Sex Differences in Dietary-Induced Liver Steatosis and Insulin Receptor-Related Signaling in Aged Mice Lacking Serotonin Transporter

Sex differences remain largely underexplored in metabolic disorders, particularly in the context of genetic predisposition to type 2 diabetes, the impact of aging, and environmental factors such as exposure to high-caloric diets. Previous studies using serotonin transporter (SERT)-knockout (SERT-KO) mice, which recapitulate metabolic conditions related to the lowered function of this transporter in humans, revealed an aggravated negative response of these mutants to housing on a high-fat/sugar 'Western diet' (WD). However, the role of sex in SERT-KO mice has not yet been studied. Available human and animal data suggest the differential regulation of insulin receptor-mediated signaling in males and females, which can be altered with aging. This study aimed to compare fat accumulation, blood biochemical changes, glucose tolerance, and insulin receptor (IR)-related signaling in the liver and various brain structures of 12-month-old male and female SERT-KO mice fed WD for 21 days. Relative to the dietary-unchallenged group and their wild-type (WT) littermates, WD-fed mutants of both sexes displayed markedly increased fat accumulation and impaired glucose and insulin tolerance. Body mass increase was more prominent in females than in males. The two sexes revealed a similar suppression of the gene expression of isoforms A and B of IR but distinct expression of IR-related factors. IR-related genes such as <i>Cd36</i>, <i>Enpp</i>, <i>Ptpn1</i>, <i>Cyp4a14</i>, <i>Acsl1</i>, and <i>Pten</i> showed differential expression between male and female SERT-KO mice fed WD. Several differences in gene expression were also found between the WT groups of the two sexes. Overall, the manifestations of hepatic steatosis, insulin resistance, and glucose tolerance were similar between the age groups of animals, whereas the gene expression of IR-related regulation differed between the groups. We conclude that aging and genetic absence of the serotonin transporter likely override sex differences in the end effects of WD challenge, while molecular mechanisms of adaptation of IR-mediated signaling are distinct between male and female SERT-KO mice fed WD.