Search

Thyroid hormone (TH) and thyroid hormone receptor (THR) regulate stem cell proliferation and differentiation during development, as well as during tissue renewal and repair in the adult. THR undergoes posttranslational modification by small ubiquitin-like modifier (SUMO). We generated the THRA (K283Q/K288R)-/- mouse model for in vivo studies and used human primary preadipocytes expressing the THRA sumoylation mutant (K283R/K288R) and isolated preadipocytes from mutant mice for in vitro studies. THRA mutant mice had reduced white adipose stores and reduced adipocyte cell diameter on a chow diet, compared to wild-type, and these differences were further enhanced after a high fat diet. Reduced preadipocyte proliferation in mutant mice, compared to wt, was shown after in vivo labeling of preadipocytes with EdU and in preadipocytes isolated from mice fat stores and studied in vitro. Mice with the desumoylated THRA had disruptions in cell cycle G1/S transition and this was associated with a reduction in the availability of cyclin D2 and cyclin-dependent kinase 2. The genes coding for cyclin D1, cyclin D2, cyclin-dependent kinase 2 and Culin3 are stimulated by cAMP Response Element Binding Protein (CREB) and contain CREB Response Elements (CREs) in their regulatory regions. We demonstrate, by Chromatin Immunoprecipitation (ChIP) assay, that in mice with the THRA K283Q/K288R mutant there was reduced CREB binding to the CRE. Mice with a THRA sumoylation mutant had reduced fat stores on chow and high fat diets and reduced adipocyte diameter.

BackgroundRecurrent hypoglycemia (RH) is well known to impair awareness of hypoglycemia and increase the risk of severe hypoglycemia; the underlying mechanism requires further understanding. We aimed to investigate the metabolic characteristic profile for RH in type 2 diabetes mellitus (T2DM) patients and explore the potential metabolic mechanism and prevention strategies.MethodsWe screened 553 community-based T2DM patients. T2DM with RH (DH group, n=40) and T2DM without hypoglycemia (DC group, n=40) were assigned in the case-control study, matched by propensity score matching. Non-targeted, global metabolite profiling was conducted using ultra-high performance liquid chromatography-mass spectrometry. Principal component analysis and supervised projections to latent structures-discriminant analysis were constructed to evaluate the potential biomarkers. Metabolites with a fold change of >2.0 or 1 were identified as significantly differential metabolites. MetaboAnalyst was performed to analyze the related metabolic pathways.ResultsWe identified 12 significantly distinct metabolites as potential biomarkers of RH, which were enriched in five pathways; the caffeine metabolic pathway was the most dominant related one. Caffeine and its main downstream metabolites (theophylline and paraxanthine, all q