Daily Endocrinology Research Analysis

Obesity is a major public health challenge. Glucagon-like peptide-1 receptor agonists (GLP1-RA) and bariatric surgery (BS) are effective weight loss interventions; however, the genetic factors influencing treatment response remain largely unexplored. Moreover, most previous studies have focused on race and ethnicity rather than genetic ancestry. Here we analyzed 10,960 individuals from 9 multiancestry biobank studies across 6 countries to assess the impact of known genetic factors on weight loss. Between 6 and 12 months, GLP1-RA users had an average weight change of -3.93% or -6.00%, depending on the outcome definition, with modest ancestry-based differences. BS patients experienced -21.17% weight change between 6 and 48 months. We found no significant associations between GLP1-RA-induced weight loss and polygenic scores for body mass index or type 2 diabetes, nor with missense variants in GLP1R. A higher body mass index polygenic score was modestly linked to lower weight loss after BS (+0.7% per s.d., P = 1.24 × 10

Non-coding variants discovered by genome-wide association studies (GWASs) are enriched in regulatory elements harboring transcription factor (TF) binding motifs, strongly suggesting a connection between disease association and the disruption of cis-regulatory sequences. Occupancy of a TF inside a region of open chromatin can be detected in ATAC-seq where bound TFs block the transposase Tn5, leaving a pattern of relatively depleted Tn5 insertions known as a "footprint." Here, we sought to identify variants associated with TF binding, or "footprint quantitative trait loci" (fpQTLs), in ATAC-seq data generated from 170 human liver samples. We used computational tools to scan the ATAC-seq reads to quantify TF binding likelihood as "footprint scores" at variants derived from whole-genome sequencing generated in the same samples. We tested for association between genotype and footprint score and observed 809 fpQTLs associated with footprint-inferred TF binding (FDR < 5%). Given that Tn5 insertion sites are measured with base-pair resolution, we show that fpQTLs can aid GWAS and QTL fine-mapping by precisely pinpointing TF activity within broad trait-associated loci where the underlying causal variant is unknown. Liver fpQTLs were strongly enriched across ChIP-seq peaks, liver expression QTLs (eQTLs), and liver-related GWAS loci, and their inferred effect on TF binding was concordant with their effect on underlying sequence motifs in 78% of cases. We conclude that fpQTLs can reveal causal GWAS variants, define the role of TF binding-site disruption in complex traits, and provide functional insights into non-coding variants, ultimately informing novel treatments for common diseases.

Maintaining normal thyroid function is crucial in pregnancy, and the thyroid hormone signaling pathway is involved in embryo implantation. However, the regulation of iodothyronine deiodinase 2 (DIO2), which is the central hub controlling thyroid hormone signaling, and the intracellular pathway activated by triiodothyronine (T3) binding to the thyroid hormone receptor (THR) in endometrial cells, remains unclear. Here, we demonstrate that DIO2 expression increases in endometrium during the establishment of endometrial receptivity and is involved in this process. Iopanoic acid inhibition of DIO2 in vivo can cause a delayed receptive state. In vitro adhesion models have consistently confirmed that knocking down DIO2 in epithelial cells inhibited receptivity establishment. Membrane lipidomics was performed to explore how DIO2 regulates the morphological transformation of endometrial epithelial cells. We found that the deletion of Dio2 inhibited the increase in the degree of lipid unsaturation, which subsequently decreased membrane fluidity. Transcriptomics analysis was employed to explore the downstream target gene of T3-THR signaling mediated by Dio2-mediated T3-THR signaling, and Scd1 is confirmed as the direct target gene of THR in endometrial epithelial cells. These data reveal that DIO2 could regulate lipid metabolism by targeting Scd1 through the T3-THR signaling pathway, thereby modifying membrane fluidity of endometrial epithelial cells and promoting cell morphological transformation to establish endometrial receptivity. These findings contribute to filling the gap in downstream pathways activated by T3-THR signaling in endometrial cells and provide insights into the new therapeutics, prediagnosis, and preventive strategies for the derailment of endometrial receptivity and subsequently adverse "ripple effect" including infertility.