OBJECTIVE: GDF11 is a member of the TGF-β superfamily that was recently implicated as potential "rejuvenating" factor, which can ameliorate metabolic disorders. The main objective of the presented study was to closely characterize the role of GDF11 signaling in the glucose homeostasis and in the differentiation of white adipose tissue. METHODS: We performed microscopy imaging, biochemical and transcriptomic analyses of adipose tissues of 9 weeks old ob/ob mice and murine and human pre-adipocyte cell lines. RESULTS: Our in vivo experiments employing GDF11 treatment in ob/ob mice showed improved glucose/insulin homeostasis, decreased weight gain and white adipocyte size. Furthermore, GDF11 treatment inhibited adipogenesis in pre-adipocytes by ALK5-SMAD2/3 activation in cooperation with the WNT/β-catenin pathway, whose inhibition resulted in adipogenic differentiation. Lastly, we observed significantly elevated levels of the adipokine hormone adiponectin and increased glucose uptake by mature adipocytes upon GDF11 exposure. CONCLUSION: We show evidence that link GDF11 to adipogenic differentiation, glucose, and insulin homeostasis, which are pointing towards potential beneficial effects of GDF11-based "anti-obesity" therapy.
- MeSH
- adipogeneze * MeSH
- adiponektin metabolismus MeSH
- beta-katenin * metabolismus MeSH
- buněčná diferenciace fyziologie MeSH
- glukosa metabolismus MeSH
- inzulin metabolismus MeSH
- kostní morfogenetické proteiny metabolismus MeSH
- lidé MeSH
- myši MeSH
- protein Smad2 MeSH
- protein Smad3 MeSH
- receptory regulované proteiny Smad MeSH
- růstové diferenciační faktory metabolismus MeSH
- signální dráha Wnt MeSH
- TGF-beta receptor I. typu MeSH
- transformující růstový faktor beta metabolismus MeSH
- tukové buňky metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- adiponektin MeSH
- beta-katenin * MeSH
- GDF11 protein, human MeSH Prohlížeč
- Gdf11 protein, mouse MeSH Prohlížeč
- glukosa MeSH
- inzulin MeSH
- kostní morfogenetické proteiny MeSH
- protein Smad2 MeSH
- protein Smad3 MeSH
- receptory regulované proteiny Smad MeSH
- růstové diferenciační faktory MeSH
- SMAD2 protein, human MeSH Prohlížeč
- Smad2 protein, mouse MeSH Prohlížeč
- SMAD3 protein, human MeSH Prohlížeč
- Smad3 protein, mouse MeSH Prohlížeč
- TGF-beta receptor I. typu MeSH
- TGFBR1 protein, human MeSH Prohlížeč
- Tgfbr1 protein, mouse MeSH Prohlížeč
- transformující růstový faktor beta MeSH
BACKGROUND & AIMS: Growth Differentiation Factor 11 (GDF11) is an anti-aging factor, yet its role in liver diseases is not established. We evaluated the role of GDF11 in healthy conditions and in the transition from non-alcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH). RESULTS: GDF11 mRNA levels positively correlated with NAFLD activity score and with CPT1, SREBP, PPARγ and Col1A1 mRNA levels, and associated to portal fibrosis, in morbidly obese patients with NAFLD/NASH. GDF11-treated mice showed mildly exacerbated hepatic collagen deposition, accompanied by weight loss and without changes in liver steatosis or inflammation. GDF11 triggered ALK5-dependent SMAD2/3 nuclear translocation and the pro-fibrogenic activation of HSC. CONCLUSIONS: GDF11 supplementation promotes mild liver fibrosis. Even considering its beneficial metabolic effects, caution should be taken when considering therapeutics that regulate GDF11. METHODS: We analyzed liver biopsies from a cohort of 33 morbidly obese adults with NAFLD/NASH. We determined the correlations in mRNA expression levels between GDF11 and genes involved in NAFLD-to-NASH progression and with pathological features. We also exposed wild type or obese mice with NAFLD to recombinant GDF11 by daily intra-peritoneal injection and monitor the hepatic pathological changes. Finally, we analyzed GDF11-activated signaling pathways in hepatic stellate cells (HSC).
- Klíčová slova
- NAFLD, NASH, fibrosis, growth differentiation factor 11, liver,
- MeSH
- buněčné linie MeSH
- dospělí MeSH
- experimentální cirhóza jater chemicky indukované metabolismus patologie MeSH
- jaterní cirhóza diagnóza etiologie genetika metabolismus MeSH
- jaterní hvězdicovité buňky metabolismus patologie MeSH
- játra metabolismus patologie MeSH
- kostní morfogenetické proteiny genetika metabolismus toxicita MeSH
- lidé středního věku MeSH
- lidé MeSH
- morbidní obezita komplikace diagnóza MeSH
- myši inbrední C57BL MeSH
- nealkoholová steatóza jater diagnóza etiologie genetika metabolismus MeSH
- progrese nemoci MeSH
- růstové diferenciační faktory genetika metabolismus toxicita MeSH
- signální transdukce MeSH
- studie případů a kontrol MeSH
- zvířata MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- GDF11 protein, human MeSH Prohlížeč
- kostní morfogenetické proteiny MeSH
- růstové diferenciační faktory MeSH
Staining mice tissues for β-galactosidase activity is a fundamental tool to detect age- or disease-associated cellular senescence. However, reported analyses of positivity for senescence-associated β-galactosidase activity or for other markers of senescence in post-mitotic cells of healthy murine tissues have been fragmentary or inconclusive. Here, we attempted to independently deepen this knowledge using multiple senescence markers within the same cells of wild type mice entering middle age (9 months of age). A histochemistry protocol for the pH-dependent detection of β-galactosidase activity in several tissues was used. At pH 6, routinely utilized to detect senescence-associated β-galactosidase activity, only specific cellular populations in the mouse body (including Purkinje cells and choroid plexus in the central nervous system) were detected as strongly positive for β-galactosidase activity. These post-mitotic cells were also positive for other established markers of senescence (p16, p21 and DPP4), detected by immunofluorescence, confirming a potential senescent phenotype. These data might contribute to understanding the functional relation between the senescence-associated β-galactosidase activity and senescence markers in post-mitotic cells in absence of disease or advanced aging.
- Klíčová slova
- markers, mice, senescence,
- MeSH
- beta-galaktosidasa metabolismus MeSH
- biologické markery metabolismus MeSH
- imunohistochemie MeSH
- koncentrace vodíkových iontů MeSH
- mitóza fyziologie MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- stárnutí buněk fyziologie MeSH
- stárnutí fyziologie MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- beta-galaktosidasa MeSH
- biologické markery MeSH
