A missense mutation in zinc finger homeobox‐3 ( <scp>ZFHX3</scp> ) impedes growth and alters metabolism and hypothalamic gene expression in mice
Bibliographic record
Abstract
Abstract A protein altering variant in the gene encoding zinc finger homeobox‐3 ( ZFHX3 ) has recently been associated with lower BMI in a human genome‐wide association study. We investigated metabolic parameters in mice harboring a missense mutation in Zfhx3 ( Zfhx3 Sci/+ ) and looked for altered in situ expression of transcripts that are associated with energy balance in the hypothalamus to understand how ZFHX3 may influence growth and metabolic effects. One‐year‐old male and female Zfhx3 Sci/+ mice weighed less, had shorter body length, lower fat mass, smaller mesenteric fat depots, and lower circulating insulin, leptin, and insulin‐like growth factor‐1 (IGF1) concentrations than Zfhx3 +/+ littermates. In a second cohort of 9–20‐week‐old males and females, Zfhx3 Sci/+ mice ate less than wildtype controls, in proportion to body weight. In a third cohort of female‐only Zfhx3 Sci/+ and Zfhx3 +/+ mice that underwent metabolic phenotyping from 6 to 14 weeks old, Zfhx3 Sci/+ mice weighed less and had lower lean mass and energy expenditure, but fat mass did not differ. We detected increased expression of somatostatin and decreased expression of growth hormone‐releasing hormone and growth hormone‐receptor mRNAs in the arcuate nucleus (ARC). Similarly, ARC expression of orexigenic neuropeptide Y was decreased and ventricular ependymal expression of orphan G protein‐coupled receptor Gpr50 was decreased. We demonstrate for the first time an energy balance effect of the Zfhx3 Sci mutation, likely by altering expression of key ARC neuropeptides to alter growth, food intake, and energy expenditure.
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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 | 0.001 | 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) | 0.000 | 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".