Metabolic syndrome (MetS) is a cluster of associated metabolic traits that collectively confer unsurpassed risk for development of cardiovascular disease (CVD) and type 2 diabetes compared to any single CVD risk factor. Truncal obesity plays an exceptionally critical role among all metabolic traits of the MetS. Consequently, the prevalence of the MetS has steadily increased with the growing epidemics of obesity. Pharmacotherapy has been available for obesity for more than one decade, but with little success in improving the metabolic profiles. The serotonergic drugs and inhibitors of pancreatic lipases were among the few drugs that were initially approved to treat obesity. At the present time, only the pancreatic lipase inhibitor orlistat is approved for long-term treatment of obesity. New classes of anti-diabetic drugs, including glucagon-like peptide 1 receptor (GLP-1R) agonists and Dipeptidyl-peptidase IV (DPP-IV) inhibitors, are currently being evaluated for their effects on obesity and metabolic traits. The genetic studies of obesity and metabolic syndrome have identified novel molecules acting on the hunger and satiety peptidergic signaling of the gut-hypothalamus axis or the melanocortin system of the brain and are promising targets for future drug development. The goal is to develop drugs that not only treat obesity, but also favorably impact its associated traits.

Nonsyndromic patent ductus arteriosus (PDA) is a common congenital heart defect (CHD) with both inherited and acquired causes, but the disease mechanisms have remained elusive. Using combined genome-wide linkage analysis and whole-exome sequencing (WES), we identified independent mutations in PRDM6, which encodes a nuclear protein that is specific to vascular smooth muscle cells (VSMC), has histone methyl transferase activities, and acts as a transcriptional suppressor of contractile proteins. In vitro assays showed that the mutations cause loss of function either by intracellular redistribution of the protein and/or by alteration of its methyltransferase activities. Wild-type embryonic ductus arteriosus (DA) exhibited high levels of PRDM6, which rapidly declined postnatally as the number of VSMCs necessary for ductus contraction increased. This dynamic change suggests that PRDM6 plays a key role in maintaining VSMCs in an undifferentiated stage in order to promote their proliferation and that its loss of activity results in premature differentiation and impaired remodeling of the DA. Our findings identify PRDM6 mutations as underlying genetic causes of nonsyndromic isolated PDA in humans and implicates the wild-type protein in epigenetic regulation of ductus remodeling.

Factors that underlie the clustering of metabolic syndrome traits are not fully known. We performed whole exome sequence analysis in kindreds with extreme phenotypes of early-onset atherosclerosis and metabolic syndrome and identified novel loss-of-function mutations in the gene encoding the pancreatic elastase CELA2A. We further show that CELA2A is a circulating enzyme that reduces platelet hyperactivation, triggers both insulin secretion and degradation, and increases insulin sensitivity. CELA2A plasma levels rise postprandially and parallel insulin levels in humans. Loss of these functions by the mutant proteins provides insight into disease mechanisms and suggests that CELA2A could be an attractive therapeutic target.

Wnt signaling is as a major regulator of adipogenesis. It differentially regulates the fate of mesenchymal stem cells (MSC) by promoting osteogenesis and myogenesis, and inhibiting adipogenesis[1]. Its loss of function has been associated with impaired osteogenesis[2] and diverse congenital and adult cardiovascular disorders[3,4]. Our group has identified loss of function mutations in Wnt coreceptor LRP6 that underlie autosomal dominant early onset coronary artery (CAD), osteoporosis and most features of the metabolic syndrome, including high plasma triglyceride and LDL-C, diabetes, hypertension, hyperuricemia and fatty liver disease (unpublished data). Following we will describe our most pertinent findings related to Wnt/LRP6 regulation of de novo lipogenesis and adipogenesis and the role of impaired Wnt signaling in generation of ectopic fat, insulin resistance, elevated plasma lipids and non-alcoholic fatty liver disease (NAFLD).