Quantitative (phospho)-proteomics identifies a novel role for hedgehog in reprogramming adipocyte energy metabolism
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Bibliographic record
Abstract
Hedgehog (HH) signaling plays a fundamental role in developmental processes conserved from flies to humans, whereas aberrant HH reactivation has been linked to multiple cancer types.Recent data from our laboratory identified (i) a key role for HH in inhibiting white but not brown adipocyte differentiation in vitro and in vivo, and (ii) that this inhibitory HH effect on white fat cell differentiation can be blocked by the activated T-cell cytokine interferon-gamma (IFN-).However, no studies have so far addressed the impact of HH on mature adipocytes and no data at all are available on HH induced (phospho)-proteomic changes.Therefore, we set out to address both aspects and made use of quantitative proteomic approaches to identify for the first time new HH targets and mechanisms in mature adipocytes.We performed 2D-PAGE and quantitative label-free 1D-GeLC/MSMS with (i) phosphoprotein enriched samples; and (ii) cytoplasmic fractions to gain unbiased insight into rapid phosphorylation and lasting expression changes, respectively.Western blots were performed to validate results.Cellular metabolites were measured by ELISA.Phospho-protein-specific 1D-and 2D-gels revealed a highly reproducible phosphorylation of pyruvate dehydrogenase (PDH) E1 alpha in HH treated samples.In line with this data we observed a significant up-regulation of PDH-kinase in the cytoplasmic fraction.Furthermore, the glycolytic key enzymes phosphofructokinase (PFK) and pyruvate kinase M2 (PKM2) were significantly altered in HH treated samples, leading to a shift towards lactate production.Pathway analyses identified major changes in glycolysis and mitochondrial function (OXPHOS, TCA cycle).Of note, increased NAD + /NADH and NADP + /NADPH ratios further reflected HH induced metabolic reprogramming.In summary, our unbiased (phospho)-proteomic screen identified HH as a hitherto unknown regulator of cellular energy metabolism, leading to increased glucose turnover and lactate production.IV ZUSAMMENFASSUNG Der sogenannte Hedgehog Signaltransduktionsweg (HH-STW) spielt eine essentielle Rolle in Entwicklungsprozessen von der Fruchtfliege bis hin zum Mensch.Eine unzureichende Funktion des HH-STW fhrt zu schweren Missbildungen, wobei eine berreaktion mit Tumorentstehung in Verbindung steht.Rezente Daten unserer Forschungsarbeiten besttigten (i) eine Schlsselfunktion des HH-STW in der Inhibierung der Differenzierung weier, aber nicht brauner Fettzellen sowohl in vitro als auch in vivo und (ii) dass diese hemmende Wirkung durch das aktivierte T-Zellen Zytokin Interferon-gamma (IFN-) blockiert wird.Interessanterweise hat sich bis dato keine Studie damit befasst, den HH-
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from it