Off-campus UMass Amherst users: To download dissertations, please use the following link to log into our proxy server with your UMass Amherst user name and password.
Non-UMass Amherst users, please click the view more button below to purchase a copy of this dissertation from Proquest.
(Some titles may also be available free of charge in our Open Access Dissertation Collection, so please check there first.)
Decreased expression of prohormone convertase I and II contributes to adult onset obesity in Nhlh2 knockout mice
Although over 20 different neuron ally-expressed genes have been implicated in the regulation of body weight, the transcriptional mechanisms controlling expression of these genes remain unclear. Evidence from our laboratory suggested that the basic helix-loop-helix transcription factor Nhlh2, plays a key role in the regulation of these body weight control genes. Nhlh2 knockout mice are obese after maturation. We found that Nhlh2 is expressed in hypothalamic areas that control body weight such as arcuate nucleus (ARC), paraventricular nucleus (PVN), dorsal and ventral medial hypothalamus (DMH and VMH), and lateral hypothalamus (LHA). In ARC, we showed that pro-opiomelanocortin (POMC) neurons co-expressed Nhlh2 mRNA in a rostral-caudal pattern. In these neurons, the POMC pro-peptide is processed into several bioactive signaling peptides that regulate food intake and energy expenditure. We found that while POMC mRNA levels are comparable in normal and Nhlh2 knockout mice, levels of hypothalamic POMC derived peptides such as β-endorphin and α-MSH were dramatically reduced in the preobese KO mice. These findings suggested that Nhlh2 KO animals could have a defect that prevents production of bio-active POMC derived peptides post-transcriptionally. Since POMC is processed by prohormone convertases such as pro-hormone convertase I (PC1) and prohormone convertase II (PC2), we set out to investigate if differential expression of POMC derived peptides in wild type and Nhlh2 KO mice are regulated via regulation of PC1 and PC2 expression. Indeed, levels of PC1 and PC2 mRNAs were reduced over 50% in the KO animals. Other signaling molecules such as TRH showed the similar expression change to POMC expression that confirms our hypothesis that PC1 and/or PC2 are regulation target candidates of Nhlh2. We identified motifs in the PC1 promoters that could act as direct binding sites for Nhlh2. Thus it is likely that these genes are direct regulatory targets of the Nhlh2 transcription factor, and that decreased expression of PC1 and PC2 contribute to the maturity onset obesity in Nhlh2 KO mice.
Jing, Enxuan, "Decreased expression of prohormone convertase I and II contributes to adult onset obesity in Nhlh2 knockout mice" (2003). Doctoral Dissertations Available from Proquest. AAI3096287.