Involvement of Leptin Receptor Long Isoform (LepRb)-STAT3 Signaling Pathway in Brain Fat Mass- and Obesity-Associated (FTO) Downregulation during Energy Restriction

Pei Wang,Yun-Feng Guan,Tian-Ying Xu,Feng-Jiao Yang,Chao-Yu Miao,Hui Du,Xue-Wen Xu,Ding-Feng Su

doi:10.2119/molmed.2010.000134

Abstract

Obesity is an important risk factor for cardiovascular disease, diabetes and certain cancers. The fat mass- and obesity-associated (FTO) gene is tightly associated with the pathophysiology of obesity, whereas the exact role of FTO remains poorly understood. Here, we investigated the alternations of FTO mRNA and protein expression in the peripheral metabolic tissues and the brain upon energy restriction (ER) and explored the involvement of the leptin signaling pathway in FTO regulation under ER status. ER decreased the FTO mRNA and protein expression in hypothalamus and brainstem but not in periphery. Using double-immunofluorescence staining, FTO was found to be colocalized with the leptin receptor long isoform (LepRb) in arcuate nucleus of hypothalamus and the nucleus of the solitary tract. In LepRb mutant db/db mice, the FTO downregulation in brain and body weight reduction induced by ER were completely abolished. The enhanced phosphorylation of signal transducer and activator of transcription 3 (STAT3) induced by ER was also impaired in db/db mice. Moreover, leptin directly activated the STAT3 signaling pathway and downregulated FTO in in vitro arcuate nucleus of hypothalamus cultures and in vivo wild-type mice but not db/db mice. Thus, our results provide the first evidence that the LepRb-STAT3 signaling pathway is involved in the brain FTO downregulation during ER.

Highlights

Obesity has reached epidemic proportions worldwide, and accumulating evidence indicates that obesity is a heterogeneous disorder affected by both genetic and nongenetic factors
We determined the effect of energy restriction (ER) on fat mass– and obesity-associated (FTO) mRNA expression in tissues using real-time Polymerase chain reaction (PCR) analysis
Emerging evidence suggests that the FTO gene is an obesity gene controlling food intake or energy expenditure, or both [1,2]

Summary

Introduction

Obesity has reached epidemic proportions worldwide, and accumulating evidence indicates that obesity is a heterogeneous disorder affected by both genetic and nongenetic factors. The association between polymorphisms of the fat mass– and obesity-associated (FTO) gene and obesity was revealed by several large human genome-wide studies [1,2,3]. This result was subsequently confirmed by numerous investigations [4,5,6,7]. Many studies have examined the effect of FTO gene variation on obesity risk, the biological functions of FTO in obesity and the underlying mechanisms are largely unknown

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Results

Conclusion