypic disparities were mirrored by divergent gene expression profiles in liver and visceral white adipose tissue in males and females in response to HFD. Notably, variations in the regulation of diverse pathways and gene categories were observed between sexes in response to HFD, including differential regulation of genes within the same categories. Intriguingly, genes exhibiting sex dimorphism under regular dietary conditions were proportionally highly regulated in response to HFD. Indeed, a substantial part of the liver genes with sex dimorphism in regular diet lost their sex bias in animals in HFD, and this effect was even more pronounced in white adipose tissue, uncovering a substantial loss of sex dimorphism in the gene profile in liver and visceral white adipose tissue in response to HFD. These results indicate that there are different gene sets regulated in a sex-specific manner in response to metabolic perturbations, and metabolic disturbances are associated with a loss of sexually dimorphic gene expression in liver and adipose tissue in mice. These findings suggest that the sex bias gene expression profile is pivotal for maintaining metabolic homeostasis in both sexes, which may have broad implications in metabolic disturbances. Moreover, these sex-specific divergences highlight the importance of considering sex as a crucial factor when interpreting data related to metabolic disturbances.
