Protein kinase D1 (Prkd1) deletion in brown adipose tissue leads to altered myogenic gene expression after cold exposure, while thermogenesis remains intact

Abstract Brown adipose tissue (BAT) has in recent times been rediscovered in adult humans, and together with work from preclinical models, has shown to have the potential of providing a variety of positive metabolic benefits. These include lower plasma glucose, improved insulin sensitivity, and reduced susceptibility to obesity and its comorbidities. As such, its continued study could offer insights to therapeutically modulate this tissue to improve metabolic health. It has been reported that adipose‐specific deletion of the gene for protein kinase D1 (Prkd1) in mice enhances mitochondrial respiration and improves whole‐body glucose homeostasis. We sought to determine whether these effects were mediated specifically through brown adipocytes using a Prkd1 brown adipose tissue (BAT) Ucp1‐Cre‐specific knockout mouse model, Prkd1BKO. We unexpectedly observed that upon both cold exposure and β3‐AR agonist administration, Prkd1 loss in BAT did not alter canonical thermogenic gene expression or adipocyte morphology. We took an unbiased approach to assess whether other signaling pathways were affected. RNA from cold‐exposed mice was subjected to RNA‐Seq analysis. These studies revealed that myogenic gene expression is altered in Prkd1BKO BAT after both acute and extended cold exposure. Given that brown adipocytes and skeletal myocytes share a common precursor cell lineage expressing myogenic factor 5 (Myf5), these data suggest that loss of Prkd1 in BAT may alter the biology of mature brown adipocytes and preadipocytes in this depot. The data presented herein clarify the role of Prkd1 in BAT thermogenesis and present new avenues for the further study of Prkd1 function in BAT

ZFP92, a KRAB domain zinc finger protein enriched in pancreatic islets, binds to B1/Alu SINE transposable elements and regulates retroelements and genes.

Repressive KRAB domain-containing zinc-finger proteins (KRAB-ZFPs) are abundant in mammalian genomes and contribute both to the silencing of transposable elements (TEs) and to the regulation of developmental stage- and cell type-specific gene expression. Here we describe studies of zinc finger protein 92 (Zfp92), an X-linked KRAB-ZFP that is highly expressed in pancreatic islets of adult mice, by analyzing global Zfp92 knockout (KO) mice. Physiological, transcriptomic and genome-wide chromatin binding studies indicate that the principal function of ZFP92 in mice is to bind to and suppress the activity of B1/Alu type of SINE elements and modulate the activity of surrounding genomic entities. Deletion of Zfp92 leads to changes in expression of select LINE and LTR retroelements and genes located in the vicinity of ZFP92-bound chromatin. The absence of Zfp92 leads to altered expression of specific genes in islets, adipose and muscle that result in modest sex-specific alterations in blood glucose homeostasis, body mass and fat accumulation. In islets, Zfp92 influences blood glucose concentration in postnatal mice via transcriptional effects on Mafb, whereas in adipose and muscle, it regulates Acacb, a rate-limiting enzyme in fatty acid metabolism. In the absence of Zfp92, a novel TE-Capn11 fusion transcript is overexpressed in islets and several other tissues due to de-repression of an IAPez TE adjacent to ZFP92-bound SINE elements in intron 3 of the Capn11 gene. Together, these studies show that ZFP92 functions both to repress specific TEs and to regulate the transcription of specific genes in discrete tissues

From goal to outcome: Analyzing the progression of biomedical sciences PhD careers in a longitudinal study using an expanded taxonomy

Abstract Biomedical sciences PhDs pursue a wide range of careers inside and outside academia. However, there is little data regarding how career interests of PhD students relate to the decision to pursue postdoctoral training or to their eventual career outcomes. Here, we present the career goals and career outcomes of 1452 biomedical sciences PhDs who graduated from Vanderbilt University between 1997 and 2021. We categorized careers using an expanded three‐tiered taxonomy and flags that delineate key career milestones. We also analyzed career goal changes between matriculation and doctoral defense, and the reasons why students became more‐ or less‐interested in research‐intensive faculty careers. We linked students' career goal at doctoral defense to whether they did a postdoc, the duration of time between doctoral defense and the first non‐training position, the career area of the first non‐training position, and the career area of the job at 10 years after graduation. Finally, we followed individual careers for 10 years after graduation to characterize movement between different career areas over time. We found that most students changed their career goal during graduate school, declining numbers of alumni pursued postdoctoral training, many alumni entered first non‐training positions in a different career area than their goal at doctoral defense, and the career area of the first non‐training position was a good indicator of the job that alumni held 10 years after graduation. Our findings emphasize that students need a wide range of career development opportunities and career mentoring during graduate school to prepare them for futures in research and research‐related professions

Deletion of Ascl1 in pancreatic β-cells improves insulin secretion, promotes parasympathetic innervation, and attenuates dedifferentiation during metabolic stress

Objective: ASCL1, a pioneer transcription factor, is essential for neural cell differentiation and function. Previous studies have shown that Ascl1 expression is increased in pancreatic β-cells lacking functional KATP channels or after feeding of a high fat diet (HFD) suggesting that it may contribute to the metabolic stress response of β-cells. Methods: We generated β-cell-specific Ascl1 knockout mice (Ascl1βKO) and assessed their glucose homeostasis, islet morphology and gene expression after feeding either a normal diet or HFD for 12 weeks, or in combination with a genetic disruption of Abcc8, an essential KATP channel component. Results: Ascl1 expression is increased in response to both a HFD and membrane depolarization and requires CREB-dependent Ca2+ signaling. No differences in glucose homeostasis or islet morphology were observed in Ascl1βKO mice fed a normal diet or in the absence of KATP channels. However, male Ascl1βKO mice fed a HFD exhibited decreased blood glucose levels, improved glucose tolerance, and increased β-cell proliferation. Bulk RNA-seq analysis of islets from Ascl1βKO mice from three studied conditions showed alterations in genes associated with the secretory function. HFD-fed Ascl1βKO mice showed the most extensive changes with increased expression of genes necessary for glucose sensing, insulin secretion and β-cell proliferation, and a decrease in genes associated with β-cell dysfunction, inflammation and dedifferentiation. HFD-fed Ascl1βKO mice also displayed increased expression of parasympathetic neural markers and cholinergic receptors that was accompanied by increased insulin secretion in response to acetylcholine and an increase in islet innervation. Conclusions: Ascl1 expression is induced by stimuli that cause Ca2+-signaling to the nucleus and contributes in a multifactorial manner to the loss of β-cell function by promoting the expression of genes associated with cellular dedifferentiation, attenuating β-cells proliferation, suppressing acetylcholine sensitivity, and repressing parasympathetic innervation of islets. Thus, the removal of Ascl1 from β-cells improves their function in response to metabolic stress