A missense mutation in zinc finger homeobox‐3 (ZFHX3) impedes growth and alters metabolism and hypothalamic gene expression in mice

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Nolan, PM, Banks, G ORCID: https://orcid.org/0000-0002-8647-667X, Bourbia, N, Wilcox, AG, Bentley, L, Moir, L, Kent, L, Hillier, R, Wilson, D, Barrett, P and Dumbell, R ORCID: https://orcid.org/0000-0002-8805-3777, 2023. A missense mutation in zinc finger homeobox‐3 (ZFHX3) impedes growth and alters metabolism and hypothalamic gene expression in mice. The FASEB Journal, 37 (10): e23189. ISSN 0892-6638

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Official URL: https://doi.org/10.1096/fj.202201829r

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 (Zfhx3Sci/+) 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 Zfhx3Sci/+ 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, Zfhx3Sci/+ mice ate less than wildtype controls, in proportion to body weight. In a third cohort of female-only Zfhx3Sci/+ and Zfhx3+/+ mice that underwent metabolic phenotyping from 6 to 14 weeks old, Zfhx3Sci/+ 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 Zfhx3Sci mutation, likely by altering expression of key ARC neuropeptides to alter growth, food intake, and energy expenditure.

Item Type:	Journal article
Description:	Received: 2022-11-07; Accepted: 2023-08-28; Published: 2023-09-15
Publication Title:	The FASEB Journal
Creators:	Nolan, P.M., Banks, G., Bourbia, N., Wilcox, A.G., Bentley, L., Moir, L., Kent, L., Hillier, R., Wilson, D., Barrett, P. and Dumbell, R.
Publisher:	Wiley
Date:	October 2023
Volume:	37
Number:	10
ISSN:	0892-6638
Identifiers:	Number Type 10.1096/fj.202201829r DOI 1805628 Other
Rights:	This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Divisions:	Schools > School of Science and Technology
Record created by:	Jonathan Gallacher
Date Added:	17 Oct 2023 10:20
Last Modified:	17 Oct 2023 10:21
URI:	https://irep.ntu.ac.uk/id/eprint/49996