O hipotireoidismo dessincroniza o relógio circadiano do jejuno e a ritmicidade das proteínas envolvidas na absorção de nutrientes em camundongos C57BL/6J fêmeas: possíveis repercussões na adiposidade e no perfil lipídico diário

Abstract

Hypothyroidism is a thyroid hormone dysfunction that causes numerous changes in basal metabolism and thermoregulation. Therefore, hypothyroidism is often associated with body weight gain and changes in serum lipid concentration, and there is a correlation between hypothyroidism and metabolic syndrome. However, its effects vary between species, and even between individuals or sex, so that there is still a lot of contradiction regarding the alterations related to body composition and metabolism under hypothyroid conditions. Furthermore, we recently demonstrated that hypothyroidism desynchronizes the circadian clock of different tissues, which could contribute to the wide number of changes related to the balance of energy metabolism, considering the great importance of circadian rhythmicity for metabolic homeostasis and for the organism as a whole. This study aimed to evaluate the effects of hypothyroidism over the circadian rhythmicity of the intestinal biological clock and transporters responsible for the absorption of nutrients by the small intestine, as well as body weight, adiposity and the daily lipidemia profile of male and female mice. For this, the animals were divided between the Control and Hypothyroid (H) groups. Hypothyroidism was induced by methimazole and sodium perchlorate administration in drinking water for 45 days. After, the effectiveness of the treatment was confirmed by the increase in Tshb mRNA expression and reduction in the total T4 serum concentration. This treatment resulted in body weight stagnation in group H, as well as a lower percentage of fat in male mice without changes in food intake. Hypothyroidism also resulted in an increase in the serum concentration of total cholesterol over 24 h, and punctually increase in serum concentration of LDL and HDL in both male and female mice. The in silico analysis points to a direct and transcriptional action of thyroid hormones, as well as components of the circadian clock, on the expression of the Cd36, Slc27a4, Mttp and Slc9a3 genes. These hormones possibly also directly regulate the expression of Fabp, Npc1l1 and Slc2a2. The evaluation of gene expression showed that hypothyroidism affects the rhythmicity of the biological clock in the proximal intestine, mainly in female mice, and specific changes in the expression of genes related to the absorption of lipids and peptides. The only transcript that showed circadian oscillation was Slc2a2. Regarding protein content, the transporters CD36, FATP4, L-FABP, MTTP, PEPT1, NHE3 and GLUT2 showed circadian rhythmicity in the enterocytes of female mice, which was abolished in group H. In summary, the results demonstrated that hypothyroidism alters the regulation of the biological clock of the proximal intestine in a sex-dependent manner and, most likely, as a consequence, the rhythmic pattern of proteins related to the absorption of the three macronutrients hydrolysis products in hypothyroid female mice. These changes may contribute to the metabolic losses of hypothyroidism that result in increased cholesterol levels and fat mass in a sex-dependent manner.