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GTF2IRD1 is a PRDM16-interacting transcription factor that represses TGF-beta-mediated inhibition of beige fat differentiation
Get PDFThe identification of beige fat within the last decade, its ability to burn energy in adult humans, and its great potential for therapeutic applications has motivated many to work towards understanding how beige fat is made. Although several proteins have been identified as important for beige fat differentiation, it is clear that the differences that distinguish beige fat from other types of fat cannot be explained by the presence of these proteins alone. Additional regulatory proteins, including transcription factors and their co-factor proteins, must be involved.I took advantage of two important developments in the field of fat differentiation to develop two high throughput approaches that identified new transcription factors involved in beige fat: (1) our ability to culture beige fat cells by differentiating white fat pre-adipocytes in the presence of Rosiglitazone and (2) the established role for PRDM16 as required for beige fat differentiation. In brief, I combined RNA-seq data from beige fat cells and proteomics data from Rosiglitazone-dependent PRDM16 protein complexes to identify a set of candidate transcription factors involved in beige fat differentiation. The most promising candidate among this pool of putative beige fat regulatory transcription factors was GTF2IRD1.I determined that GTF2IRD1 is a PRDM16-interacting transcription factor that is enriched in beige and brown fat cells. In vivo, GTF2IRD1 is enriched in brown adipose tissue and is increased in beige and brown fat in response to beta-3-adrenergic stimulus. In the presence of the potent PPARgamma agonist Rosiglitazone, GTF2IRD1 overexpression enhances and shRNA-mediated knockdown reduces beige fat differentiation. GTF2IRD1 represses TGF-beta-mediated inhibition of beige fat differentiation. In summary, my data strongly supports that GTF2IRD1 is an essential regulator of beige fat differentiation through interaction with PRDM16 and inhibition of TGF-beta-mediated repression of differentiation
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Beige adipocyte maintenance is regulated by autophagy-induced mitochondrial clearance
Get PDFBeige adipocytes gained much attention as an alternative cellular target in anti-obesity therapy. While recent studies have identified a number of regulatory circuits that promote beige adipocyte differentiation, the molecular basis of beige adipocyte maintenance remains unknown. Here, we demonstrate that beige adipocytes progressively lose their morphological and molecular characteristics after withdrawing external stimuli, and directly acquire white-like characteristics bypassing an intermediate precursor stage. The beige-to-white adipocyte transition is tightly coupled to a decrease in mitochondria, increase in autophagy, and activation of MiT/TFE transcription factor-mediated lysosome biogenesis. The autophagy pathway is crucial for mitochondrial clearance during the transition; inhibiting autophagy by UCP1+-adipocyte-specific deletion of Atg5 or Atg12 prevents beige adipocyte loss after withdrawing external stimuli, maintaining high thermogenic capacity and protecting against diet-induced obesity and insulin resistance. The present study uncovers a fundamental mechanism by which autophagy-mediated mitochondrial clearance controls beige adipocyte maintenance, thereby providing new opportunities to prevent obesity
Emerging debates and resolutions in brown adipose tissue research
No full text100000062 National Institute of Diabetes and Digestive and Kidney Disease
Mammary Alveolar Epithelial Cells Convert to Brown Adipocytes in Post-lactating Mice
Get PDFDuring pregnancy and lactation, subcutaneous white adipocytes in the mouse mammary gland transdifferentiate reversibly to milk-secreting epithelial cells. In this study, we demonstrate by transmission electron microscopy that in the post-lactating mammary gland interscapular multilocular adipocytes found close to the mammary alveoli contain milk protein granules. Use of the Cre-loxP recombination system allowed showing that the involuting mammary gland of whey acidic protein-Cre/R26R mice, whose secretory alveolar cells express the lacZ gene during pregnancy, contains some X-Gal-stained and uncoupling protein 1-positive interscapular multilocular adipocytes. These data suggest that during mammary gland involution some milk-secreting epithelial cells in the anterior subcutaneous depot may transdifferentiate to brown adipocytes, highlighting a hitherto unappreciated feature of mouse adipose organ plasticity. This article is protected by copyright. All rights reserved
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Dissecting the molecular mechanisms of cellular injury in the kidney
No full textMore than 850 million people are affected by chronic kidney disease (CKD) globally. Despite the prevalence of CKD, there are few options for treatment apart from dialysis or kidney transplantation. The complexities underlying kidney biology and limited in vitro models have impeded advancements in treatments for CKD. Thus, the goal of this research is to further our understanding of kidney disease mechanisms and effectively model kidney disease biology to find new therapeutic strategies.
First, given the current limited experimental models for studying podocytes, essential post-mitotic cells of the kidney filter, we introduced the application of human iPSC-derived 2D and 3D in vitro models and an experimentally tractable PAN nephrosis rat model as tools to study podocyte biology. We established the functional presence of disease-relevant TRPC5 channel activity in human iPSC-derived podocytes and demonstrated the podocyte-protective effects of inhibiting TRPC5 channel activity.
To further explore podocyte-specific injury mechanisms, we studied a rare genetic mutation in PDSS2, an enzyme involved in the first committed step of Coenzyme Q (CoQ) biosynthesis in the inner mitochondrial membrane. Transcriptomics and metabolomic analyses revealed that loss of PDSS2 induces changes in polyunsaturated fatty acid metabolism and lipid peroxidation accompanied by perturbations in Braf/Mapk signaling. Treatment with Braf-targeting GDC-0879 restored the integrity of the kidney filter in CoQ deficient mice. This study revealed new insights about podocyte biology and a podocyte-protective therapeutic strategy.
Beyond rare monogenic disorders, perturbations in lipid metabolism are strongly associated with highly prevalent chronic kidney diseases. To investigate lipid-related injury in the kidney, we identified free fatty acids that induce toxicity in kidney tubular epithelial cells (TECs). A genome-wide CRISPR/Cas9 screen revealed new genetic mediators of lipotoxicity in TECs. We specifically found that FAF2 depletion protects cells from exposure to palmitic acid, a saturated fatty acid, by regulating membrane fluidity in an SCD1-dependent manner. Further, regulation of SCD1 levels by FAF2 was dependent on VCP and proteasomal activity. Thus, we revealed a novel FAF2-dependent mechanism for the regulation of lipid metabolism in the context of lipotoxicity. Altogether, these findings revealed new injury mechanisms in the kidney and identified targetable pathways for therapeutic development.Medical SciencesMedical Science
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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