Reduced Body Weight and Increased Energy Expenditure in Transgenic Mice Over-Expressing Soluble Leptin Receptor

Phing-How Lou,Lu Huang,George K Radda,Cai Li,Yunxia Cui,Weiping Han,Tiffany Pourbahrami,Guoqing Yang,Aimin Xu

doi:10.1371/journal.pone.0011669

Abstract

BackgroundSoluble leptin receptor (OBRe), one of several leptin receptor isoforms, is the only bona fide leptin binding protein in plasma. Our earlier studies demonstrated that OBRe modulates leptin levels in circulation. Both clinical and in vitro studies have shown that OBRe expression is inversely correlated to body weight and leptin levels. However, it is not clear whether OBRe plays an active role, either in collaboration with leptin or independently, in the maintenance of body weight.Methodology/Principal FindingsTo investigate the function of OBRe in the regulation of energy homeostasis, we generated transgenic mice that express OBRe under the control of human serum amyloid P (hSAP) component gene promoter. The transgene led to approximately doubling of OBRe in circulation in the transgenic mice than in wild type control mice. Transgenic mice exhibited lower body weight at 4 weeks of age, and slower rate of weight gain when compared with control mice. Furthermore, transgenic mice had lower body fat content. Indirect calorimetry revealed that transgenic mice had reduced food intake, increased basal metabolic rate, and increased lipid oxidation, which could account for the differences in body weight and body fat content. Transgenic mice also showed higher total circulating leptin, with the majority of it being in the bound form, while the amount of free leptin is comparable between transgenic and control mice.ConclusionsThese results are consistent with the role of OBRe as a leptin binding protein in regulating leptin's bioavailability and activity.

Highlights

Obesity, a result of disruption in energy homeostasis, is increasingly becoming a prevalent global pandemic
Generation of human serum amyloid P (hSAP)-OBRe mice To test the effects of increased circulating OBRe on energy homeostasis, we generated transgenic mice to achieve consistent and sustained OBRe over-expression
Expression of the transgene was under the hSAP promoter (Figure 1A), which has been used previously to drive high-level expression in livers of transgenic mouse models [27,28]

Summary

Introduction

A result of disruption in energy homeostasis, is increasingly becoming a prevalent global pandemic. The full-length receptor, OBRb has been shown to transmit leptin signal through its C-terminal tyrosine residues and associated proteins, and is responsible for most, if not all of the leptin’s regulatory function in energy homeostasis, as the mutation that ablates OBRb expression causes a phenotype that is indistinguishable from that in animals without leptin [10,12,14]. Our earlier studies demonstrated that OBRe modulates leptin levels in circulation Both clinical and in vitro studies have shown that OBRe expression is inversely correlated to body weight and leptin levels. It is not clear whether OBRe plays an active role, either in collaboration with leptin or independently, in the maintenance of body weight

Methods

Results

Conclusion