Methods in the treatment of obesity

Obesity is a widespread crippling and life-shortening disease that can be defined as a pathologic accumulation of fat reserves. In spite of its epidemic distribution, no fully effective treatments are available. The strategies used for the treatment of obesity have relied mainly on the limitation of energy intake or/and increasing energy expenditure. The most widely used method to limit energy intake has been the use of hypocaloric diets. Their effectivity is limited and fade away rapidly with time. Nevertheless, the sound use of hypocaloric diets is yet the mainstay of the fight against overweight. Inhibition of the absorption of nutrients through specific digestive enzyme inhibitors has been also used. Bariatric surgery is now practically the only fairly effective way to treat the morbidly obese. Conductist conditioning has been used to maintain the obese as far as possible from food, but the results are often poor. However, adequate instruction of the obese on basic nutritional knowledge, and nutritional reeducation are a tool not to be neglected. Exercise is the easiest way to increase energy expenditure. but this increase is only transient; in any case it potentiates the slimming effects of dietary restriction. There are a growing number of drugs used for the treatment of obesity, and more are just being under study and development. The main target of these drugs is to diminish the cravings of appetite as a way to help the obese to limit ingestion, but other drugs tend to increase thermogenesis, easing the consumption of fat reserves; often both effects add up. The most widely studied drugs are serotonergic drugs acting on the brain and adrenergic agents acting both on appetite and heat production. Several hormones, metabolites and even poisons have been postulated as antiobesity agents, but now the most promising areas of study rely on hypothalamic control of appetite, thermogenesis and regulatory control of the mass of fat, the latter achieved through signalling molecules produced by the adipose tissue. Many avenues have been Resum L’obesitat és una malaltia molt estesa que Iimita I’activitat i escurça Ia vida, i que es pot definir com un emmagatzemament patològic de reserves de greix. Malgrat Ia difusió epidèmica, no hi ha cap sistema plenament efectiu disponible per tractar-Ia. Les estratègies emprades per al tractament de I’obesitat s’han basat principalment en Ia Iimitació de Ia ingesta i/o l’increment de Ia despesa energètica. EI mètode més emprat per Iimitar Ia ingesta energètica ha estat Ia utilització de dietes hipocalòriques, però l’efectivitat és Iimitada i es perd ràpidament amb el temps. Malgrat això, Ia utilització adequada de dietes hipocalòriques constitueix encara el principal procediment en Ia Iluita contra el sobrepès. També s’ha emprat el bloqueig de I’absorció de nutrients mitjançant Ia inhibició específica d’enzims digestius. La cirurgia bariàtrica és ara pràcticament I’únic mètode prou efectiu per tractar els obesos mòrbids. S’ha utilitzat el condicionament conductista per mantenir els obesos allunyats del menjar, però els resultats són sovint poc satisfactoris. No obstant això, Ia informació adequada que reben els obesos sobre els principis elementals de Ia nutrició, així com Ia reeducació nutricional són una eina que no s’ha de deixar de costat. L’exercici és Ia forma més senzilla d’augmentar Ia despesa energètica i, tot i que aquest increment és sols transitori, potencia els efectes aprimadors de Ia restricció dietètica. Hi ha un nombre considerable de fàrmacs que han estat emprats per al tractament de I’obesitat i encara n’hi ha més que estan essent estudiats i desenvolupats. EI principal objectiu d’aquests fàrmacs és disminuir Ia gana a fi d’ajudar I’obès a reduir la quantitat de menjar, però altres drogues tendeixen a incrementar Ia termogènesi, tot facilitant Ia utilització de Ies reserves grasses; sovint ambdós efectes tenen lloc a l’hora. les drogues més àmpliament estudiades són Ies serotoninèrgiques, que actuen sobre el cervell, i els agents adrenèrgics que actuen sobre Ia gana i Ia producció de calor. Diverses hormones, metabòlits i fins i tot verins han estat postulats pee al tractament de I’obesitat, però ara per ara Ies àrees d’estudi amb més possibilitats de futur són Ies basades en el control hipotalàmic de Ia gana, Ia termogènesi i el control regulador de Ia massa de greix mitjançant molècules senyal produïdes pel propi teixit adipós. S’han investigat moltes vies per trobar formes efectives per tractar I’obesitat, però Ia major part dels esforços encara es* Author for correspondence: Marià Alemany, Grup de Recerca Nitrogen-Obesitat, Centre Especial de Recerca en Nutrició i Ciència dels Aliments, Departament de Nutrició i Bromatologia, Facultat de Biología, Universitat de Barcelona. Avda. Diagonal, 645. 08028 Barcelona, Catalonia (Spain). Tel. 34 93 4034606, Fax: 34 93 4021559. Email: [email protected] probed to try to find an effective way to treat obesity. However, most of the efforts are yet focussed on the development of partial solutions to the complex problem of obesity. Coordinated effort of basic research, and the development of effective drugs together with adequate information of the patients and actualization of the knowledge of the health personnel working in the field are needed to face the threat of dangerous and uncontrollably spreading obesity tan orientats a trobar solucions parcials al complex problema de l’obesitat. L’esforç coordinat en recerca bàsica i el desenvolupament de fàrmacs efectius, junt amb una adequada informació als pacients i I’actualització dels coneixements del personal sanitari que treballa en aquest camp, són les condicions essencials per poder fer front a aquesta malaltia perillosa que s’estén d’una manera incontrolada: I’obesitat. Obesity is one of the main health hazards afflicting our contemporary society. Its widespread occurrence and increasing severity would undoubtedly qualify it as an epidemic [1], if only its origins could be traced to a transmissible agent. Obesity has for too long now been considered simply as a case of an unbalanced energy budget, the emphasis being placed on the intake [2]; the association between excessive food intake and obesity having been established at a time beyond historical memory and frequently in conjunction with sinfulness, lack of control and a delight in earthly pleasures [3, 4]. Unfortunately, most of these time-worn beliefs remain alive and deeply ingrained in the minds of a large section of our society, even in those of a sizeable part of the medical establishment [5]. An awareness of the perils of obesity and being overweight has been awakened by major medical advances in the treatment of many of the other scourges facing humankind in the last century. However, the efforts devoted to the treatment of obesity have not kept pace with our knowledge of other diseases; furthermore, the assumption that obesity is more a consequence of moral flaws or feeding incontinence has given rise to an often complacent indifference in the fruitless struggle of the obese to shed their sinful blubber. Attempts at the global treatment or prevention of obesity have led to marked alterations in the diet of whole countries restricting the intake of carbohydrates, energy, fats, and other dietary components [6-8]. These large scale experiments failed to achieve their goals and instead led to higher incidences of obesity, disrupted dietary habits, and increases in the pathologic fears of being overweight resulting in anorexia and bulimia [9]. However, the ever-growing numbers of people afflicted with weight problems and obesity [10, 11], the increasing numbers of people fearful of becoming obese [12], the limited effects of anti-obesity therapy, and a better scientific knowledge of the disease, mean that these beliefs are now being called into question. Obesity is a disease [13] -a crippling and life-shortening disease that probably has no single metabolic origin [14]. Our understanding of certain obesity syndromes in rodents has persuaded a number of researchers to look upon genetics as the source of human obesity [15]. Obesity as a disease Obesity can be defined as a pathologic accumulation of fat reserves; the extent of lipid storage far outstrips what the body would be able to use in an emergency, and so this storage just adds weight, thereby limiting movement, overloading the respiratory and cardiovascular systems and destabilising the homeostatic equilibrium of the body [16]. The medical definition of obesity, however, is somewhat more difficult, since a considerable grey area extends between what is considered normal and being overweight and also between this mild situation and a fully developed obesity. In addition, the actual mass of fat is not as critical as is its specific location in terms of the pathological effects of this fat and its impact on the hormonal and metabolic environment. In fact, there are a number of grossly obese patients that show much less marked metabolic abnormalities than others in whom fat accumulation is not severe but who present concurrent pathologic traits. These include hypertension, hypercholestrolemia, hypertriacylglycerolemia and type 2 diabetes mellitus: the metabolic or X syndrome [17]. It is still unclear as to whether hormonal alterations (i.e. in insulin and glucocorticoids) are an early consequence of excessive fat accumulation, or whether the latter is a consequence of the former. Given the wide diversity of obesities, there are probably many explanations of the etiology of obesity. There is a considerable body of evidence, however, linking obesity and type 2 diabetes mellitus, which suggests that alterations in insulin functionality and responses play a key role in the development and maintenance of obesity; the almost universal existence of insulin resistance in the obese points to this single metabolic alteration as the most critical element in the etiopathogenics of obesity [18, 19]. Figure 1 shows a simplified diagram of the system that controls body weight. The hypothalamic control of food intake is modulated by signals from the intestine, the levels of metabolites in the blood and by signals from other brain nuclei; these also control efferent signals through the sympathetic nervous system that regulates fat mobilisation and thermogenesis. Two other major elements complete the picture: insulin, the main endocrine agent enhancing the build464 X. Remesar, J.A. Fernández-López, M. Foz and M. Alemany