LBODP080 Mc3r Expression In Liver Tissue Is Partially Responsible For The Severity Of Murine MC3R Deficiency Associated Obesity
Bibliographic record
Abstract
Abstract The Melanocortin 3 Receptor (MC3R) is highly expressed in the hypothalamus, where it regulates energy balance and pubertal development. Function-altering SNPs in MC3R have been found to be associated with greater adiposity in both children and adults. Global Mc3r knockout mice show a phenotype of increased fat mass and develop metabolic syndrome. However, in otherwise Mc3r null mice, recovery of Mc3r expression only in the CNS shows greater adiposity compared to controls. Thus, peripheral MC3R expression might have a role in regulating energy homeostasis. Using droplet digital PCR, we found evidence for Mc3r expression in murine liver tissue. A liver-specific MC3R recovery model was generated by crossbreeding mice with a floxed transcriptionally blocked Mc3r (Mc3rtb/tb) to mice expressing albumin-Cre recombinase (Alb-Cre+/+). MC3R reactivation in the liver caused a partial recovery from the obesity phenotype of Mc3rtb/tb mice exposed to 45 kcal% energy fat diet for 12 weeks, particularly in female mice. Recovery of hepatic Mc3r was sufficient to partially reverse the increased percentage fat mass of Mc3rtb/tb (Mc3rtb/tb: n=11, 55.3 ± 0.8% (SEM); Mc3rtb/tb, Alb-Cre+/+: n=13, 52.4 ± 0.8%; BL/6: n=14, 39.7 ± 2.1%, p=0. 017). Similar recovery was observed for total fat mass (p=0. 0012), % lean mass (p=0. 02), and body weight (p=0. 007), with no differences in total lean mass (p=0.1). Hepatic recovery mice also showed trends towards reduced total liver mass compared to the global knockout (p=0. 07). Glucose Area Under Curve (AUCg) analysis of ITT showed no improvement in insulin sensitivity with liver recovery (Mc3rtb/tb: n=11, 16223 ± 1223; Mc3rtb/tb, Alb-Cre+/+: n= 9, 14524 ± 1479; BL/6: n=9, 11725 ± 1024 min*mg/dL, p=0.3), and no evidence for recovery was observed in the GTT AUCg (Mc3rtb/tb: n=10, 31137 ± 2882; Mc3rtb/tb, Alb-Cre+/+: n=9, 27553 ± 1887; BL/6: n=9, 21355 ± 1205 min*mg/dL, p=0.32). In addition to liver-specific recovery, we generated a liver-specific Mc3r knockout mouse by crossing a floxed-Mc3r (LoxP+/+) line with the Alb-Cre+/+ mouse line. In the liver-specific Mc3r knockout mice, no significant total body composition changes and a nonsignificant trend towards worsened ITT AUCg (Alb-Cre+/+: n=8, 12795 ± 943; LoxP+/+, Alb-Cre+/+: n=8, 14893 ± 855 min*mg/dL, p=0.12) were observed; however, GTT AUCg was higher (Alb-Cre+/+: n=8, 19691 ± 1351; LoxP+/+, Alb-Cre+/+: n=9, 24450 ± 1657 min*mg/dL, p=0. 042), and there was an increase in liver weight (Alb-Cre+/+: n=8, 1. 025 ± 0. 09 g; LoxP+/+, Alb-Cre+/+: n=9, 1.44 ± 0. 09 g, p=0. 0007). We conclude that hepatic Mc3r deficiency contributes to the obesity phenotype in Mc3r-deficient mice, and that MC3R in the liver is responsible for localized metabolic effects in peripheral tissues. Further analysis of tissue samples from these mice may guide a more specific understanding of the role of hepatic MC3R. Presentation: No date and time listed
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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 | 0.002 | 0.001 |
| 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) | 0.000 | 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".