Daily Endocrinology Research Analysis

UNLABELLED: Recent evidence has shown that adipose tissue eventually develops fibrosis through complex cellular cross talk. Although advances in single-cell transcriptomics have provided new insights into cell diversity during this process, little is known about the interactions among the distinct cell types. In this study, we used single-cell analytical approaches to investigate cell-to-cell communications between macrophages and fibroblasts in the adipose tissue of diet-induced obese mice. Spatial transcriptomics was used to understand local cellular interaction within crown-like structures (CLS), a characteristic histological feature of adipose tissue in obesity driving inflammation and fibrosis. Macrophages and fibroblasts were divided into several subclusters that appeared to interact more intensely and complexly with the degree of obesity. Besides previously reported lipid-associated macrophages (LAMs), we found a small subcluster expressing macrophage-inducible C-type lectin (Mincle), specifically localizing to CLS. Mincle signaling increased the expression of oncostatin M (Osm), suppressing collagen gene expression in adipose tissue fibroblasts. Consistent with these findings, Osm deficiency in immune cells enhanced obesity-induced adipose tissue fibrosis in vivo. Moreover, OSM expression was positively correlated with MINCLE expression in human adipose tissue during obesity. Our results suggest that Osm secreted by Mincle-expressing macrophages is involved in dynamic adipose tissue remodeling in the proximity of CLS. ARTICLE HIGHLIGHTS: Adipose tissue fibrosis is a complex and dynamic process that involves many cell types, such as macrophages and fibroblasts. Crown-like structures, which drive inflammation and fibrosis in obesity, are excellent targets for single-cell and spatial transcriptomics. We found novel cell-to-cell communications between macrophages and fibroblasts in adipose tissue from diet-induced obese mice, particularly during the fibrotic phase. We elucidated the role of the macrophage-inducible C-type lectin-oncostatin M axis in obesity-induced adipose tissue fibrosis.

BACKGROUND: In women, both earlier and later age at menarche (AAM) are associated with increased risk of coronary artery disease (CAD). This study examined if the relationship of AAM with CAD and CAD risk factors differs for different underlying sources of variation in AAM-specifically, variation that is attributable to common genetic variants, as represented by a polygenic score (PGS), vs variation in AAM that is independent of the PGS (eg, from environment, rare genetic variants). METHODS: Primary analyses were conducted on data from 201 037 women in the UK Biobank and validation studies on data from 23 268 women in the Women's Genome Health Study. For each individual, a PGS for AAM was calculated; then, 2 variables were estimated from linear regression models: genetically predicted AAM (the estimated AAM for each woman solely due to the effects of common genetic variants) and PGS-adjusted AAM (the estimated AAM for each woman solely due to factors other than the PGS). Logistic and linear regression with linear splines were then used to study the relationships of these variables with CAD and CAD risk factors. RESULTS: Genetically predicted AAM demonstrated linear or roughly linear relationships with CAD and CAD risk factors. In contrast, PGS-adjusted AAM demonstrated a U-shaped relationship with CAD, hemoglobin A1c, triglycerides, high-density lipoprotein cholesterol, and waist-hip ratio. CONCLUSION: These results are consistent with earlier AAM causally increasing risk of CAD but suggest that later AAM itself does not cause increased risk of CAD; rather, sources of variation in AAM other than common genetic variants can cause both later AAM and increased risk of CAD. Dysglycemia, dyslipidemia, and central adiposity are candidate mediators of the association of later AAM with increased risk of CAD.

OBJECTIVE: Studies of primary adrenal insufficiency (PAI) in African children are rare, but in Sudan, congenital adrenal hyperplasia (CAH) and triple A syndrome are the most common genetic causes. Differential diagnosis is challenging, especially in resource-limited settings, where presentation can mimic common childhood diseases and facilities for biochemical and genetic testing may be restricted. DESIGN: Forty-eight patients from 43 families (31 male:17 female) with PAI were included (CAH/triple A excluded). Additional features seen included white matter changes on magnetic resonance imaging, auto-immune features, and/or obesity. Sanger and whole exome sequencing (WES) were employed for diagnosis, confirmation, and segregation with in vitro assays to investigate potential splice defects. RESULTS: In 21/43 families, a genetic aetiology consistent with non-autoimmune PAI was discovered, and in 3 families, autoimmune regulator (AIRE) mutations were found, indicating an autoimmune origin. In Sudan, adenosine triphosphate (ATP) binding cassette subfamily D member 1 (ABCD1)/nicotinamide nucleotide transhydrogenase (NNT)/AIRE mutations were commonest, including recurrent NNT splice and AIRE deletion mutations. In 2 families, we identified ARSA mutations fitting a diagnosis of metachromatic leucodystrophy (MLD), in which adrenal insufficiency has not previously been described. In the remaining 17 families, no causative gene mutations were found. Putative causal variants for comorbidities were concomitantly detected. CONCLUSIONS: In this population, WES revealed itself as a useful frontline tool for the differential diagnosis of individuals presenting with adrenal insufficiency, including discrimination between MLD and adrenoleucodystrophy and giving plausible gene defects for additional comorbidities such as obesity. Such genetic diagnoses are crucial to design optimal treatment plans and for genetic counselling in affected individuals and their families.