Mice lacking GPR3 receptors display late-onset obese phenotype due to impaired thermogenic function in brown adipose tissue

Grzegorz Godlewski,Judith Harvey-White,Tony Jourdan,Pál Pacher,Douglas Osei-Hyiaman,Bani Mukhopadhyay,Jie Liu,Resat Cinar Resat Cinar,Gergő Szanda,George Kunos George Kunos,Fong Ming Mo,Joseph Tam

doi:10.1038/srep14953

Abstract

We report an unexpected link between aging, thermogenesis and weight gain via the orphan G protein-coupled receptor GPR3. Mice lacking GPR3 and maintained on normal chow had similar body weights during their first 5 months of life, but gained considerably more weight thereafter and displayed reduced total energy expenditure and lower core body temperature. By the age of 5 months GPR3 KO mice already had lower thermogenic gene expression and uncoupling protein 1 protein level and showed impaired glucose uptake into interscapular brown adipose tissue (iBAT) relative to WT littermates. These molecular deviations in iBAT of GPR3 KO mice preceded measurable differences in body weight and core body temperature at ambient conditions, but were coupled to a failure to maintain thermal homeostasis during acute cold challenge. At the same time, the same cold challenge caused a 17-fold increase in Gpr3 expression in iBAT of WT mice. Thus, GPR3 appears to have a key role in the thermogenic response of iBAT and may represent a new therapeutic target in age-related obesity.

Highlights

We report an unexpected link between aging, thermogenesis and weight gain via the orphan G protein-coupled receptor GPR3
Gpr[3] is expressed in several metabolically active peripheral tissues, at lower levels than in the central nervous system (CNS) (Fig. 1A), and its partial or total deletion leads to genotype-specific changes in body weights of older (12-month-old) mice (Fig. 1B)
Over the course of one year, GPR3 heterozygous (Het) and knockout (KO) mice maintained on a regular mouse chow gained on average ~15% and ~30% more weight, respectively, than their age-matched wild type (WT) littermates and were visually distinguishable from each other (Fig. 1B)

Summary

Introduction

We report an unexpected link between aging, thermogenesis and weight gain via the orphan G protein-coupled receptor GPR3. By the age of 5 months GPR3 KO mice already had lower thermogenic gene expression and uncoupling protein 1 protein level and showed impaired glucose uptake into interscapular brown adipose tissue (iBAT) relative to WT littermates. These molecular deviations in iBAT of GPR3 KO mice preceded measurable differences in body weight and core body temperature at ambient conditions, but were coupled to a failure to maintain thermal homeostasis during acute cold challenge. Mice lacking GPR3 display late-onset obesity associated with a reduction in uncoupling protein 1 protein level in iBAT and thermogenesis

Methods

Results

Conclusion