Adipokines - removing road blocks to obesity and diabetes therapy

Abstract

Prevention of obesity and therapeutic weight loss interventions have provided only limited long term success. Therefore there is an urgent need to develop novel pharmacological treatment strategies, which target mechanisms underlying positive energy balance, excessive fat accumulation and adverse fat distribution. Adipokines may have potential for future pharmacological treatment strategies of obesity and metabolic diseases, because they are involved in the regulation of appetite and satiety, energy expenditure, endothelial function, blood pressure, insulin sensitivity, adipogenesis, fat distribution and insulin secretion and others. There are important road blocks on the way from an adipokine candidate to the clinical use a therapeutic compound. Such road blocks include an incomplete understanding of the mechanism of action, resistance to a specific adipokine, side effects of the adipokine and others. This review focuses on the potential of selected adipokines as therapeutic tools or targets and discusses important road blocks, which currently prevent their clinical use.

Keywords: Adipokines; Adiponectin; Apelin; BMP7; DPP4; Leptin; Nampt/visfatin; Nesfatin-1; Obesity; Road blocks; Therapeutic compounds; Type 2 diabetes; Vaspin.

Figure 1

Adipokines regulate important physiologic processes. Secreted factors from adipose tissue play an important role in the regulation of appetite and satiety, energy expenditure, insulin sensitivity and insulin secretion, inflammation, blood pressure, hemostasis, endothelial function and others. In addition to an endocrine mode of action, adipokines contribute to the modulation of adipogenesis, adipose tissue lipolysis, adipocyte metabolism and function in an autocrine and paracrine manner.

Figure 2

Current road blocks for the clinical use of selected adipokines. There are important obstacles on the road from an adipokine candidate to the clinical use as a therapeutic compound. Such road blocks include an incomplete understanding of the mechanism of action, a mechanistic concept derived from rodent studies does not translate into effective treatment in humans, lack of human data, development of adipokine resistance, side effects.

Figure 3

Schematic pathway of drug discovery from an adipokine candidate to its approval for clinical use as pharmacotherapy by the authorities. The path from candidates to an approved medication may take more than 15 years. At any step in the development there are potential road blocks (RB). Despite advances in technology and understanding of biological systems, drug discovery is a long, expensive, difficult, and inefficient process still with a low rate of new therapeutic discoveries. KO, knockout; TG, transgenic; FDA, Food and Drug Administration; EMA, European Medicines Agency.