TNFα exposure induces neuroinflammation and insulin resistance in a rat‐derived hypothalamic cell model, rHypoE‐7
Bibliographic record
Abstract
Obesity is approaching epidemic levels. One of the main characteristics of obesity is the development of insulin resistance, leading to other comorbidities, such as type 2 diabetes mellitus (T2DM) and cardiovascular disease. Insulin resistance has been shown to be induced with obesity in peripheral tissues, such as liver, muscle, and adipocytes, by the pro‐inflammatory cytokine tumor necrosis factor alpha (TNFα). In the hypothalamus, the main brain region for energy regulation, neuroinflammation‐induced insulin resistance has been demonstrated to occur upon prolonged treatment with high levels of insulin and palmitate, and we are exploring whether TNFα, a downstream surrogate for palmitate, has similar effects. We hypothesized that TNFα‐treated rat hypothalamic neurons would exhibit cellular neuroinflammation and insulin resistance as evidenced by increased expression of pro‐inflammatory genes and attenuated phosphorylation of Akt (pAkt) in the insulin signaling pathway. Using an immortalized rat hypothalamic cell line (rHypoE‐7), a well‐characterized NPY‐expressing neuronal line derived from male embryonic hypothalamii, we studied changes in pAkt and inflammatory gene marker mRNA expression after TNFα treatment by Western blot and quantitative real‐time PCR, respectively. A qPCR array of 84 inflammatory markers (receptors, chemokines, and cytokines) demonstrated an increase in the expression of a number of genes encoding inflammatory markers, including Tollip and Caspase‐1 , upon exposure to 100 ng/mL TNFα for 4 h. Neurons pre‐exposed to TNFα (50 ng/mL) for 6 or 16 h exhibited a significant reduction in pAkt compared to control after insulin treatment. TNFα also significantly increased mRNA expression of TNF , IK‐κB , Tollip , Tnfrsf1a , and IL6 at 4 h. In conclusion, pre‐treatment with the inflammatory cytokine TNFα causes cellular insulin resistance in the rHypoE‐7 neurons, consistent with effects seen with TNFα in peripheral tissues. It also mimics insulin‐ and palmitate‐induced insulin resistance in hypothalamic neurons. Further, these results demonstrate that components of the IKK‐β/NF‐κB pathway appear to be activated upon exposure to TNFα, providing a putative target to reverse neuroinflammation and insulin resistance with anti‐inflammatory agents. Support or Funding Information This research was supported by grants from the CIHR, CRC, CFI, NSERC, APS and BBDC.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
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 source (direct Gemma or distilled Codex), 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".