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Metabolic insights from a GHSR-A203E mutant mouse model
Lola J Torz1, Sherri Osborne-Lawrence2, Juan Rodriguez2
1Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
Molecular Metabolism
|April 28, 2020
Summary
Constitutive growth hormone secretagogue receptor (GHSR) activity influences metabolism and growth. A specific GHSR mutation (A203E) ablates this activity, leading to altered metabolic responses and reduced growth, consistent with human mutations.
Area of Science:
- Endocrinology
- Neuroscience
- Molecular Biology
Background:
- Ghrelin receptor (GHSR) signaling impacts growth hormone (GH) release, appetite, and glucose metabolism.
- Constitutive (basal) GHSR activity, independent of ghrelin, may also play a physiological role.
- Naturally occurring GHSR mutations and inverse agonists suggest impairment of constitutive activity affects metabolic and growth parameters.
Purpose of the Study:
- To investigate the physiological relevance of constitutive GHSR activity.
- To characterize the effects of a specific GHSR mutation (A203E) that impairs constitutive activity.
Main Methods:
- Generated mice with a GHSR-A203E mutation, analogous to a human mutation.
- Conducted ex vivo neuronal electrophysiology and in vivo metabolic assessments in mutant mice.
- Measured cellular signaling in HEK293T and COS-7 cells transfected with wild-type (GHSR-WT) or GHSR-A203E constructs.
Main Results:
- The GHSR-A203E mutation reduced baseline signaling in cell assays and altered neuronal activity.
- GHSR-A203E mice exhibited impaired GH release and exaggerated blood glucose drops during caloric restriction.
- Mutant mice showed reduced responses to administered ghrelin, including appetite and GH secretion, and reduced growth in aged animals.
Conclusions:
- The A203E mutation effectively ablates constitutive GHSR activity.
- Constitutive GHSR activity contributes to the normal electrical activity of specific neurons in the hypothalamus.
- Impaired constitutive GHSR activity leads to metabolic dysregulation and reduced growth, mirroring human conditions.
