Search bioRxiv⌕ Search

Biology subjects

Klingenspor, M.

Publications and source records attributed to Klingenspor, M..

2 recordsLinked to original sources
bioRxiv2019

TIS7 and SKMc15 Regulate Adipocyte Differentiation and Intestinal Lipid Absorption

Delta-like homolog 1 (DLK1), an inhibitor of adipogenesis, controls the cell fate of adipocyte progenitors. Here we identify two independent regulatory mechanisms, transcriptional and translational, by which TIS7 (IFRD1) and its orthologue SKMc15 (IFRD2) regulate DLK1 levels. Mice deficient in both TIS7 and SKMc15 (dKO) had severely reduced adipose tissue and were resistant to high fat diet-induced obesity. Wnt signaling, a negative regulator of adipocyte differentiation was significantly up regulated in dKO mice. Elevated levels of the Wnt/{beta}-catenin target protein Dlk-1 inhibited the expression of adipogenesis regulators PPAR{gamma} and C/EBP, and fatty acid transporter CD36. Although both, TIS7 and SKMc15, contributed to this phenotype, they utilized two different mechanisms. TIS7 acted by controlling Wnt signaling and thereby transcriptional regulation of Dlk-1. On the other hand, here we provide distinctive experimental evidence that SKMc15 acts as a general translational inhibitor significantly affecting DLK-1 protein levels. Our study provides data describing novel mechanisms of DLK1 regulation in adipocyte differentiation involving TIS7 and SKMc15. SYNOPSIS O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=184 SRC="FIGDIR/small/719922v3_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@77d89corg.highwire.dtl.DTLVardef@2e0ad4org.highwire.dtl.DTLVardef@c923fdorg.highwire.dtl.DTLVardef@159d117_HPS_FORMAT_FIGEXP M_FIG C_FIG This study uncovered that IFRD1 (TIS7) and its orthologue IFRD2 (SKMc15) are two essential regulators of adipogenesis. These proteins are highly similar on the sequence level, yet they regulate adipocyte differentiation using different but complementary mechanisms. Our main findings are: O_LIIFRD1 (TIS7) and IFRD2 (SKMc15) knockout mice are resistant against diet-induced obesity C_LIO_LIIFRD1 (TIS7) and IFRD2 (SKMc15) are critical for proper nutritional fat uptake and adipogenesis C_LIO_LIIFRD1 (TIS7) controls adipogenesis via Wnt/{beta}-catenin-dependent transcriptional regulation of adipocyte-specific genes C_LIO_LIIFRD2 (SKMc15) regulates adipocyte-specific genes acting as a novel general translational inhibitor C_LI

cell biology↗
bioRxiv2019

A novel growth factor-dependent thermogenic brown adipocyte cell line from defined precursor cells

Molecular pathways regulating brown adipocyte formation and metabolism can be exploited as targets for the treatment of obesity and disorders of glucose and lipid metabolism such as type-2 diabetes. Investigations in this direction require adequate cell models for brown adipocytes and their precursors. We report the establishment of a novel clonal cell line derived from defined Lin-Sca1+ adipocyte precursors from murine interscapular brown fat. In contrast to most currently available lines, immortalization was achieved by serial passaging without viral or genetic manipulation. Instead, the media were supplemented with basic fibroblast growth factor, which was required for the maintenance of stable long-term growth and immature morphology. BATkl2 cells differentiated to adipocytes with high efficiency upon standard adipogenic induction independently of PPARg agonists and even at higher passage numbers. BATkl2 adipocytes showed readily detectable Uncoupling protein 1 (Ucp1) protein expression and acutely responded to norepinephrine with increased Ucp1 mRNA expression, lipolysis and uncoupled mitochondrial respiration. Highly efficient siRNA-mediated knockdown was demonstrated in the growth state as well as in differentiating adipocytes, whereas plasmid DNA transfection was achieved in immature cells. These features make the BATkl2 cell line an attractive brown (pre)-adipocyte cell model.

cell biology↗