Physiopathology and Treatment of Obesity and Overweight: A Proposal for a New Anorectic

The “new epidemic,” as WHO calls obesity, is caused by overeating, which, having exceeded the body's actual needs, accumulates in the form of health-damaging fat deposits. Moving more and eating less is the main remedy, but eating belongs to vital instincts, which are beyond the control of reason. In this sense, eating is different from drinking and breathing because without food it is possible to survive for a few weeks, without water for a few days, without oxygen for a few minutes. The first part of this article provides an overview of obesity and its treatment, focusing on the new anorectic anticipated in the title. The second part focuses on compulsive obesity, typically represented by constitutional obesity and food addiction. The article concludes with a discussion of the pharmacological treatment of compulsive diseases, to which some forms of obesity belong.


Obesity: Different Approaches to Treatment
Obesity and overweight are defned as abnormal or excessive fat accumulation leading to health risks and reduced life expectancy estimated between 2 and 20 years [1][2][3][4].According to WHO, obesity and overweight afect about 60% of the European population and 40-50% worldwide [1,5].

Possible Approaches for Efective Body Weight Control.
All causes of obesity are important, but one prevails over the others: the imbalance between overeating and low physical activity [6].Te imbalance between overeating and low physical activity is one of the results of scientifc and technological progress.Food production has more than doubled, while a farmer's labor, which until 2-3 generations ago required up to 500-1000 cal/hour, has dropped to 200-300.In developed countries, millions of young people, adults, and the elderly keep ft through exercise and sports.An elderly person walking or jogging every day is no longer an unusual sight.Walking involves an energy expenditure of about 300 cal/hour.By giving up transportation and walking one hour a day, in one month a person would consume about 9,000 calories, corresponding to more than 1 kg of body fat.Tere are also millions of people coping with overweight and obesity by eating less.Body fat is worth an average of 8000 cal/kg, while in adults, energy consumption is on the order of 2000 cal/day.It follows that halving your diet would allow you to reduce almost 4 kg of body fat in one month.It is only necessary to have determination and perseverance [7,8]."Eating less" is as efective as "moving more," but as long as you take in all the foods that are essential for the body to function properly.In this sense, the Mediterranean diet is among the most credited [9].Table 1 shows the possible advantages/disadvantages of the two most common dietary approaches based on food restriction and fasting [10].
A less demanding approach relies on low-digestible foods that swell with water, generating a sense of satiety associated with reduced caloric intake.Another option is to reduce the fat content of foods, but lipoglycides and lipoproteins play a crucial role in the growth, renewal, and maintenance of the body.In addition, some saturated fats play a structural role, typically demonstrated by inhibition of erythrocyte hemolysis [11,12].An excess of these so-called "bad fats" causes atheromatous plaque formation, but at adequate doses, they inhibit protein denaturation [13], potentially involved in conformation diseases and dementia [14].Incidentally, a somewhat similar approach is provided by orlistat, which prevents fat absorption by acting as a lipase inhibitor, thus reducing caloric intake [15].A diferent approach involves selectively reducing sugars to induce the body to burn fat.Caution is needed here, too, because sugars play a structural and functional role in the form of glycoproteins and glycolipids.Reducing sugars in the diet is likely to stimulate fat burning.In addition to being the body's basic fuel, sugars play a structural and functional role in the form of glycoproteins and glycolipids.Terefore, a hypoglycemic diet can be just as risky as a hypolipidemic diet [16].
Over the past decade, there has been an increase in the use of various surgical procedures of varying levels of complexity, with the aim of reducing gastric capacity, creating diversions, or a combination of both.Bariatric surgery is the most efective intervention for weight loss and is associated with a favorable impact on obesity-related complications [17].Unfortunately, despite the initial benefts, increased weight regain occurs in 21% of patients after initial weight loss [18].In addition, the procedure may carry some long-term risks and requires careful preoperative psychosocial assessment for compliance, ongoing nutritional counseling, and vitamin and micronutrient supplementation [19].

Conventional Anorectics.
Anorectics provide support for other measures against obesity and overweight by promoting appetite reduction.Amphetamines remain, despite their side efects, the main model.Teir mechanism of action resembles the fght reaction, which in stressful situations triggers a rush of humoral mediators (catecholamines such as adrenaline, indolamines, serotonin, glucocorticoids, mineralocorticoids, and other hormones) that mobilize the body's physical and mental resources, enabling it to perform at its best [20][21][22].Energy consumption increases while hunger decreases: this is the dual mechanism of action of the attack reaction and amphetamine [23].Unfortunately, the physiological reaction has self-regulation that limits its intensity and risks, whereas drugs do not.Te consequences can be devastating.Te problem frst emerged with the death of cyclist Tom Simpson from cardiovascular collapse during the 1967 Tour de France.Since then, amphetamines have been progressively confned to otherwise incurable conditions, such as attention defcit hyperactivity disorder (ADHD), but anorectics continue to proliferate.In addition to numerous amphetamine derivatives and analogs, they include several active substances [24].Most weight loss drugs work by reducing appetite or increasing satiety.Some do both.Te exception is orlistat, which acts by reducing fat absorption.Table 2 details the mechanism of action and common side efects of antiobesity drugs approved by the FDA for long-term use [15,[25][26][27][28][29].In order to reduce the risks related to these treatment options, careful consideration of contraindications to the use of each individual anorectics becomes strategic.In addition, recent studies appear to support promising evidence on the possible use of combination therapy as a strategy to optimize efcacy for weight management while minimizing adverse efects [30].
Other emerging approaches should also be considered for future development of obesity treatment.Tere is evidence that the level of certain bioactive endocrine factors, such as adipokines, can be altered in several metabolismrelated diseases.In particular, the results of diferent investigations support a possible central role for an upregulation of leptin, chemerin, and resistin associated with a downregulation of adiponectin in obesity.A possible approach directed at modulating the imbalance of these adipokines may prove to be an efective future strategy for the treatment of obesity [31].In addition, recent studies have supported the possibility of expanding pharmacological treatment options for obesity using new methods.In this regard, adipocyte-specifc CAMK2 inhibition has been shown to be useful against metabolic dysfunction [32].

A New Anorectic.
Te anorectic described below is inspired by the idea that hunger refects a lack of food centrally, as well as peripherally: hence a "mental food," consisting of glucose and tryptophan administered sublingually, to act on the central nervous system [33].Glucose is the main energy substrate in the brain, where it binds to receptors in the reward system of the nucleus accumbens [34].Tryptophan is the precursor of serotonin, which has the ability to reduce hunger and body weight [35][36][37].In particular, it activates the brain homeostatic circuit that matches energy intake with energy expenditure and the hedonic circuit, which is involved in the rewarding and motivational aspects of eating [38].Sublingual administration results in up to a tenfold increase in blood-brain barrier crossing and central efects.More specifcally, the new anorectic consists  Journal of Obesity of a sublingual tablet containing glucose and tryptophan at doses approximately 100 and 10 times lower than their normal dietary intake.Tis composition is notifed as a dietary supplement, which as a class has the ability to "maintain, sustain, or optimize a physiological parameter" [39].In the present case, this parameter consists of appetite regulation according to normal nutritional requirements.Incidentally, the words in quotes are from a Council of Europe document.Te new anorectic is distinguished from current ones by its safety and ease of use [33].Tese features nominate it as a possible frst-line treatment of obesity and overweight.

Compulsive Obesity
Te fght against obesity relies not only on "moving more and eating less," the decisive measure promoted globally by WHO [40], but also on the rich and varied list of anorexics.Yet, nearly 50% of the human population is obese or overweight.Te reasons are to be found in compulsive behaviors, which are beyond the control of reason.
Constitutional obesity is the main example of this.It is a condition rooted in the genome, in which fat accumulation is associated with distinctive physical traits [41,42].Its origin dates back to the Darwinian struggle for survival [43], where fat reserve allows hibernating animals to survive the lack of food in winter.It allows undernourished mothers to feed the creatures growing in their wombs.It is still this reserve that facilitated survival during the famines of the past, the seven lean cows of the Bible.
Developed countries are characterized by the abundance of food rather than its scarcity, yet the accumulation of fat related to the constitution persists.
One particular aspect deserving attention is obesity associated with stress.From a physiological point of view, the stress response should mobilize the necessary resources to increase mental and physical performance, allowing for more intense eforts than normal in the face of a difculty.Specifcally, in an efort to expand energy availability, an increase in glycolysis with an increase in blood glucose is an important part of the stress response.Increased blood glucose levels should normally inhibit hunger.However, there is ample evidence that in some individuals, stress, especially when prolonged, can produce a seemingly paradoxical response with increased hunger.Interindividual variability in the relationship between chronic stress and obesity risk has been related to diferences in glucocorticoid action.In particular, individuals may have diferent sensitivity to glucocorticoids, which may infuence food consumption and fat accumulation [44].Tere are students who under the stress of the exam eat little and lose weight, but there are also those who eat too much and gain weight [45].Tis drive is best described by an obese patient who, after several failed attempts, resorted to bariatric surgery: "Te surgery was a success.Compared to a year ago, I weigh 60 kg less!I now play sports, regaining the muscle tone I had lost during the rapid decline.It is true that you can fnd ways to lose excess fat, but keeping ft is another thing.I had surgery on my stomach, but not on my brain!Resisting temptation will be a lifelong war."A drive rooted in the brain is inevitable, the obese man who gave up tells us, but it doesn't have to be.Here is the testimony of another constitutional obese: "It was hard"-he writes to the doctor thanking him-"but in six months I managed to lose 15 kg.Tanks to the diet, sports, the bet with myself, but also to your help, which has been invaluable."Tis is the spirit with which one should approach compulsive obesity.Never give up.
Food addiction, understood as gratifcation that compensates for life's bitterness and defeats, is the second compulsive eating behavior [46,47].Here is how it is described by an obese patient: "Food is the only good thing that gives me a feeling of well-being.Do you want to take that away from me too?I know fat hurts especially with the years, but I am tired and without it I could not live an ugly and unsatisfying life."Addiction is defned as the subjection to something that deprives the body of a vital function, exercising it instead.Morphine and morphine-like drugs calm and relieve sufering, cocaine and amphetamines give the vigor needed to deal with emergencies, and nicotine supports cognitive processes and relaxes [48,49].Tese physiological capacities are set aside by a substance of abuse, which exercises them instead of the body.Tis enslavement manifests itself in the withdrawal syndrome in the form of efects that, without their physiological control, are exacerbated: hyperexcitation in the absence of a calming drug, prostration in the absence of excitatory drugs, and mental obnubilation without the nicotine that sustains mental alertness.Treatment of addiction begins with withdrawal syndrome, caused by the absence of the addictive substance.According to WHO, this is a real disease, with signs and symptoms that are dangerous to oneself and others.Te frst treatment consists of controlled administration of the addictive substance.Examples are oral methadone and buprenorphine, which mimic the efects of morphine in an attenuated form, facilitating cessation.Teir equivalent in the case of obesity is provided by appetizing, low-calorie diets [50,51].A diferent approach is disulfram, which alters alcohol metabolism with side efects (palpitations, headaches, vomiting, etc.) that generate a sense of revulsion toward alcohol [52].With food, this phenomenon is occasionally observed in cases of indigestion, but so far has not found medical use.Te third approach alleviates unpleasant withdrawal symptoms to facilitate abstinence.For example, alcohol deprivation is characterized by insomnia, which can be treated with drugs with opposite efects, such as trazodone [53].In essence, food addiction obesity is difcult to treat, but it makes use of a pharmacological armamentarium that should not be underestimated.

Concluding Reflection
Te "new epidemic," as WHO calls obesity, is a varied medical condition that requires thorough diagnosis and comprehensive medical support."Move more and eat less" is the sovereign remedy, which in the case of simple obesity and overweight can be addressed by relying on psychotherapy, anorexia, and education.Te problem of childhood obesity arises mainly at the level of families who do not know 4 Journal of Obesity the elementary principles of nutrition or encourage sports activities.Compulsive obesity is diferent.Te experience of obesity teaches how delicate and difcult its treatment is, but it also shows that it must always be attempted, perhaps with the help of drugs that did not exist in Cesare Beccaria's time [54].In this context, the new anorectic described in this article could carve out a nonmarginal role.

Table 1 :
Main advantages and disadvantages of caloric restriction and fasting dietary approaches for obesity.

Table 2 :
Mechanism of action and main side efects of FDA-approved antiobesity medications for long-term use.Only for people aged 6 and older who have obesity due to inherited conditions: (i) pro-opiomelanocortin defciency; (ii) proprotein subtilisin-kexin type 1 defciency; (iii) leptin receptor defciency. *