Cargando…

Mice Lacking Gpr75 are Hypophagic and Thin

PURPOSE: Humans with haploinsufficiency of GPR75, an orphan GPCR, are thin. Gpr75 knockout (KO) mice are also thin with improved glucose homeostasis. We wanted to confirm these findings in Gpr75 KO mice and determine whether decreased energy intake and/or increased energy expenditure contributed to...

Descripción completa

Detalles Bibliográficos
Autores principales: Powell, David R, Doree, Deon D, DaCosta, Christopher M, Platt, Kenneth A, Brommage, Robert, Buhring, Lindsey, Revelli, Jean-Pierre, Shadoan, Melanie K
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Dove 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8743382/
https://www.ncbi.nlm.nih.gov/pubmed/35023939
http://dx.doi.org/10.2147/DMSO.S342799
_version_ 1784629891248947200
author Powell, David R
Doree, Deon D
DaCosta, Christopher M
Platt, Kenneth A
Brommage, Robert
Buhring, Lindsey
Revelli, Jean-Pierre
Shadoan, Melanie K
author_facet Powell, David R
Doree, Deon D
DaCosta, Christopher M
Platt, Kenneth A
Brommage, Robert
Buhring, Lindsey
Revelli, Jean-Pierre
Shadoan, Melanie K
author_sort Powell, David R
collection PubMed
description PURPOSE: Humans with haploinsufficiency of GPR75, an orphan GPCR, are thin. Gpr75 knockout (KO) mice are also thin with improved glucose homeostasis. We wanted to confirm these findings in Gpr75 KO mice and determine whether decreased energy intake and/or increased energy expenditure contributed to the thin phenotype. METHODS: Gpr75 KO mice were generated by homologous recombination. All studies compared female and male Gpr75 KO mice to their wild type (WT) littermates. Body composition was measured by DXA and QMR technologies. Glucose homeostasis was evaluated by measuring glucose and insulin levels during oral glucose tolerance tests (OGTTs). Food intake was measured in group-housed mice. In singly housed mice, energy expenditure was measured in Oxymax indirect calorimetry chambers, and locomotor activity was measured in Oxymax and Photobeam Activity System chambers. RESULTS: In all 12 cohorts of adult female or male mice, Gpr75 KO mice had less body fat; pooled data showed that, compared to WT littermates (n = 103), Gpr75 KO mice (n = 118) had 49% less body fat and 4% less LBM (P < 0.001 for each). KO mice also had 8% less body fat at weaning (P < 0.05), and during the month after weaning as the thin phenotype became more exaggerated, Gpr75 KO mice ate significantly less than, but had energy expenditure and activity levels comparable to, their WT littermates. During OGTTs, Gpr75 KO mice showed improved glucose tolerance (glucose AUC 23% lower in females, P < 0.05, and 26% lower in males, P < 0.001), accompanied by significantly decreased insulin levels and significantly increased insulin sensitivity indices. CONCLUSION: Gpr75 KO mice are thin at weaning, are hypophagic as the thin phenotype becomes more exaggerated, and exhibit improved glucose tolerance and insulin sensitivity as healthy-appearing adults. These results suggest that inhibiting GPR75 in obese humans may safely decrease energy intake and body fat while improving glucose tolerance and insulin sensitivity.
format Online
Article
Text
id pubmed-8743382
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Dove
record_format MEDLINE/PubMed
spelling pubmed-87433822022-01-11 Mice Lacking Gpr75 are Hypophagic and Thin Powell, David R Doree, Deon D DaCosta, Christopher M Platt, Kenneth A Brommage, Robert Buhring, Lindsey Revelli, Jean-Pierre Shadoan, Melanie K Diabetes Metab Syndr Obes Original Research PURPOSE: Humans with haploinsufficiency of GPR75, an orphan GPCR, are thin. Gpr75 knockout (KO) mice are also thin with improved glucose homeostasis. We wanted to confirm these findings in Gpr75 KO mice and determine whether decreased energy intake and/or increased energy expenditure contributed to the thin phenotype. METHODS: Gpr75 KO mice were generated by homologous recombination. All studies compared female and male Gpr75 KO mice to their wild type (WT) littermates. Body composition was measured by DXA and QMR technologies. Glucose homeostasis was evaluated by measuring glucose and insulin levels during oral glucose tolerance tests (OGTTs). Food intake was measured in group-housed mice. In singly housed mice, energy expenditure was measured in Oxymax indirect calorimetry chambers, and locomotor activity was measured in Oxymax and Photobeam Activity System chambers. RESULTS: In all 12 cohorts of adult female or male mice, Gpr75 KO mice had less body fat; pooled data showed that, compared to WT littermates (n = 103), Gpr75 KO mice (n = 118) had 49% less body fat and 4% less LBM (P < 0.001 for each). KO mice also had 8% less body fat at weaning (P < 0.05), and during the month after weaning as the thin phenotype became more exaggerated, Gpr75 KO mice ate significantly less than, but had energy expenditure and activity levels comparable to, their WT littermates. During OGTTs, Gpr75 KO mice showed improved glucose tolerance (glucose AUC 23% lower in females, P < 0.05, and 26% lower in males, P < 0.001), accompanied by significantly decreased insulin levels and significantly increased insulin sensitivity indices. CONCLUSION: Gpr75 KO mice are thin at weaning, are hypophagic as the thin phenotype becomes more exaggerated, and exhibit improved glucose tolerance and insulin sensitivity as healthy-appearing adults. These results suggest that inhibiting GPR75 in obese humans may safely decrease energy intake and body fat while improving glucose tolerance and insulin sensitivity. Dove 2022-01-05 /pmc/articles/PMC8743382/ /pubmed/35023939 http://dx.doi.org/10.2147/DMSO.S342799 Text en © 2022 Powell et al. https://creativecommons.org/licenses/by-nc/3.0/This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/ (https://creativecommons.org/licenses/by-nc/3.0/) ). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).
spellingShingle Original Research
Powell, David R
Doree, Deon D
DaCosta, Christopher M
Platt, Kenneth A
Brommage, Robert
Buhring, Lindsey
Revelli, Jean-Pierre
Shadoan, Melanie K
Mice Lacking Gpr75 are Hypophagic and Thin
title Mice Lacking Gpr75 are Hypophagic and Thin
title_full Mice Lacking Gpr75 are Hypophagic and Thin
title_fullStr Mice Lacking Gpr75 are Hypophagic and Thin
title_full_unstemmed Mice Lacking Gpr75 are Hypophagic and Thin
title_short Mice Lacking Gpr75 are Hypophagic and Thin
title_sort mice lacking gpr75 are hypophagic and thin
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8743382/
https://www.ncbi.nlm.nih.gov/pubmed/35023939
http://dx.doi.org/10.2147/DMSO.S342799
work_keys_str_mv AT powelldavidr micelackinggpr75arehypophagicandthin
AT doreedeond micelackinggpr75arehypophagicandthin
AT dacostachristopherm micelackinggpr75arehypophagicandthin
AT plattkennetha micelackinggpr75arehypophagicandthin
AT brommagerobert micelackinggpr75arehypophagicandthin
AT buhringlindsey micelackinggpr75arehypophagicandthin
AT revellijeanpierre micelackinggpr75arehypophagicandthin
AT shadoanmelaniek micelackinggpr75arehypophagicandthin