The role of the hypothalamic melanocortin system in behavioral appetitive processes.

Much evidence suggests that the hypothalamic melanocortin (MC) system plays an important role in the control of food intake. However, investigations of the potential behavioral mechanisms have been limited to measures of aversion. The purpose of the present experiment was to assess whether other behavioral consequences of administration of MC peptides were similar to those produced by 0- or 24-h food deprivation, respectively. Rats were first trained while food deprived that a tone predicted the delivery of peanut oil. They then received exposure to oil under food deprivation, satiation, intra-third-cerebroventricular (i3vt) infusion of MTII (a potent MC agonist) or SHU-9119 (a potent MC antagonist). All rats were then tested during extinction for levels of responding to the tone under food satiation. Previous results demonstrated that sated exposure reduces subsequent test responding to the tone. During the present extinction test, rats that received sated exposure exhibited reduced responding to the tone, relative to rats that received deprived exposure. Unlike satiation, rats that received exposure after MTII exhibited continued high levels of responding to the tone. Further, rats that received SHU-9119 exhibited a small reduction in responding. These data suggest that MTII and SHU-9119 do not influence intake via the same mechanisms as hunger and food satiation, respectively.

Characterization of the mouse Ron/Stk receptor tyrosine kinase gene.

In an effort to understand the mechanisms governing the regulation of the mouse Ron receptor gene, a mouse genomic library was screened and overlapping clones coding for the Ron gene and flanking DNA were identified. Continuous DNA sequence was obtained for approximately 16.4 kilobases. The gene, from the initiator methionine to the polyadenylation site, is contained within 13 244 basepairs and contains 19 exons. Primer extension analyses were performed to determine the transcription start site of the mouse Ron transcript. Multiple transcription start sites were found which also appear to be used in transfected reporter constructs containing Ron 5' flanking DNA. To determine the location of sites which may be critical for the function of the Ron gene promoter, a series of chimeric genes containing serial deletions of the Ron gene promoter fused to the coding sequences for the chloramphenicol acetyl-transferase gene were constructed. Transient transfection analyses of these hybrid genes into various cell lines demonstrated that two regions of the Ron gene promoter, encompassing nucleotides -585 to -465 and from -465 to -285, are important for expression of this transcript in CMT-93 cells. Further analysis of the Ron promoter utilizing gel mobility shift analyses suggests that regions encompassing nucleotides -585 to - 508 and nucleotides -375 to -285 appear to bind specific proteins which may be involved in the negative and positive regulation, respectively, of the mouse Ron gene.