A311 INTERACTION BETWEEN SOCS3 AND NITRIC OXIDE SIGNALLING IN THE EFFECTS OF DIET-INDUCED OBESITY AND LEPTIN ON VAGAL AFFERENT EXCITABILITY
Bibliographic record
Abstract
We have recently shown that suppressor of cytokine signaling-3 (SOCS3), a negative regulator in leptin signalling, plays a role in vagal hyposensitivity associated with diet-induced obesity and high concentrations of leptin. Diet-induced obesity also enhances nitric oxide (NO) production, which also has a negative effect on vagal afferent sensitivity. The present study aimed to examine the potential interaction between SOCS3 and NO signalling pathways in diet-induced obesity and in vitro effect of leptin. C57Bl6J mice were rendered obese by feeding a diet of 60% calories from fat (HFF) for 12–16 weeks; mice fed 10% calories from fat (LFF) were used as controls. To mimic the hyperleptinemia that is seen in obesity, in vitro, nodose neurons from standard diet fed mice were incubated overnight with leptin (100nM). Zoledronic acid (ZA) used as an inhibitor of SOCS3. Current clamp recordings were performed 18–24 h post-dissociation. NO was measured in culture media using a Nitrate/Nitrite fluorometric Assay kit. Media was collected after cell incubation for 24 hrs. ZA prevented the inhibitory effect of high concentration of leptin and diet-induced obesity on vagal afferent excitability. ZA (10 mM) significantly decreased rheobase in leptin incubated neuron (86.4 ± 8.2 pA (n=14, Leptin) vs. 57.1 ± 5.5 pA (n=17, ZA+Leptin, **p=0.0045)). ZA significantly decreased rheobase in neurons from HFF mice (111.9 ± 9.1 pA (n=16, HFF) vs. 45.3 ± 4.7 pA (n=15, HFF + ZA) ***p<0.0001), but not in LFF mice (66.9 ± 5.1 pA (n=16, LFF) vs. 59.3 ± 7.6 pA (n=15, LFF + ZA) NS). The NOS inhibitor L-NNA (0.1 mM, 30 min) significantly decreased rheobase in leptin-incubated neurons (99.3 ± 14.9 pA (n=15, leptin) vs. 42.1 ± 3.7 pA (n=14, leptin + L-NNA) **p=0.0013). L-NNA (0.1 mM, 30 min incubation) also significantly decreased rheobase in HFF neurons (112.1 ± 14.6 pA (n=14, HFF) vs. 57.8 ± 10.9 pA (n=9, HFF + L-NNA) **p=0.041), not in LFF. The effect of ZA on endogenous NO production was tested. ZA significantly reduced NO fluorescence in HFF (43.4 ± 0.7 (HFF) vs. 31.8 ± 2.1 (HFF+ZA), ***0.0003 n=6), but not in LFF (27.8 ± 1.3 (LFF) vs. 31.4 ± 1.9 (LFF+ZA), NS n=6). Leptin significantly increased NO fluorescence (23.6 ± 1.0 (control) vs. 33.1 ± 2.1 (Leptin), **0.0027, n=6). ZA reduced NO fluorescence in leptin-incubated media (27.5 ± 2.5 (Leptin+ZA), n=6). Inhibition of SOCS3 reversed the inhibitory effects of obesity and high leptin concentrations and reduced NO levels. We suggest there is a link between SOCS3 and NO signaling in vagal afferents. SOCS3/NO pathway may be an important therapeutic target in obesity/hyperleptinemia. CIHR
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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 | 0.000 |
| 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) | 0.002 | 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 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".