New targets to treat obesity and the metabolic syndrome

Abstract

Metabolic syndrome (MetS) is a cluster ofassociated 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 epidemic 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.

Keywords: Diabetes; Drugs; Humans; Metabolic syndrome; Obesity; Targets; Therapeutics.

Fig. 1

Schematic of Peptidergic pathways in interplay between gut, adipose tissue hormones and central nervous system regulation of appetite

Fig. 2

Schematic of canonical and non-canonical Wnt regulation of PPARgamma (PPARG) transcription in adipogenesis

Fig. 3

Schematic of interplay between leptin, ghrelin, NPY and Dyrk1A (and possibly B) in central regulation of FOXO1 and food intake. The effects of R102C mutation on these pathways are shown in red.