Anti-Obesity Drug Discovery and Development

Obesity is considered to be caused by an imbalance in individual energy. The basic therapies for obesity are appropriate dietary restriction for the purpose of decreasing energy intake and effective exercise for the purpose of promoting energy expenditure. At present, drug therapies for obesity are secondary treatments. Therapeutic strategies using pharmacotherapy are divided into the following three types: 1) suppressing appetite, 2) inhibiting nutritional absorption, and 3) accelerating energy expenditure. Mazindol and Phentermine have long been recognized as drugs for increasing satiety, and Orlistat and Cetilistat have been developed as drugs that inhibit lipid absorption from the intestine. Moreover, ß3 agonists have been developed to accelerate energy combustion. In this chapter, we first introduce drugs that are on the market, after which drugs that are in clinical or preclinical stages of development will be introduced. Furthermore, obese animal models that are now available will be introduced in the last section.

In this chapter, we review the current concepts about Nesfatin-1 as a new anti-obesity treatment and evaluate the existing issues about this knowledge and the available literature. The intent is to inform clinicians about Nesfatin-1 as a new kind of anti-obesity treatment and make a rational decision based on this perspective as possible clinical application. It can be potentially helpful in the therapy of metabolic disorders and obesity of various origins. In fact, the details of nesfatin-1 physiology could be clarified, and it may be considered suitable in the future as a potential drug in the pharmacotherapy of obesity, due to its anorexigenic effects, and as a new potential modulator of appetite in the therapy of eating disorders such as anorexia nervosa by using selective nesfatin-1 antagonists. Therefore, further progress of pharmacological researches in this field is still very limited. Further research on this topic certainly merit attention.

Adipose tissue (AT) with a central role in body weight homeostasis, inflammation and insulin resistance, is a highly orchestrated tissue involving receptor and second messenger pathways with steps and passes that influence hyperplasia, hypertrophy, adipocyte differentiation, turnover, lipolysis, free-fatty acid (FFA) metabolism, lipogenesis and the secretome profile. Due to the limitations of the classical molecular biological methods only pieces of the puzzle have been studied, with studies failing to consider the global, time-resolved changes that are evident in this highly plastic organ. “Proteomics”, first coined in 1995 is a large-scale characterization of the entire protein profile of a cell line, tissue, or organism not only from the perspective of expression but also post-translational modifications. As such proteomic technologies offer powerful tools for identifying key components of the adipose proteome, which may contribute to the pathogenesis of adipose tissue dysfunction in obesity. In this review, we plan to address the recent advances in the proteomic characterization of pediatric obesity, in particular the newly identified proteins that potentially play relevant roles and offer targets for novel therapies.

The thrifty genotype, exposed to modern and industrialized societies, characterized by food availability and reduced physical activity, recently culminated in an epidemic obesity of giant proportions. Even more alarming than the figures regarding adult obesity is the increasing rate of obese children that has augmented almost 3-fold within the last 3 decades.

Obesity is associated with significant adverse effects on health, including metabolic, endocrine, cardiovascular, gastrointestinal, respiratory, neurologic, psychiatric, hematologic, and skeletal complications, and development of some types of malignancies. Studies strongly suggest that vascular, histopathological and metabolic changes begin in childhood. The development of metabolic problems associated with obesity during childhood track into adulthood increases the risk for type 2 diabetes, dyslipidemia and early cardiovascular disease.

In this paper, firstly we examine the numerous links between neuroendocrine peptides and cytokines, which contribute to inflammation and oxidative stress (OS) in obesity. A number of cytokine, mediators of inflammation, are produced by adipose tissue. In obese patients, increase in IL-6, C reactive protein (CRP), TNF-alpha and decrease in adiponectin and IL-10, induce pro-inflammatory stage, resulting in insulin resistance and endothelial dysfunction. Decreasing the levels of chronic inflammation and OS in childhood may prevent subsequent metabolic derangement along with increased cardiovascular morbidity and mortality in adulthood. OS has been proposed to be a potential mechanism linking obesity and endothelial dysfunction. In fact, oxidative reactions are critical in all the events which lead to atherogenesis. OS plays an important role in the pathogenesis of vascular alterations by either triggering exacerbating the biochemical processes accompanying endothelial dysfunction.

The production of Radical Oxygen species (ROS) and Radical Nitrogen Species (RNS) can occur at the cellular level in response to metabolic overload caused by an overabundance of macronutrients. Excessive generation of ROS in adipose tissue occurs by several interrelated pathophysiologic mechanisms, including nutrient metabolic overload, mitochondrial dysfunction, and endothelial reticulum stress. ROS generation is maintained by an inflammatory response, sustaining a vicious cycle. Puberty alters some of the inflammatory markers associated with endothelial dysfunction (adipocytokine levels, OS and insulin sensitivity) in obese children.

However, other than to inflammation, OS can be related to hormonal derangement in a reciprocal way. Some hormones influence antioxidant levels, but OS also can modify synthesis, activity and metabolism of hormones. Therefore, in the second section we examine some hormonal patterns which are influenced by obesity and their role in the regulation of antioxidant systems. In conclusion it seems that oxidative stress is certainly related to systemic inflammation but also to hormonal derangement.

Aside from the excess energy intake, nutrients have a specific role in the development of inflammation via the regulation of adipokine gene expression and secretion. In this way, it is possible to choose “non-inflammatory” or “anti-inflammatory” foods to minimize postprandial OS and inflammation. Therefore, lifestyle modifications, consisting in a reduction of caloric intake, a diet focused on particular macronutrient or micronutrient intake, and the encouragement of a regular exercise program with a personalized format, type and duration may reduce the consequences of childhood obesity. In particular we review the role of natural antioxidant in diet, as well as the administration of pharmacological antioxidants. Whether this approach is effective in improving vascular function in the short-term, but also in adult life remains to be established.

The obesity epidemic has proven to have a significant burden on the current of state of healthcare. At an individual level, obesity and its sequelae have numerous effects on the state of health and quality of life. On a global perspective, treatment of obesity and its sequelae come at a high cost. Obesity, in terms of intestinal dysbiosis, is a complicated disequilibrium that offers many unclear complications. Thus, restoration of the commensal microflora serves a potential therapeutic option in combatting the obesity epidemic be it via antibiotic therapy, probiotics, prebiotics, symbiotics (combination of prebiotic and probiotic therapy), or fecal microbiota transplant. This manuscript will review the role of intestinal dysbiosis in the pathogenesis of obesity and the potential role for microflora manipulation as therapy.