It is known that prenatal hyperandrogenization induces alterations since early stages of life, contributing to the development of polycystic ovary syndrome affecting the reproductive axis and the metabolic status, thus promoting others associated disorders, such as dyslipidemia, insulin resistance, liver dysfunction, and even steatosis. In this study, we aimed to evaluate the effect of fetal programming by androgen excess on the hepatic lipid content and metabolic mediators at adult life. Pregnant rats were hyperandrogenized with daily subcutaneous injections of 1 mg of free testosterone from days 16 to 19 of pregnancy. The prenatally hyperandrogenized (PH) female offspring displayed two phenotypes: irregular ovulatory phenotype (PHiov) and anovulatory phenotype (PHanov), with different metabolic and endocrine features. We evaluated the liver lipid content and the main aspect of the balance between fatty acid (FA) synthesis and oxidation. We investigated the status of the peroxisomal proliferator-activated receptors (PPARs) alpha and gamma, which act as lipid mediators, and the adipokine chemerin, one marker of liver alterations. We found that prenatal hyperandrogenization altered the liver lipid profile with increased FAs levels in the PHanov phenotype and decreased cholesterol content in the PHiov phenotype. FA metabolism was also disturbed, including decreased mRNA and protein PPARgamma levels and impaired gene expression of the main enzymes involved in lipid metabolism. Moreover, we found low chemerin protein levels in both PH phenotypes. In conclusion, these data suggest that prenatal hyperandrogenization exerts a negative effect on the liver and alters lipid content and metabolic mediators’ expression at adult age.

The intrauterine environment and early-life nutrition are regulated by maternal biomarkers in the blood and breast milk. We aimed to explore epigenetic modifications that may contribute to differential chemerin expression in maternal plasma, colostrum, and breast milk and find its association with fetal cord blood and infant weight at 6 weeks postpartum. Thirty-three gestational diabetes mellitus (GDM) mothers and 33 normoglycemic mothers (NGT) were recruited. Two maternal blood samples (28th week of gestation and 6 weeks postpartum), cord blood, colostrum, and mature milk were collected. Methylation-specific polymerase chain reaction and enzyme-linked immunosorbent assay were conducted. The weight of the babies was measured at birth and 6 weeks postpartum. Serum chemerin levels at the 28th gestational week and 6 weeks postpartum were significantly lower for the NGT group as compared to the GDM group; (P < 0.05). Higher colostrum chemerin concentrations were observed in the GDM group and remained elevated in mature milk as compared to NGT (P < 0.05). Colostrum and breast milk chemerin levels showed an independent association with infant weight at 6 weeks postpartum (r = 0.270; P = 0.034) (r = 0.464; P < 0.001). Forty percent GDM mothers expressed unmethylated chemerin reflecting increased chemerin concentration in the maternal blood. This pattern was also observed in newborn cord blood where 52% of samples showed unmethylated chemerin in contrast to none in babies born to normoglycemic mothers. The results of this study highlight the critical importance of altered chemerin regulation in gestational diabetic mothers and its effect during early life period and suggest a possible role in contributing to childhood obesity.

A strong causal link between increased adipose tissue mass and insulin resistance in tissues such as liver and skeletal muscle exists in obesity-related disorders such as type 2 diabetes. Increased adipose tissue mass in obese patients and patients with diabetes is associated with altered secretion of adipokines, which also includes chemotactic proteins. Adipose tissue releases a wide range of chemotactic proteins including many chemokines and chemerin, which are interesting targets for adipose tissue biology and for biomedical research in obesity and obesity-related diseases. This class of adipokines may be directly linked to a chronic state of low-grade inflammation and macrophage infiltration in adipose tissue, a concept intensively studied in adipose tissue biology in recent years. The inflammatory state of adipose tissue in obese patients may be the most important factor linking increased adipose tissue mass to insulin resistance. Furthermore, chemoattractant adipokines may play an important role in this situation, as many of these proteins possess biological activity beyond the recruitment of immune cells including effects on adipogenesis and glucose homeostasis in insulin-sensitive tissues. The present review provides a summary of experimental evidence of the role of adipose tissue-derived chemotactic cytokines and their function in insulin resistance in vivo and in vitro.