2,4-Di-tert-butylphenol Induces Adipogenesis in Human Mesenchymal Stem Cells by Activating Retinoid X Receptors.

2,4-Di-tert-butylphenol (2,4-DTBP) is an important commercial antioxidant and a toxic natural secondary metabolite that has been detected in humans. However, there is scant information regarding its toxicological effects. We asked whether 2,4-DTBP is a potential obesogen. Using a human mesenchymal stem cell adipogenesis assay, we found that exposure to 2,4-DTBP led to increased lipid accumulation and expression of adipogenic marker genes. Antagonist assays revealed that 2,4-DTBP increased lipid accumulation by activating the peroxisome proliferator-activated receptor (PPAR) γ-retinoid X receptor (RXR) heterodimer. 2,4-DTBP likely activated the PPARγ/RXRα heterodimer by activating RXRα but not directly binding to PPARγ. We confirmed that 2,4-DTBP directly bound to RXRα by solving the crystal structure of this complex, then predicted and demonstrated that related compounds could also activate RXRα. Our study demonstrated that 2,4-DTBP and related chemicals could act as obesogens and endocrine disruptors via RXRs. These data showed that 2,4-DTBP belongs to a family of compounds whose endocrine-disrupting and obesogenic effects can be strongly modulated by their chemical composition. Structure-activity studies such as the present one could help guide the rational development of safer antioxidants that do not interact with important nuclear receptors having broad effects on human development and physiology.

Association between variations of physiological prolactin serum levels and the risk of type 2 diabetes: A systematic review and meta-analysis.

AIM: To determine the pooled association between variations of prolactin serum levels within the physiological range and the risk of type 2 diabetes mellitus (T2D). METHODS: Pubmed, Scopus, Web of Science, and grey literature were searched for studies investigating the association between variations of prolactin serum levels in the normal range and the risk of T2D in adults. The risk of prevalent and incident T2D was summarized as the odds ratio or relative risk according to the quartile of prolactin serum concentration, using random-effects meta-analysis. RESULTS: Of 2,014 articles identified, 6 met the inclusion criteria. Data were pooled from cross-sectional studies including 6,670 subjects and longitudinal studies involving 13,203 subjects. Men with prolactin levels in the fourth quartile versus those in the first quartile had decreased risk of prevalent T2D (OR 0.52; 95%CI 0.35-077). The same association was seen in women (OR 0.46; 95%CI 0.30-0.73). Conversely, prolactin levels in the fourth versus first quartile were not associated with the risk of incident T2D in men (RR 1.21; 95%CI 0.79-1.87) or women (RR 0.77; 95%CI 0.48-1.22). CONCLUSION: Higher prolactin serum levels within the normal range were associated with reduced risk of prevalent but not incident T2D. Further studies are necessary to address whether this association is causal, but these findings raise the discussion regarding the optimal level of prolactin suppression in subjects undergoing therapy with dopaminergic agonists.

Modulation of nuclear receptor function: Targeting the protein-DNA interface.

Nuclear receptors (NRs) are a superfamily of ligand-dependent transcription factors that modulate several biological processes. Traditionally, modulation of NRs has been focused on the development of ligands that recognize and bind to the ligand binding domain (LBD), resulting in activation or repression of transcription through the recruitment of coregulators. However, for more severe diseases, such as breast and prostate cancer, the conventional treatment addressing LBD modulation is not always successful, due to tumor resistance. To overcome these challenges and aiming to modulate NR activity by inhibiting the NR-DNA interaction, new studies focus on the development of molecules targeting alternative sites and domains on NRs. Here, we discuss two different approaches for this alternative NR modulation: one targeting the NR DNA binding domain (DBD); and the other targeting the DNA sites recognized by NRs. Our aim is to present the challenges and perspectives for developing specific inhibitors for each purpose, alongside with already reported examples.