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Targeting Energy Expenditure—Drugs for Obesity Treatment

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Targeting Energy Expenditure—Drugs for Obesity Treatment pharmaceuticals Review Targeting Energy Expenditure—Drugs for Obesity Treatment Carlos M. Jimenez-Munoz 1 , Marta López 1 , Fernando Albericio 2,3,4,* and Kamil Makowski 2,3,* 1 School of Chemical Sciences and Engineering Yachay Tech University, San Miguel de Urcuquí 100119, Ecuador; [email protected] (C.M.J.-M.); [email protected] (M.L.) 2 Department of Surfactants and Biotechnology, Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), 08034 Barcelona, Spain 3 CIBER-BBN, Networking Centre of Bioengineering, Biomaterials, and Nanomedicine, and Department of Organic Chemistry, University of Barcelona, 08028 Barcelona, Spain 4 School of Chemistry and Physics, University of KwaZulu-Natal, Durban 4001, South Africa * Correspondence: [email protected] (F.A.); [email protected] or [email protected] (K.M.) Abstract: Obesity and overweight are associated with lethal diseases. In this context, obese and overweight individuals infected by COVID-19 are at greater risk of dying. Obesity is treated by three main pharmaceutical approaches, namely suppressing appetite, reducing energy intake by impairing absorption, and increasing energy expenditure. Most compounds used for the latter were first envisaged for other medical uses. However, several candidates are now being developed explicitly for targeting obesity by increasing energy expenditure. This review analyzes the compounds that show anti-obesity activity exerted through the energy expenditure pathway. They are classified on the basis of their development status: FDA-approved, Withdrawn, Clinical Trials, and Under Citation: Jimenez-Munoz, C.M.; Development. The chemical nature, target, mechanisms of action, and description of the current López, M.; Albericio, F.; Makowski, K. stage of development are described for each one. Targeting Energy Expenditure— Drugs for Obesity Treatment. Pharmaceuticals 2021, 14, 435. https:// Keywords: obesity; energy expenditure; thermogenesis; energy metabolism; FDA-approved; treat- doi.org/10.3390/ph14050435 ments under development; clinical trials; withdrawn treatments Academic Editors: Magdalena Kota´nska,Amélia Pilar Rauter, Małgorzata Szafarz and 1. Introduction Monika Kubacka Obesity can be defined as conditions characterized by excessive body fat. In 2016, there were about 650 million obese adults, and this number is increasing each year [1]. Received: 29 March 2021 It is estimated that more people are currently dying as a consequence of overweight or Accepted: 29 April 2021 obesity than underweight due to undernutrition [2]. Obesity commonly encompasses other Published: 6 May 2021 health problems, particularly type 2 diabetes mellitus, coronary disorders, and an increased incidence of various forms of cancer, among other diseases. This susceptibility has been Publisher’s Note: MDPI stays neutral highlighted during the COVID-19 pandemic, where obesity has been associated with a with regard to jurisdictional claims in higher risk of death among those infected [3]. Additionally, obesity is associated with published maps and institutional affil- unemployment and social disadvantages. To make a clear distinction from being just a risk iations. factor, the World Obesity Federation and other organizations have recently declared obesity as a chronic progressive disease. Additional to health risks directly related to overweight, obesity presents different pathophysiology as strong homeostatic mechanisms promote further weight gain. Whereas healthy eating and exercise is undoubted the best way to Copyright: © 2021 by the authors. prevent obesity, this can be not enough for individuals with already developed obesity [2]. Licensee MDPI, Basel, Switzerland. Obesity has nowadays become a significant health and financial burden for developed This article is an open access article and developing societies. distributed under the terms and Though overweight causes many medical disorders, obesity treatment is still not the conditions of the Creative Commons Attribution (CC BY) license (https:// first medical prescription of choice. However, modern society is under pressure to become creativecommons.org/licenses/by/ fitter, which would not only save lives but also improve quality of life. Currently, exercise 4.0/). and diet followed by bariatric surgery are the gold standard treatment for obesity. While Pharmaceuticals 2021, 14, 435. https://doi.org/10.3390/ph14050435 https://www.mdpi.com/journal/pharmaceuticals Pharmaceuticals 2021, 14, x FOR PEER REVIEW 2 of 25 Pharmaceuticals 2021, 14, 435 2 of 23 and diet followed by bariatric surgery are the gold standard treatment for obesity. While dietdiet andand exerciseexercise areare thethe safestsafest andand healthiesthealthiest approaches,approaches, itit hashas beenbeen reportedreported thatthat theythey areare onlyonly long-termlong-term effectiveeffective inin aa smallsmall percentagepercentage ofof individualsindividuals [[4].4]. OnOn thethe otherother hand,hand, bariatricbariatric surgerysurgery intervention intervention come come with with some some significant significant risk, risk, so it so is onlyit is only used used for extreme for ex- casestreme of cases obesity. of obesity. Therefore,Therefore, in this context, context, there there is is an an urgent urgent and and highly highly demanded demanded need need for forthe thede- developmentvelopment of ofnew new drugs drugs to to treat treat obesity, obesity, either either as as an an alternative alternative or complement toto diet,diet, exercise,exercise, oror bariatricbariatric surgerysurgery treatment.treatment. ThreeThree pharmacologicalpharmacological approachesapproaches can can be be usedused toto achieveachieve aa caloriccaloric deficiencydeficiency thatthat wouldwould leadlead toto aa lossloss ofof bodybody weight:weight: (i)(i) decreasingdecreasing energyenergy intakeintake byby appetiteappetite suppression,suppression, (ii)(ii) reducingreducing energyenergy intakeintake bybyimpaired impaired absorption,absorption, andand (iii)(iii) increasingincreasing energyenergy expenditure expenditure [ 5[5]] (Figure (Figure1 ).1). FigureFigure 1.1. ExcessExcess intakeintake ofof calories calories causes causes overweight overweight and and obesity. obesity. There There are are three three main main pharmacolog- pharmaco- icallogical strategies strategies to achieve to achieve a caloric a caloric deficit. deficit. Two Two of them of them aim aim to prevent to prevent the th storagee storage of excess of excess calories, calo- firstries, byfirst acting by acting on the on central the centra nervousl nervous system system to cause to cause an anorexic an anorexic effect effect and regulateand regulate appetite, appetite, and secondand second by inducing by inducing early excretionearly excretion and thus and preventing thus preventing ingested ingested food from food becoming from becoming a useful a source useful source of calories. The third strategy, and the topic of this review, is the use of drugs that increase of calories. The third strategy, and the topic of this review, is the use of drugs that increase energy energy expenditure by causing the body to use calories already stored in the form of fat. expenditure by causing the body to use calories already stored in the form of fat. PrincipalPrincipal concernsconcerns regarding regarding pharmacological pharmacological energy energy intake intake reduction reduction strategy strategy are theare homeostaticthe homeostatic mechanisms mechanisms of the of human the human body body overcoming overcoming caloric caloric restriction restriction and long-term and long- clinicalterm clinical efficacy. efficacy. The energy The energy expenditure expenditure strategy strategy to fight to obesity fight obesity is crucial is becausecrucial because it does notit does prevent not prevent the absorption the absorption of essential of essentia nutrientsl nutrients such as vitamins such as vitamins and minerals and minerals and it might and beit might used alone be used orreinforce alone or thereinforce calorific the restriction calorific restriction strategies. strategies. Additionally, Additionally, there are only there a feware only available a few drugs available that drugs target that energy target expenditure, energy expenditure, hence making hence their making use an their attractive use an andattractive promising and promising approach forapproach obesity for treatment. obesity treatment. Identifying Identifying safe pharmaceutical safe pharmaceutical products forproducts this purpose for this ispurpose challenging is challenging because manybecause compounds many compounds that have that been have studied been studied do not showdo not a highshow selectivity a high selectivity for their for target, their resulting target, resulting in dangerous in dangerous side effects. side Nevertheless, effects. Never- a significanttheless, a significant number of number the drugs of studiedthe drugs to stud dateied have to reacheddate have clinical reached phases. clinical phases. ThereThere areare severalseveral processesprocesses inin thethe humanhuman bodybody thatthat areare inefficientinefficient inin termsterms ofof energyenergy preservation,preservation, where where energy energy is is lost lost as as heat heat and and not not used used to to drive drive another another cellular cellular process. process. In casesIn cases where where energy energy is lost is lost in a in significant a significant proportion, proportion, those those processes processes are calledare called uncoupled. uncou-
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