The anorexigenic neuromodulator α-melanocyte-stimulating hormone (α-MSH; referred to here as α-MSH 1-13 ) undergoes extensive posttranslational processing, and its in vivo activity is short lived due to rapid inactivation. The enzymatic control of α-MSH 1-13 maturation and inactivation is incompletely understood. Here we have provided insight into α-MSH 1-13 inactivation through the generation and analysis of a subcongenic mouse strain with reduced body fat compared with controls. Using positional cloning, we identified a maximum of 6 coding genes, including that encoding prolylcarboxypeptidase (PRCP), in the donor region. Realtime PCR revealed a marked genotype effect on Prcp mRNA expression in brain tissue. Biochemical studies using recombinant PRCP demonstrated that PRCP removes the C-terminal amino acid of α-MSH 1-13 , producing α-MSH 1-12 , which is not neuroactive. We found that Prcp was expressed in the hypothalamus in neuronal populations that send efferents to areas where α-MSH 1-13 is released from axon terminals. The inhibition of PRCP activity by small molecule protease inhibitors administered peripherally or centrally decreased food intake in both wild-type and obese mice. Furthermore, Prcp-null mice had elevated levels of α-MSH 1-13 in the hypothalamus and were leaner and shorter than the wild-type controls on a regular chow diet; they were also resistant to high-fat diet-induced obesity. Our results suggest that PRCP is an important component of melanocortin signaling and weight maintenance via control of active α-MSH 1-13 levels.
BACKGROUND: Congenic mouse strains contain donor mouse strain DNA in genomes otherwise identical to a background strain. They can be used to identify defined chromosomal regions containing obesity genes with small effects. OBJECTIVE: The objective of this study was to discover congenic strains containing genes that influence body fat in mice and to examine interactions between these genes. DESIGN: A survey of congenic strains showed that the B6.C-Tyr c H1 b Hbb d /By (B6.C-H1) congenic strain, with a 24 centiMorgan (cM) donor region from strain BALB/cBy on chromosome 7, had 50% less fat than background C57BL/6By (B6By) mice. The congenic donor region was then divided into 11 smaller overlapping subcongenic regions. Genotype effects on obesity traits in the subcongenics were determined by breeding heterozygotes for each line and comparing phenotypes of littermates with different donor genotypes. RESULTS: At least three subcongenic strains, two with overlapping donor regions and one with a nonoverlapping donor strain region, were found to exhibit significant influences of donor region genotype on obesity. A cross of the two overlapping subcongenics demonstrated that a single gene in the overlap region could not account for the observed obesity effects. We also observed significant obesity differences between genetically identical progeny that were contingent on the genotype of their subcongenic mothers.CONCLUSIONS: These results demonstrate the existence of at least three genes influencing obesity in three subcongenic strains with donor strain chromosomal regions whose size ranges from 0.5 to 5 cM. A maternal effect gene influencing obesity may be present in some subcongenic strains. IntroductionIdentification of natural alleles for complex traits such as obesity remains difficult but important because these studies survey the cumulative effects of evolution. While quantitative trait locus (QTL) mapping can identify broad chromosomal regions containing genes influencing complex traits, isolation of the specific underlying genes requires production of monogenic models. Congenic mouse strains can be used as monogenic models of complex traits. 1 Breeding two inbred strains to each other, and repeatedly backcrossing the progeny to the background strain for at least 10 generations produce congenic strains. The final congenic strain is identical to the background strain except for a selected donor region of highly variable size, and any unintended passenger donor regions (perhaps on other chromosomes) and spontaneous mutations occurring during breeding of the congenics. Although size, number and frequency of passenger donor chromosomal regions are usually unknown, their existence cannot be ruled out except by appropriate control experiments, such as those described in this manuscript.The congenic mouse strains surveyed for obesity traits in this study were originally produced by investigators studying histocompatability responses. 2 Historically, genes underlying the complex trait of tissue rejection were identified in...
The exon 8 ins/del polymorphism of UCP2 appears to be associated with childhood-onset obesity. The UCP2/UCP3 genetic locus may play a role in childhood body weight.
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