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[email protected] Mini-Reviews in Medicinal Chemistry, 2016, 16, 000-000
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REVIEW ARTICLE
Obesity: Current Treatment and Future Horizons Ziad Omran* College of Pharmacy, Umm AlQura University, Al-Abidiyya, Makkah 21955, Kingdom of Saudi Arabia
ARTICLE HISTORY Received: December 05, 2015 Revised: February 02, 2016 Accepted: June 15, 2016 DOI: 10.2174/13895575166661606171003 28
Abstract: Obesity is growing at an alarming rate with huge consequences on health and economy. The worldwide prevalence of obesity has nearly doubled in less than 35 years. Obesity causes many physiological dysfunctions that affect nearly every organ producing multiple morbidities. Despite these facts, there is still no clear, well-defined solution. Notwithstanding the devastating prevalence and consequences of obesity, today only five medicines, orlistat, lorcaserin, phentermine-topiramate, bupropion-naltrexone and liraglutide, are approved by the FDA for long-term treatment of obesity. In this review, the current approaches to treat obesity such as the development of diacylglycerol O-acyltransferase-1 inhibitors, growth hormone Z. Omran secretagogue receptor-1a antagonists/inverse agonists, melanocortin-3 receptors agonists and melanin concentrating hormone receptor-1 antagonists, will be discussed. The main focus will be on the molecules that were able to reach clinical trials. The last section is dedicated to the “browning” phenomenon of white adipose tissues and the potential of Aldh1a1 inhibitors to treat obesity.
Keywords: Adipose tissues plasticity, Aldh1a1, Brown adipose tissues, DGAT-1 inhibitors, GHS-R1 antagonists/inverse agonists, MCHR1 antagonists, Melanocortin-3 receptors agonists, Obesity. INTRODUCTION World Health Organization (WHO) defines overweight and obesity as abnormal or excessive fat accumulation that may impair health. Body Mass Index (BMI) is a simple index of weight-for-height that is universally used to classify overweight and obesity. BMI is calculated by dividing a person's weight in kilograms by the square of his height in meters (kg/m2). WHO classifies people with BMI ≥ 25 as overweight, those with BMI ≥ 30 as obese, and individuals with BMI ≥ 40 as morbidly obese [1]. The obesity pandemic is growing at an alarming rate with an estimated economic burden of US$150 billion per year in the USA alone [2]. Recent studies suggest that one death out of five in the USA is linked to obesity, much more than the previously thought rate of 5% [2]. The worldwide prevalence of obesity has more than doubled in less than 35 years. In 2014, 11% of men and 15% of women in the world were obese as opposed to 5% for men and 8% for women in 1980. Today, more than 1.9 billion adults are overweight. Of these, over 600 million are obese [1]. Obesity causes numerous physiological dysfunctions that affect almost every organ producing multiple morbidities [3]. *Address correspondence to this author at the College of Pharmacy, Umm AlQura University, Al-Abidiyya, Makkah 21955, Kingdom of Saudi Arabia; Tel: +966 546461441; Fax: +966 125270000/4217; E-mail:
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Obesity increases the risk of diabetes, heart diseases, fatty liver, arthritis, certain types of cancer and reproductive abnormalities [4, 5]. Recent studies linked abdominal obesity with organ failure in critically ill patients [3]. Furthermore, obese people appear to have a lower quality of life, indicating psychosocial impact as well [6]. For very long time, obesity was believed to result from a simple energy imbalance; the calorie intake exceeds calorie expenditure [7]. Today, scientists acknowledge that obesity is a complex disease caused by the interaction of several internal and external factors [8]. Recent genetic studies have identified 42 loci with single-nucleotide polymorphisms associated with BMI [9]. The increase of obesity prevalence over the last three decades could be attributed mainly to high-calorie food intake coupled with a sedentary lifestyle. At the same time, the fact that the prevalence of obesity has tripled in certain societies, especially among children, in the past 30 years would be difficult to be linked with notion that genetics are the key cause for obesity. Now, it is widely accepted that environmental factors can affect the genetic background contributing to the increase in prevalence of obesity [10]. Epigenetic mechanisms where environmental factors change the expression of genes, may explain this increase in obesity prevalence [8].
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CURRENT OBESITY TREATMENT In spite of the above-mentioned facts about obesity, there is still no clear, well-defined solution [11]. The first line treatment today is to target physiological processes that promote energy balance to expedite the process of fat/weight loss through various weight loss protocols that combine limiting energy intake and increasing physical activities [6]. By the end of twentieth century, bariatric surgery emerged as an effective [12, 13], albeit expensive and invasive, treatment for obesity. Despite the devastating prevalence and consequences of obesity, today only five medicines, orlistat, lorcaserin, phentermine-topiramate, bupropion-naltrexone and liraglutide, are approved by the FDA for long-term treatment of obesity [14] (Fig. 1). These treatments can be considered as adjunct to the life-style interventions. These drugs are prescribed for patients with a BMI ≥ 30 or with a BMI ≥ 27 with one or more comorbidities such as hypertension, type-II diabetes and dyslipidemia [15]. Orlistat is the only FDA-approved obesity treatment that can be prescribed for adolescents between 12-18 years of age. All the other medications are to be used for adult patients only. Orlistat Orlistat (Fig. 1) was approved by the FDA in 1999 as the first gastric and pancreatic lipase inhibitor. It reduces fat absorption from the gastrointestinal tract by 30%. Orlistat is prescribed in conjunction with low calorie diet. Orlistat is also prescribed as an OTC drug at half the prescription dose [16, 17]. Thanks to its minimal gastrointestinal absorption (
