Melanocortin-4 receptor mRNA expressed in sympathetic outflow neurons to brown adipose tissue: neuroanatomical and functional evidence

Abstract

Song CK, Vaughan CH, Keen-Rhinehart E, Harris RB, Richard D, Bartness TJ. Melanocortin-4 receptor mRNA expressed in sympathetic outflow neurons to brown adipose tissue: neuroanatomical and functional evidence. Am J Physiol Regul Integr Comp Physiol 295: R417-R428, 2008. First published June 11, 2008 doi:10.1152/ajpregu.00174.2008.-A precise understanding of neural circuits controlling lipid mobilization and thermogenesis remains to be determined. We have been studying the sympathetic nervous system (SNS) contributions to white adipose tissue (WAT) lipolysis largely in Siberian hamsters. Central melanocortins are implicated in the control of the sympathetic outflow to WAT, and, moreover, the melanocortin 4 receptors (MC4-R) appear to be principally involved. We previously found that acute third ventricular melanotan II (MTII; an MC3/4-R agonist) injections increase sympathetic drive (norepinephrine turnover) to interscapular brown adipose tissue (IBAT) and IBAT temperature. Here we tested whether MC4-R mRNA is expressed in IBAT SNS outflow neurons using in situ hybridization for the former and injections of the transneuronal viral retrograde tract tracer, pseudorabies virus (PRV) into IBAT, for the latter. Significant numbers of double-labeled cells for PRV and MC4-R mRNA were found across the neuroaxis (mean of all brain sites ϳ60%), including the hypothalamic paraventricular nucleus (PVH; ϳ80%). Acute parenchymal MTII microinjections into the PVH of awake, freely-moving hamsters, using doses below those able to increase IBAT temperature when injected into the third ventricle, increased IBAT temperature for as long as 4 h, as measured by temperature transponders implanted below the tissue. Collectively, these data add significant support to the view that central melanocortins are important in controlling IBAT thermogenesis via the SNS innervation of this tissue, likely through the MC4-Rs.Siberian hamsters; in situ hybridization; pseudorabies virus; tract tracing; melanocortins A COMPLETE UNDERSTANDING OF the neural circuits controlling the sympathetic nervous system (SNS) mobilization of lipid from white adipose tissue (WAT) and those triggering thermogenesis in brown adipose tissue (BAT) remain to be determined, although our knowledge has increased markedly in the past decade (for review, see Refs. 6 and 16). We have been studying the SNS contributions to the reversal of the naturally-occurring seasonal obesity of Siberian hamsters (Phodopus sungorus; for a review, see Ref. 5) in WAT, and to a lesser extent BAT (4,11,12,18,49). Of the many remaining unknown details of the SNS outflow circuitry to WAT and BAT is the identification of their neurochemical phenotype, although some progress has been made for both tissues (e.g., 8,39,48,51,53,56). One of the neurochemicals strongly implicated in the sympathetic control of these adipose tissues is the melanocortins (for review, see Refs. 6 and 45). The most important members of the melanocortin family for the control of energy balance is ␣-melanocyte stimulating hor...

Anterograde transneuronal viral tract tracing reveals central sensory circuits from white adipose tissue

“…We cannot, however, be certain that these are actual differences in the circuitries labeled by the two viruses because it is possible that the apparent discrepancies could result from the different survival times used for each virus, as well as potential differential rates for transmission of the virus through the two circuitries. We have observed, however, cells in forebrain areas such as the PVH and LH that are dually labeled with PRV and with H129 when both viruses are injected into the same WAT pad (Song, Smith and Bartness, unpublished observations) or into interscapular BAT (42). This suggests that the viruses, although progressing through their respective circuits, reached these neurons at about the same time, given that infection of cells by one virus will inhibit subsequent infection by another virus (for a review, see Ref.…”

“…In general, H129 appears to cause greater infection in the forebrain. For example, H129 produces greater infection in the Pe at 114 h (4.75 days) postinoculation than does PRV at 6 days when PRV is injected into WAT (3,36,39,41) or BAT (4,42). By contrast, H129 causes little infection in the SCH and Arc at its maximal postinoculation time (4.75 days) than does PRV at its maximal postinoculation time [6 days (3, 39, 41)].…”

Sympathetic nervous system control of triglyceride metabolism: novel concepts derived from recent studies

“…Since the MC4R colocalizes with SNS outfl ow neurons to BAT, it might be speculated that the MC4R can affect BAT thermogenesis by modulating the SNS outfl ow to BAT ( 74 ). Indeed, a single injection of MTII, an MC3/4R agonist, into the third ventricle of rats increased BAT thermogenesis and UCP-1 expression ( 74 ), which was blocked by surgical sympathetic denervation of BAT ( 75 ).…”

Anterograde transneuronal viral tract tracing reveals central sensory circuits from brown fat and sensory denervation alters its thermogenic responses

“…After the capsaicin injections, a temperature transponder [Implantable Programmable Temperature Transponder (IPTT) 300, BioMedic Data Systems, Seaford, DE] that was gas sterilized was tied to sterile silk sutures and then secured under the left IBAT pad as we described previously (8,35,56). The dorsum was closed with sterile wound clips (Stoelting, Wood Dale, IL), and then a ventral incision was made through the skin and peritoneal cavity for iButton implantation.…”