Prolylcarboxypeptidase (PRCP) as a new target for obesity treatment

B Shariat-Madar1, D Kolte2, A Verlangieri2, Z Shariat-Madar21College of Literature, Science, and the Arts, University of Michigan, Ann Arbor MI, USA; 2School of Pharmacy, Department of Pharmacology, University of Mississippi, University, MS, USAAbstract: Recently, we serendipitously discovered that mice with the deficiency of the enzyme prolylcarboxypeptidase (PRCP) have elevated α-melanocyte-stimulating hormone (α-MSH) levels which lead to decreased food intake and weight loss. This suggests that PRCP is an endogenous inactivator of α-MSH and an appetite stimulant. Since a modest weight loss can have the most profound influence on reducing cardiovascular risk factors, the inhibitors of PRCP would be emerging as a possible alternative for pharmacotherapy in high-risk patients with obesity and obesity-related disorders. The discovery of a new biological activity of PRCP in the PRCP-deficient mice and studies of α-MSH function indicate the importance and complexity of the hypothalamic pro-opiomelanocortin (POMC) system in altering food intake. Identifying a role for PRCP in regulating α-MSH in the brain may be a critical step in enhancing our understanding of how the brain controls food intake and body weight. In light of recent findings, the potential role of PRCP in regulating fuel homeostasis is critically evaluated. Further studies of the role of PRCP in obesity are much needed.Keywords: prolylcarboxypeptidase, melanocyte-stimulating harmone, appetite, weight loss, cardiovascular risk, obesit

α-Tocopherol Is Ineffective in Preventing the Decomposition of Preformed Lipid Peroxides and May Promote the Accumulation of Toxic Aldehydes: A Potential Explanation for the Failure of Antioxidants to Affect Human Atherosclerosis

The decomposition of peroxidized lipids of low-density lipoprotein (LDL) has been suggested to be involved in atherosclerosis. In this study, an in vitro system with 13-hydroperoxylinoleic acid (13-HPODE) was used to determine the effects of antioxidants on its decomposition. Decomposition of 13-HPODE was not affected by α-tocopherol, several other antioxidants, or antioxidant enzymes. Moreover, the inclusion of α-tocopherol during the decomposition of 13-HPODE resulted in an accumulation of aldehydes. Further oxidation of aldehydes to carboxylic acids by a number of oxidases was prevented by α-tocopherol. Conversely, the formation of carboxylic acids may be conducive to plaque stabilization via immunomodulation, rapid degradation, and by calcium sequestration. Thus, the inhibition of formation of carboxylic acids could be a serious deleterious effect of antioxidant treatment. In contrast, α-keto acids, like pyruvic acid, promoted the conversion of 13-HPODE to 13-hydroxylinoleic acid (13-HODE) by readily undergoing decarboxylation into acetate. These observations suggest that agents that promote the reduction of lipid peroxides into lipid hydroxides could be far more effective in treating cardiovascular diseases as opposed α-tocopherol–like antioxidants that could affect additional steps in the oxidation cascade. Antioxid. Redox Signal. 11, 1237–1248