SAT002 Liver-specific Loss Of The Nuclear Receptor Co-regulator ARGLU1 Protects Against Diet-induced Obesity In Female Mice Independent Of Food Intake And Energy Expenditure
Bibliographic record
Abstract
Abstract Disclosure: S.B. Cash: None. L. Magomedova: None. R. Tsai: None. C.L. Cummins: None. Arginine and glutamate rich 1 (ARGLU1) has been shown to be a co-regulator for several nuclear receptors including ER, GR and the peroxisome proliferator-activated receptors (PPARs), which are key modulators of nutrient metabolism. We have previously reported that loss of ARGLU1 in the liver protects aged male mice against high-fat diet induced obesity and type 2 diabetes [1]. Here, we assessed the importance of ARGLU1 in lipid and carbohydrate metabolism in aged female mice and used indirect calorimetry to understand the metabolic basis of the resistance to weight gain observed with liver-specific loss of ARGLU1. Aged (11-month-old) female wildtype floxed-Arglu1 mice (Arglu1fl/fl) and liver-specific Arglu1-null mice (Arglu1LKO) were fed a high fat, high cholesterol diet (HFD, 42% calories from fat, TD.88137 Envigo) for 12-weeks (N=7-17). Female mice were housed in Promethion Metabolic Cages (Sable Systems) at room temperature for 5 days during which their food intake, water intake, physical activity, O2 consumption, and CO2 production were measured (N=5-7). Female mice were also subjected to a glucose tolerance test and insulin tolerance test (N=4-8). In agreement with our previous results in male Arglu1LKO mice [1], female Arglu1LKO mice were resistant to diet-induced obesity with final body weights compared to HFD-fed Arglu1fl/fl mice of 30.6 ± 0.9 g vs 35 ± 1 g (P<0.05). Likewise, female Arglu1LKO mice were more glucose tolerant and insulin tolerant compared to HFD-fed Arglu1fl/fl mice. The metabolic cage data showed no change in food intake, locomotor activity or energy expenditure between HFD-fed Arglu1fl/fl and Arglu1LKO mice when accounting for body mass as a covariate (ANCOVA, CalR). Surprisingly, HFD-fed female Arglu1LKO mice had significantly higher water intake compared to HFD-fed Arglu1fl/fl mice (P<0.02). These data support the conclusion that resistance to diet-induced obesity in Arglu1LKO mice is independent of sex. To our surprise, based on the metabolic cage data, we conclude that the mechanism by which Arglu1LKO mice are resistant to diet induced obesity is not due to enhanced energy expenditure or decreased food intake. Future studies will explore whether differential intestinal lipid absorption (independent of food intake) could account for the differences we observed in weight gain between the genotypes. [1] Magomedova, L., Tsai, R., & Cummins, C. L. (2017, April). Hepatic Ablation of the Nuclear Receptor Coactivator, ARGLU1, Is Protective Against the Development of Type 2 Diabetes and Fatty Liver in High-Fat Diet Fed Mice. In 99th Annual Meeting of the Endocrine Society. Endocrine Society. Presentation: Saturday, June 17, 2023
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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) | 0.000 | 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 | 0.001 | 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".