The novel E3 ligase of PPAR?? TRIM25 regulates adipocyte differentiation

Department of Biological SciencesPeroxisome proliferator-activated receptor ?? (PPAR??) is a ligand-dependent transcription factor which regulates glucose homeostasis and adipocyte differentiation. Its transcriptional activity is regulated by not only ligands but also post-translational modifications (PTMs). In this study, we demonstrate a novel E3 ligase of PPAR??, TRIM25 directly induces ubiquitination of PPAR?? followed by proteasome-dependent degradation. During the adipocyte differentiation, both mRNA and protein expression of TRIM25 significantly decreased and negatively correlated with the expression of PPAR??. Stable expression of TRIM25 reduces PPAR?? protein levels, but not mRNA expression, and suppressed adipocyte differentiation in 3T3-L1 cells. In contrast, specific knock-down of TRIM25 increases PPAR?? protein levels and stimulates adipocyte differentiation. Furthermore, TRIM25 knock-out mouse embryonic fibroblast (MEFs) shows an increased ability for adipocyte differentiation compared with wild-type MEFs. Taken together, these data indicate that TRIM25 is a novel E3 ubiquitin ligase of PPAR??, and depict TRIM25 as a novel target for PPAR??-involved metabolic diseases.ope

Noggin depletion in adipocytes promotes obesity in mice.

ObjectiveObesity has increased to pandemic levels and enhanced understanding of adipose regulation is required for new treatment strategies. Although bone morphogenetic proteins (BMPs) influence adipogenesis, the effect of BMP antagonists such as Noggin is largely unknown. The aim of the study was to define the role of Noggin, an extracellular BMP inhibitor, in adipogenesis.MethodsWe generated adipose-derived progenitor cells and a mouse model with adipocyte-specific Noggin deletion using the AdiponectinCre transgenic mouse, and determined the adipose phenotype of Noggin-deficiency.ResultsOur studies showed that Noggin is expressed in progenitor cells but declines in adipocytes, possibly allowing for lipid accumulation. Correspondingly, adipocyte-specific Noggin deletion in vivo promoted age-related obesity in both genders with no change in food intake. Although the loss of Noggin caused white adipose tissue hypertrophy, and whitening and impaired function in brown adipose tissue in both genders, there were clear gender differences with the females being most affected. The females had suppressed expression of brown adipose markers and thermogenic genes including peroxisome proliferator activated receptor gamma coactivator 1 alpha (PGC1alpha) and uncoupling protein 1 (UCP1) as well as genes associated with adipogenesis and lipid metabolism. The males, on the other hand, had early changes in a few BAT markers and thermogenic genes, but the main changes were in the genes associated with adipogenesis and lipid metabolism. Further characterization revealed that both genders had reductions in VO2, VCO2, and RER, whereas females also had reduced heat production. Noggin was also reduced in diet-induced obesity in inbred mice consistent with the obesity phenotype of the Noggin-deficient mice.ConclusionsBMP signaling regulates female and male adipogenesis through different metabolic pathways. Modulation of adipose tissue metabolism by select BMP antagonists may be a strategy for long-term regulation of age-related weight gain and obesity

GALNT2 as a novel modulator of adipogenesis and adipocyte insulin signaling

Background/objectives: A better understanding of adipose tissue biology is crucial to tackle insulin resistance and eventually coronary heart disease and diabetes, leading causes of morbidity and mortality worldwide. GALNT2, a GalNAc-transferase, positively modulates insulin signaling in human liver cells by down-regulating ENPP1, an insulin signaling inhibitor. GALNT2 expression is increased in adipose tissue of obese as compared to that of non-obese individuals. Whether this association is secondary to a GALNT2-insulin sensitizing effect exerted also in adipocytes is unknown. We then investigated in mouse 3T3-L1 adipocytes the GALNT2 effect on adipogenesis, insulin signaling and expression levels of both Enpp1 and 72 adipogenesis-related genes. Methods: Stable over-expressing GALNT2 and GFP preadipocytes (T 0 ) were generated. Adipogenesis was induced with (R+) or without (R−) rosiglitazone and investigated after 15 days (T 15 ). Lipid accumulation (by Oil Red-O staining) and intracellular triglycerides (by fluorimetric assay) were measured. Lipid droplets (LD) measures were analyzed at confocal microscope. Gene expression was assessed by RT-PCR and insulin-induced insulin receptor (IR), IRS1, JNK and AKT phosphorylation by Western blot. Results: Lipid accumulation, triglycerides and LD measures progressively increased from T 0 to T 15 R- and furthermore to T 15 R+. Such increases were significantly higher in GALNT2 than in GFP cells so that, as compared to T 15 R+GFP, T 15 R- GALNT2 cells showed similar (intracellular lipid and triglycerides accumulation) or even higher (LD measures, p < 0.01) values. In GALNT2 preadipocytes, insulin-induced IR, IRS1 and AKT activation was higher than that in GFP cells. GALNT2 effect was totally abolished during adipocyte maturation and completely reversed at late stage maturation. Such GALNT2 effect trajectory was paralleled by coordinated changes in the expression of Enpp1 and adipocyte-maturation key genes. Conclusions: GALNT2 is a novel modulator of adipogenesis and related cellular phenotypes, thus becoming a potential target for tackling the obesity epidemics and its devastating sequelae

Seipin oligomers can interact directly with AGPAT2 and lipin 1, physically scaffolding critical regulators of adipogenesis

This work was supported by a Merit Scholarship from the Islamic Development Bank (to M.M.U.T.), The Agency for Science, Technology and Research, Singapore (A*STAR) (M.F.M.S), the Medical Research Council (MRC) [NIRG GO800203 and Research Grant MR/L002620/1 (to J.J.R.), Program GrantG09000554 (to S.O.R)], The Wellcome Trust [078986/Z/06/Z (to S.O.R.)], the MRC Centre for Obesity and Related Metabolic Disorders (MRC-CORD) [GO600717] and the NIHR Comprehensive Biomedical Research Centre [CG50826].Peer reviewedPublisher PD

The Differentiation Balance of Bone Marrow Mesenchymal Stem Cells Is Crucial to Hematopoiesis.

Bone marrow mesenchymal stem cells (BMSCs), the important component and regulator of bone marrow microenvironment, give rise to hematopoietic-supporting stromal cells and form hematopoietic niches for hematopoietic stem cells (HSCs). However, how BMSC differentiation affects hematopoiesis is poorly understood. In this review, we focus on the role of BMSC differentiation in hematopoiesis. We discussed the role of BMSCs and their progeny in hematopoiesis. We also examine the mechanisms that cause differentiation bias of BMSCs in stress conditions including aging, irradiation, and chemotherapy. Moreover, the differentiation balance of BMSCs is crucial to hematopoiesis. We highlight the negative effects of differentiation bias of BMSCs on hematopoietic recovery after bone marrow transplantation. Keeping the differentiation balance of BMSCs is critical for hematopoietic recovery. This review summarises current understanding about how BMSC differentiation affects hematopoiesis and its potential application in improving hematopoietic recovery after bone marrow transplantation

The Effects of Eicosapentaenoic Acid (EPA) and Docosahexaenoic Acid (DHA) on Brown Adipogenesis in Stem Cell Culture

Polyunsaturated fatty acids (PUFAs), especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are major maternal dietary supplements due to their positive benefits on neurological tissue growth during the first 12 weeks of gestation. Previous studies show that EPA and DHA inhibit muscle formation but promote adipogenesis. However, no research has addressed the question whether high intake of EPA and DHA affects brown fat development during gestation. The objective of this study was to measure the effect of EPA and DHA supplement on brown adipogenesis and potential pathways related to mitochondrial biosynthesis using fibroblasts as in vitro model. Using Oil-Red-O staining and PCR testing, lipid droplet formation and tested six genes were examined and PGC1α presented statistically significant difference from the control group when treated with PUFAs. Results indicated that PGC1α gene expression can be to be alternated by EPA and DHA treatment. Mitochondrial biosynthesis can potentially be promoted by increased PGC1α gene expression. However, the lipid droplets accumulated in the PUFAs treated group show an unknown mechanism of the n-3 PUFA on adipogenesis that needs to be revealed