Factor XIII-A and Transglutaminase 2 â Novel regulators of adipocyte differentiation and energy metabolism
Bibliographic record
Abstract
Obesity is a growing health problem worldwide, and is associated with the development of insulin resistance and type 2 diabetes. Factor XIII-A (FXIII-A) transglutaminase â a protein crosslinking enzyme - was recently identified as a top novel obesity causative gene in white adipose tissue of monozygotic twin pairs discordant for obesity. However, the role of FXIII-A or other transglutaminase enzyme in obesity or function of adipose tissue is not known. The studies in this thesis investigated the role of two transglutaminase family members in adipocyte differentiation and obesity. The work presented here demonstrate that white adipose tissue expresses only FXIII-A and transglutaminase 2 (TG2) of the transglutaminase family. Cell culture data from 3T3-L1 preadipocyte cell line and mouse embryonic fibroblasts showed that FXIII-A is a negative regulator of adipogenesis. In cell cultures, FXIII-A promoted the assembly of plasma fibronectin into preadipocyte extracellular matrix; the assembled plasma fibronectin matrix promoted preadipocyte proliferation, and potentiated the pro-proliferative effects of insulin while suppressing the pro-differentiating insulin signalling. TG2 was also demonstrated as a negative regulator of adipocyte differentiation, by using TG2 deficient mouse embryonic fibroblasts. TG2 inhibited adipogenesis by regulating Pref-1/Dlk1 protein levels, activating Wnt/β-catenin signalling and ROCK kinase activity. Finally, this thesis reports on the metabolic phenotype of FXIII-A knockout mice. FXIII-A deletion protected the mice from developing high-fat diet induced insulin resistance. Improved insulin sensitivity in these mice was seen in epididymal and inguinal adipose tissue, and muscle. Increased insulin sensitivity in obese FXIII-A deficient mice were associated with healthier adipose tissue characterized by reduced macrophage infiltration, increased adipocyte size, and reduced collagen levels. In summary, the finding of this thesis demonstrates that both FXIII-A and TG2 are inhibitors of adipocyte differentiation, and that FXIII-A is an important regulator of insulin sensitivity and energy metabolism. Therapeutic approaches aimed at modulating FXIII-A and TG2 levels or activity in adipose tissue may have great potential in the treatment of obesity and its co-morbidities.
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How this classification was reachedexpand
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) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 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 | 0.001 | 0.001 |
| 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 itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".