Role of the central melanocortin circuitry in adaptive thermogenesis of brown adipose tissue.
The central melanocortin 4 receptor (MC4R) plays a critical role in energy homeostasis, although little is known regarding its role in the regulation of adaptive thermogenesis of brown adipose tissue (BAT). Here we show using retrograde transsynaptic tracing with attenuated pseudorabies virus coupled with dual-label immunohistochemistry that specific subsets of MC4R-expressing neurons in multiple nuclei of the central nervous system known to regulate sympathetic outflow polysynaptically connect with interscapular BAT (IBAT). Furthermore, we show that MC4R-/- and agouti-related peptide-treated mice are defective in HF diet-induced up-regulation of uncoupling protein 1 in IBAT. Additionally, MC4R-/- mice exposed to 4 C for 4 h exhibit a defect in up-regulation of uncoupling protein 1 levels in IBAT. Our results provide a neuroanatomic substrate for MC4R regulating sympathetically mediated IBAT thermogenesis and demonstrate that the MC4R is critically required for acute high-fat- and cold-induced IBAT thermogenesis.
Voss-Andreae
Adriana
A
Center for the Study of Weight Regulation and Associated Disorders and Vollum Institute, Oregon Health and Sciences University, Portland, Oregon 97239-3098, and Division of Endocrinology, Rhode Island Hospital, Providence 02903, USA.
Murphy
Jonathan G
JG
Ellacott
Kate L J
KL
Stuart
Ronald C
RC
Nillni
Eduardo A
EA
Cone
Roger D
RD
Fan
Wei
W
D000064:Acclimatization / Q000502:physiology*; D002001:Adipose Tissue, Brown / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D054369:Agouti-Related Protein; D000818:Animals; D002490:Central Nervous System / Q000737:chemistry; D003080:Cold Temperature; D004036:Diet, Atherogenic; D011558:Herpesvirus 1, Suid; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D007473:Ion Channels / Q000378:metabolism; D008297:Male; D053486:Melanocortins / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000378:metabolism; D008954:Models, Biological; D044105:Receptor, Melanocortin, Type 4 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D022722:Thermogenesis / Q000502:physiology*; D000071256:Uncoupling Protein 1
D054369:Agouti-Related Protein; D036341:Intercellular Signaling Peptides and Proteins; D007473:Ion Channels; D053486:Melanocortins; D024101:Mitochondrial Proteins; D044105:Receptor, Melanocortin, Type 4; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1