👤 Melanie Kershaw

White adipose tissue (WAT) expansion occurs through generation of new adipocytes from adipose progenitor cells (APC). The objective of this study was to characterize and validate a new transcriptional profile of APC. Single-cell (sc)/nuclei (sn) RNA-Seq was performed on nuclei from whole WAT (n = 20), cells from WAT stromal vascular fraction (n = 5), and cultured APC in vitro (n = 8) using ICELL8 smart-Seq technology. Additional snRNA-Seq was performed on WAT using 10x genomic platform. Pseudotime analyses and differentiation of hiPSCs was used to track the temporal patterns of novel gene signatures. Immunohistochemistry was performed to validate a new marker. A pre-adipocyte population was found across the four independent datasets that expressed known pre-adipocyte markers (ZNF423 and DLK1) in addition to genes typically associated with neurogenes (DPP10, PTRPT, CTNNA2, NRXN3, CTNNA2, PTPRD, CNTNAP2 and RBFOX1). The expression of these genes were temporally regulated with adipocyte differentiation. Immunohistochemistry analyses confirmed these pre-adipocytes are located in the neurovascular niche of WAT but are not neurons or endothelial cells. This work has defined a new transcriptional signature of pre-adipocytes in human subcutaneuous WAT that are distinct from mesencyhmal stem cell populations and represent novel targets for WAT expansion. Show less

Declines in skeletal muscle and cognitive function in older adults have been linked to abnormalities in abdominal subcutaneous adipose tissue (ASAT), yet the underlying molecular mediators remain poorly understood. Here, leveraging ASAT transcriptomics and explant-conditioned media proteomics from participants in the Study of Muscle, Mobility and Aging (SOMMA; age ≥70 years, n = 229), we identified ASAT gene clusters and secreted proteins strongly associated with comprehensive assessments of physical and cognitive function in older adults. ASAT inflammation and secreted immunoglobulins were identified as key signatures of aging-associated physical and cognitive performance limitations. Systems genetics analysis confirmed secreted-SERPINF1 as a negative regulator of skeletal muscle contraction and highlighted its potential role in inducing inflammation in the heart in silico. Additionally, novel ASAT-secreted proteins such as NID2 and APOA4 were implicated in mediating ASAT crosstalk with skeletal muscle and brain in silico. Our framework provides insights into ASAT-driven tissue crosstalk underlying physical and cognitive performance in older adults and offers a valuable resource for understanding the role of ASAT in human aging. Show less

Declines in skeletal muscle and cognitive function in older adults have been linked to abnormalities in abdominal subcutaneous adipose tissue (ASAT), yet the underlying molecular mediators remain poorly understood. Here, leveraging ASAT transcriptomics and explant-conditioned media proteomics from participants in the Study of Muscle, Mobility and Aging (SOMMA; age ≥70 years, n = 229), we identified ASAT gene clusters and secreted proteins strongly associated with comprehensive assessments of physical and cognitive function in older adults. ASAT inflammation and secreted immunoglobulins were identified as key signatures of aging-associated physical and cognitive performance limitations. Systems genetics analysis confirmed secreted-SERPINF1 as a negative regulator of skeletal muscle contraction and highlighted its potential role in inducing inflammation in the heart Show less

We performed exome sequencing and targeted resequencing in 2548 children who presented with severe obesity, and we unexpectedly identified 22 Almost all Because pathogenic mutations may manifest with obesity alone, screening of children with severe obesity for Show less

Liver X receptors (LXRs) are transcription factors essential for cholesterol homeostasis and lipogenesis. LXRα has been implicated in regulating hepatic triglyceride (TG) accumulation upon both influx of adipose-derived fatty acids (FAs) during fasting and stimulation of de novo FA synthesis by chemical agonism of LXR. However, whether or not a convergent mechanism is employed to drive deposition of FAs from these 2 different sources in TGs is undetermined. Here, we report that the G0/G1 Switch Gene 2 (G0S2), a selective inhibitor of intracellular TG hydrolysis/lipolysis, is a direct target gene of LXRα. Transcriptional activation is conferred by LXRα binding to a direct repeat 4 (DR4) motif in the G0S2 promoter. While LXRα Show less