The paper uses Zfhx3Sci/+ mice as a genetic model to test how a missense mutation in Zfhx3 affects growth, metabolism, and hypothalamic gene expression.
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Zfhx3Sci/+ mouse missense mutation model
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Zfhx3Sci, Zfhx3Sci/+, Zfhx3 Sci mutation
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Zfhx3Sci/+ mice eat less than wildtype controls in proportion to body weight.
In a second cohort of 9-20-week-old males and females, Zfhx3Sci/+ mice ate less than wildtype controls, in proportion to body weight.
The Zfhx3Sci mutation is associated with increased somatostatin expression and decreased Ghrh, Ghr, Npy, and Gpr50 expression in hypothalamic regions including the arcuate nucleus.
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.
The paper concludes that the Zfhx3Sci mutation affects energy balance likely by altering expression of key arcuate nucleus neuropeptides that influence growth, food intake, and energy expenditure.
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.
In female mice aged 6 to 14 weeks, Zfhx3Sci/+ animals weigh less and have lower lean mass and energy expenditure, while fat mass does not differ from controls.
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.
Zfhx3Sci/+ mice show reduced growth and altered metabolic traits relative to wildtype littermates.
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.