Tumour necrosis factor α induces neuroinflammation and insulin resistance in immortalised hypothalamic neurones through independent pathways
Bibliographic record
Abstract
The links between obesity, inflammation and insulin resistance, which are all key characteristics of type 2 diabetes mellitus, are yet to be delineated in the brain. One of the key neuroinflammatory proteins detected in the hypothalamus with over‐nutrition is tumour necrosis factor ( TNF) α. Using immortalised embryonic rat and mouse hypothalamic cell lines ( rH ypoE‐7 and mH ypoE‐46) that express orexigenic neuropeptide Y and agouti‐related peptide, we investigated changes in insulin signalling and inflammatory gene marker mRNA expression after TNF α exposure. A quantitative polymerase chain reaction array of 84 inflammatory markers (cytokines, chemokines and receptors) demonstrated an increase in the expression of multiple genes encoding inflammatory markers upon exposure to 100 ng mL ‐1 TNF α for 4 hours. Furthermore, neurones pre‐exposed to TNF α (50 ng mL ‐1 ) for 6 or 16 hours exhibited a significant reduction in phosphorylated A kt compared to control after insulin treatment, indicating the attenuation of insulin signalling. mRNA expression of insulin signalling‐related genes was also decreased with exposure to TNF α. TNF α significantly increased mRNA expression of I κ B α, Tnfrsf1a and IL 6 at 4 and 24 hours, activating a pro‐inflammatory state. An inhibitor study using an inhibitor of nuclear factor kappa B kinase subunit β ( IKK ‐β) inhibitor, PS 1145, demonstrated that TNF α‐induced neuroinflammatory marker expression occurs through the IKK ‐β/ nuclear factor‐kappa B pathway, whereas oleate, a monounsaturated fatty acid, had no effect on inflammatory markers. To test the efficacy of anti‐inflammatory treatment to reverse insulin resistance, neurones were treated with TNF α and PS 1145, which did not significantly restore the TNF α‐induced changes in cellular insulin sensitivity, indicating that an alternative pathway may be involved. In conclusion, exposure to the inflammatory cytokine TNF α causes cellular insulin resistance and inflammation marker expression in the rH ypoE‐7 and mH ypoE‐46 neurones, consistent with effects seen with TNF α in peripheral tissues. It also mimics insulin‐ and palmitate‐induced insulin resistance in hypothalamic neurones. The present study provides further evidence that altered central energy metabolism may be caused by obesity‐induced cytokine expression.
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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 | 0.001 |
| 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 | 0.001 |
| 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 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".