Dysregulated editing of serotonin 2C receptor mRNAs results in energy dissipation and loss of fat mass.
RNA editing that converts adenosine to inosine replaces the gene-encoded Ile, Asn, and Ile (INI) of serotonin [5-hydroxytryptamine (5-HT)] receptor 2C (5-HT(2C)R) with Val, Gly, and Val (VGV). Up to 24 different 5-HT(2C)R isoforms are detected in different brain regions (Burns et al., 1997; Fitzgerald et al., 1999; Wang et al., 2000). To elucidate the physiological significance of 5-HT(2C)R mRNA editing, we derived mutant mouse lines harboring a knock-in INI or VGV allele, resulting in sole expression of one of two extremely different editing isoforms 5-HT(2C)R-INI (editing blocked) or -VGV (fully edited). Although INI mice grew normally, VGV mice had a severely reduced fat mass, despite compensatory hyperphagia, as a result of constitutive activation of the sympathetic nervous system and increased energy expenditure. Furthermore, serotonergic neurotransmission was oversensitized in VGV mice, most likely because of the increased cell surface expression of VGV receptors. Melanocortin 4 receptor (MC4R) regulates energy homeostasis (Balthasar et al., 2005; Heisler et al., 2006; Lam et al., 2008), and Mc4r(-/-) mice are obese because of hyperphagia and reduced energy expenditure (Huszar et al., 1997). However, the elevated energy expenditure of VGV mice could not be rescued in the Mc4r(-/-) background, indicating the presence of a distinct signaling pathway mediated via 5-HT(2C)R-VGV that dominates the MC4R-dependent pathway in control of energy expenditure. Our results highlight the importance of regulated 5-HT(2C)R mRNA editing, because dysregulation could result in the pathological consequences such as growth retardation seen in VGV mice.
Kawahara
Yukio
Y
The Wistar Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Grimberg
Adda
A
Teegarden
Sarah
S
Mombereau
Cedric
C
Liu
Sui
S
Bale
Tracy L
TL
Blendy
Julie A
JA
Nishikura
Kazuko
K
D000273:Adipose Tissue / Q000378:metabolism*; D000595:Amino Acid Sequence / Q000235:genetics; D000818:Animals; D004734:Energy Metabolism / Q000235:genetics*; D005260:Female; D055879:Gene Knock-In Techniques; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics; D017393:RNA Editing / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics*; D044105:Receptor, Melanocortin, Type 4 / Q000235:genetics / Q000378:metabolism; D044405:Receptor, Serotonin, 5-HT2C / Q000235:genetics*; D012701:Serotonin / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D013564:Sympathetic Nervous System / Q000503:physiopathology; D009435:Synaptic Transmission / Q000235:genetics
D020033:Protein Isoforms; D012333:RNA, Messenger; D044105:Receptor, Melanocortin, Type 4; D044405:Receptor, Serotonin, 5-HT2C; D012701:Serotonin