Altered metabolism in the melatonin-related receptor (GPR50) knockout mouse

Elena A. Ivanova, David A. Bechtold, Sandrine M. Dupre, John Brennand, Perry Barrett, Simon M. Luckman, Andrew S. I. Loudon

Research output: Contribution to journalArticle

59 Citations (Scopus)

Abstract

The X-linked orphan receptor GPR50 shares 45% homology with the melatonin receptors, yet its ligand and physiological function remain unknown. Here we report that mice lacking functional GPR50 through insertion of a lacZ gene into the coding sequence of GPR50 exhibit an altered metabolic phenotype. GPR50 knockout mice maintained on normal chow exhibit lower body weight than age-matched wild-type littermates by 10 wk of age. Furthermore, knockout mice were partially resistant to diet-induced obesity. When placed on a high-energy diet (HED) for 5 wk, knockout mice consumed significantly more food per unit body weight yet exhibited an attenuated weight gain and reduced body fat content compared with wild-type mice. Wheel-running activity records revealed that, although GPR50 knockout mice showed no alteration of circadian period, the overall levels of activity were significantly increased over wild types in both nocturnal and diurnal phases. In line with this, basal metabolic rate (O-2 consumption, CO2 production, and respiratory quotient) was found to be elevated in knockout mice. Using in situ hybridization (wild-type mice) and beta-galactosidase activity (from LacZ insertion element in knockout mice), brain expression of GPR50 was found to be restricted to the ependymal layer of the third ventricle and dorsomedial nucleus of the hypothalamus. GPR50 expression was highly responsive to energy status, showing a significantly reduced expression following both fasting and 5 wk of HED. These data implicate GPR50 as an important regulator of energy metabolism.

Original languageEnglish
Pages (from-to)E176-E182
Number of pages7
JournalAmerican Journal of Physiology: Endocrinology and Metabolism
Volume294
Issue number1
Early online date23 Oct 2007
DOIs
Publication statusPublished - Jan 2008

Keywords

  • dorsomedial hypothalamus
  • metabolic rate
  • obesity
  • tanycyte
  • iodothyronine deiodinase
  • dorsomedial nucleus
  • Siberian
  • gene-expression
  • hypothalamus
  • tanycytes
  • fat
  • binding
  • brain
  • rat

Cite this

Ivanova, E. A., Bechtold, D. A., Dupre, S. M., Brennand, J., Barrett, P., Luckman, S. M., & Loudon, A. S. I. (2008). Altered metabolism in the melatonin-related receptor (GPR50) knockout mouse. American Journal of Physiology: Endocrinology and Metabolism, 294(1), E176-E182. https://doi.org/10.1152/ajpendo.00199.2007

Altered metabolism in the melatonin-related receptor (GPR50) knockout mouse. / Ivanova, Elena A.; Bechtold, David A.; Dupre, Sandrine M.; Brennand, John; Barrett, Perry; Luckman, Simon M.; Loudon, Andrew S. I.

In: American Journal of Physiology: Endocrinology and Metabolism, Vol. 294, No. 1, 01.2008, p. E176-E182.

Research output: Contribution to journalArticle

Ivanova, Elena A. ; Bechtold, David A. ; Dupre, Sandrine M. ; Brennand, John ; Barrett, Perry ; Luckman, Simon M. ; Loudon, Andrew S. I. / Altered metabolism in the melatonin-related receptor (GPR50) knockout mouse. In: American Journal of Physiology: Endocrinology and Metabolism. 2008 ; Vol. 294, No. 1. pp. E176-E182.
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AB - The X-linked orphan receptor GPR50 shares 45% homology with the melatonin receptors, yet its ligand and physiological function remain unknown. Here we report that mice lacking functional GPR50 through insertion of a lacZ gene into the coding sequence of GPR50 exhibit an altered metabolic phenotype. GPR50 knockout mice maintained on normal chow exhibit lower body weight than age-matched wild-type littermates by 10 wk of age. Furthermore, knockout mice were partially resistant to diet-induced obesity. When placed on a high-energy diet (HED) for 5 wk, knockout mice consumed significantly more food per unit body weight yet exhibited an attenuated weight gain and reduced body fat content compared with wild-type mice. Wheel-running activity records revealed that, although GPR50 knockout mice showed no alteration of circadian period, the overall levels of activity were significantly increased over wild types in both nocturnal and diurnal phases. In line with this, basal metabolic rate (O-2 consumption, CO2 production, and respiratory quotient) was found to be elevated in knockout mice. Using in situ hybridization (wild-type mice) and beta-galactosidase activity (from LacZ insertion element in knockout mice), brain expression of GPR50 was found to be restricted to the ependymal layer of the third ventricle and dorsomedial nucleus of the hypothalamus. GPR50 expression was highly responsive to energy status, showing a significantly reduced expression following both fasting and 5 wk of HED. These data implicate GPR50 as an important regulator of energy metabolism.

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