Current Pharmaceutical Design - Volume 17, Issue 12, 2011

Obesity has become a global public health problem. Disability, illness, and deaths produced by overeating and lack of exercise have been the subject of study [1] and debate, as cigarette smoking advocates and researchers contest the suggestion that obesity is overtaking cigarette smoking as the nation's number one public health problem and underlying cause of death [2,3,4]. However, in the period of 1990-2000, poor diet and inactivity were considered the number 2 actual cause of death [5]. Other major problems, like breast, or colon or prostate cancers may be caused or enabled by obesity [6,7]. Considerable efforts have been made to reduce cigarette-smoking initiation and increase interventions and quit attempts, while reducing harm to those in second or third-hand contact with this environmental toxin. Overeating and obesity, long under the radar, has emerged as equally formidable and without effective public health, legal, and medical intervention and treatment strategies. Currently, obesity treatment is primarily medical, or loved one's admonitions, or self-help. Like the case of the alcoholic in the 1950s, this approach is limited and increases shame and stigma. We are told to eat less, eat better, eat slower, and exercise more, almost until the day that we are referred for a lap band or bariatric surgery. Hypertension, hyperlipidemia, joint and bone problems, type 2 diabetes, and a host of other diseases are treated while the underlying disease of continued compulsive overeating despite consequences goes unabated. Again, this is not unlike what occurred during the height of the cigarette-smoking epidemic. Smokers were treated for cough, hoarseness, polyps, upper respiratory infections, cancers, and other tobacco smoking related diseases while they continued to smoke or tried to quit on their own. A combination of physician re-education, making smoking status one of the medical vital signs, availability of nicotine OTC and newer pharmacological agents helped the smokers receive an intervention, stage of change assessment, and a quit attempt. At the same time, the public was protected by clean air laws and a reduction in marketing to potential long-term users - children. Smoking initiation rates decreased by changes in access (e.g., vending machines) and taxation. In retrospect, these medical approaches successfully “treated” the chronic recidivist smoker and prevented and “treated” the most smokers. The same comprehensive approach should apply to obesity. We must address the environment in which this epidemic has been allowed to occur, which means taking a tough look at food marketing, taxation of palatable foods, lifestyle, and the genetic effects. It has been postulated that a ‘thrifty’ genotype predisposes our generation to diabetes - what worked well for the hunter/gatherer i.e., quick efficient depositing of fat in the body during times of food abundance to sustain their lives through times of food scarcity - is now our enemy in the 21st century [8]. We have more food available than any society before us. Thus, the genotype manifests as widespread obesity and diabetes, which is passed from generation to generation and is especially risky in the maternal-child relationship. Women have a higher prevalence of obesity and it is now commonplace to birth an oversized infant out of an environment of maternal insulin resistance, hyperglycemia and preeclampsia [9]. Unfortunately, many of these infants grow to develop obesity and diabetes and the cycle repeats. We need therapeutic targets to help flip the switch. The intrauterine and postnatal environments are the foundation for a large portion of our overall taste preferences and life habits. Although women are encouraged to gain weight for healthier pregnancies, this is a risk factor for maternal obesity, birthing oversized infants in subsequent pregnancies, and childhood obesity. Cigarette smoking is an addiction and disease of the brain that was studied in the lab using nicotine implants and smoking rat models. Nicotine and newer treatments based on these translational models have been life saving for patients around the world. In obesity treatment development, most treatments have been drugs of abuse (e.g., amphetamines, fen-phen) and many new treatments have been proposed which suppress appetite, an unlikely and unfortunate target for psychopharmacological therapies. Rather than appetite, treatments like those developed for alcohol dependence and relapse, which interfere with reinforcement, are the translational goal of our work here at the University of Florida and at Princeton. Indeed, the obesity problem may be due to a pathological attachment to food as have been observed in cigarette smoking, gambling, and sex. Binge eating disorder is currently the most prevalent eating disorder [10]. However, having ‘food addiction‘ become a widely accepted diagnosis is yet to be determined. In the meantime, diet education, overeating prevention, early intervention and exercise adherence and augmentation are likely to be important interim measures against the obesity epidemic [11]. For the morbidly obese and those with significant obesity and co-morbidities, bariatric surgery remains the safe, effective, treatment of choice [12,13]. All will be reviewed in detail, in this issue of Current Pharmaceutical Design.

Overeating and associated obesity are major public health problems. In addition to its notable adverse health consequences, the behavior of overeating has significant neurobiological and psychological underpinnings. Current classification systems of mental disorders (DSM-IV and ICD-10) address this increasingly prevalent “disorder” in a limited and inconsistent manner. Several similarities between overeating and substance dependence have been documented with regards to phenomenology, shared neurobiology, and treatment. This has led to suggestions that a new category of “food addiction” be added to our psychiatric nosology and that this category be included with substance use disorders under a broad rubric of “addiction disorders”. In this article, we consider the rationale for this recommendation and evaluate its pros and cons. We summarize how the problem of overeating is addressed in our current classification systems and discuss DSM-5 approaches to the issue.

To address the causes for obesity in all of China is not feasible in a single article. There are hundreds of ethnic groups over a vast number of provinces. The diet and lifestyle of each is different based upon cultural/ethnic traditions and the environment. Several studies mentioned in this review have been done in particular areas and/or on specific population groups with regards to obesity and health risks associated with being overweight. Obesity is a multifactorial disease that is associated with genetic, physiological, environmental, and cultural/traditional perspectives in order to provide a broadened view on this epidemic in China. In this review, we will assess specific obesity gene and environment interactions, childhood obesity etiology, metabolic syndrome, and dietary and behavioral causes. We attempt to discuss obesity issues particularly in the Han Chinese population ranging from children, adolescents, adults to geriatrics.

Recent research has uncovered neurobiological and behavioral similarities between substance dependence and excess consumption of highly processed foods. These findings have led to the theory that food addiction may play a role in obesity and disordered eating. The inclusion of validated food addiction measures in clinical research, such as the Yale Food Addiction Scale, will add to the understanding of the clinical utility of this concept. Further exploring the food-addiction construct may also lead to a better clinical understanding of obesity and eating disorders and suggest future avenues for more effectively treating these problems.

New treatments for obesity are often focused on reducing appetite in otherwise healthy adults. Similarly, health guidelines and promotion programs are focused on healthy adults. We have become alarmed by the increasing prevalence of overweight and obesity in women of reproductive age. This issue has been equally overlooked in policy debates and clinical trials. The proportion of overweight or obese young women has overwhelmed the proportion of underweight and normal weight women. In order to prevent obesity in women and their offspring, clinical interventions and trials need to be developed for women before and in between pregnancies.

Over the past few decades, pediatric obesity has become a national epidemic. Up to one third of American children and adolescents currently meet criteria as overweight or obese, placing them at risk for obesity into adulthood. Multiple acute and chronic medical conditions are increasing in prevalence among youth due to their overweight status. In addition, obesity can result in serious problems related to psychosocial functioning. Efforts at prevention and treatment must address the multifactorial causes and consequences of pediatric obesity. Though many programs have been proposed, more work is needed in this area to successfully combat the problem of pediatric obesity.

Obesity has become a serious epidemic and one of the leading global health problems. However, much of the current debate has been fractious, and etiologies of obesity have been attributed to eating behavior (i.e. fast food consumption), personality, depression, addiction or genetics. One of the interesting new hypotheses for explaining the development of obesity involves a food addiction model, which suggests that food is not eaten as much for survival as pleasure and that hedonic overeating is relevant to both substance-related disorders and eating disorders. Accumulating evidence has shown that there are a number of shared neural and hormonal pathways as well as distinct differences in these pathways that may help researchers discover why certain individuals continue to overeat despite health and other consequences, and becomes more and more obese. Functional neuroimaging studies have further revealed that pleasant smelling, looking, and tasting food has reinforcing characteristics similar to drugs of abuse. Many of the brain changes reported for hedonic eating and obesity are also seen in various types of addictions. Most importantly, overeating and obesity may have an acquired drive similar to drug addiction with respect to motivation and incentive craving. In both cases, the desire and continued satisfaction occur after early and repeated exposure to stimuli. The acquired drive for eating food and relative weakness of the satiety signal would cause an imbalance between the drive and hunger/reward centers in the brain and their regulation. In the current paper, we first provide a summary of literature on food addition from eight different perspectives, and then we proposed a research paradigm that may allow screening of new pharmacological treatment on the basis of functional magnetic resonance imaging (fMRI).

Neural circuits implicated in drug conditioning, craving and relapse overlap extensively with those involved in natural reward and reinforcement like food. Exposure to drug-related cues in human addicts results in drug craving and localized activation of central circuits that are known to mediate cue-induced reinstatement of drug-seeking behavior in animal models of relapse. Similar regional activation patterns occur in humans in response to cues associated with foods. Furthermore, drug- and food-related cues not only activate common neuroanatomical regions but also result in similar activity-regulated gene expression programs within these shared areas. Cues predictive of food availability are powerful modulators of appetite as well as food-seeking and ingestive behaviors. The upregulation of a number of early genes in unique patterns within corticostriatal, thalamic, and hypothalamic networks suggests that food cues are capable of powerfully altering neuronal processing in areas mediating the integration of emotion, cognition, arousal, and the regulation of energy balance. The dopaminergic, enkephalinergic, and fos gene expressions are important regulatory genetic pathways for food craving behaviors. An umbrella term to describe common genetic antecedents of multiple impulsive, compulsive and addictive behaviors is Reward Deficiency Syndrome (RDS). Individuals possessing a paucity of serotonergic and/or dopaminergic receptors and an increased rate of synaptic dopamine catabolism, due to high catabolic genotype of the COMT gene, are predisposed to self-medicating any substance or behavior that will activate dopamine release including alcohol, opiates, psychostimulants, nicotine, glucose, gambling, sex, and even excessive internet gaming, among others. Finally, utilizing the long term dopaminergic activation approach will ultimately lead to a common safe and effective modality to treat RDS behaviors including aberrant food and drug craving behaviors.

The concept of “food addiction” is gaining acceptance among the scientific community, and much is known about the influence of various components of food (e.g. high-fat, sugar, carbohydrate, salt) on behavior and physiology. Most of the studies to date have studied these consequences following relatively long-term diet manipulations and/or relatively free access to the food of interest. It is suggested that these types of studies are primarily tapping into the energy regulation and homeostatic processes that govern food intake and consumption. More recently, the overlap between the neurobiology of “reward-related” or hedonic effects of food ingestion and other reinforcers such as drugs of abuse has been highlighted, contributing to the notion that “food addiction” exists and that various components of food may be the substance of abuse. Based on preclinical animal models of drug addiction, a new direction for this field is using self-administration procedures and identifying an addiction-like behavioral phenotype in animals following various environmental, genetic, pharmacological, and neurobiological manipulations. Here we provide examples from this research area, with a focus on fat and sugar self-administration, and how the sophisticated animal models of drug addiction can be used to study the determinants and consequences of food addiction.

‘Globesity’ is a descriptive term for the obesity epidemic now facing the U.S. and indeed, the world. Hyperphagia (i.e. overeating) can lead to metabolic syndrome which in turn can lead to Type 2 diabetes mellitus, heart disease, stroke and some cancers. The World Health Organization even states that more people die each year from the consequences of obesity than from hunger. Something must be done to stem the tsunami of obesity and its resultant medical complications. Our work and that of others suggests that new obesity treatments and anti-obesity medications should be based on those already successful in treating other addictions. This paper looks at empirical evidence linking addictions to food and to drugs such as tobacco, alcohol, cannabis, amphetamines, and cocaine. Hypotheses are put forth as to why hyperphagia is so difficult to treat. Additionally, prenatal programming for addiction is explored. Lessons from successful drug treatment are elucidated and potential pharmaceutical targets for hyperphagia and obesity are suggested.

Binge eating behavior has been noted in some eating disorders as well as in obesity. The goal of this paper is to review current, non-serotonergic pharmaceutical approaches to treat binge eating. Further, using information derived from preclinical models, we discuss candidate neurotransmitter systems for study as targets for the treatment of binge eating. Dopaminergic circuits have been implicated in both laboratory animal models and human studies of binge eating, though existing medications specifically targeting the dopaminergic system have been found to have adverse side effects. Opioidergic and gamma-aminobutyric acid (GABA) systems also appear to be highly involved in aspects of binge eating; further, opioid antagonists, such as naltrexone, and GABA agonists, such as baclofen, have all been shown to be effective in treating alcohol dependence and may be equally efficacious in attenuating binge eating. Preclinical evidence, and some clinical evidence, suggests that cannabinoid antagonism may also be useful in the treatment of binge eating, although the specific effect of antagonists on binge consumption remains unclear. Overall, each of these neurotransmitter systems provides a promising avenue for new pharmacotherapy development for binge eating, and preclinical and human studies provide a strong rationale for the development of highly-selective drugs that target this neurocircuitry.

Obesity and substance use disorders are rapidly growing problems throughout the world. Of the current mainstay therapies of diet, exercise, behavioral modification, surgery, and medications, drugs have the greatest risk for abuse and dependence. As each of these disorders share similar underpinnings mediated by the dopaminergic brain reward pathways, clinicians must seriously consider the safety of both the patient's physical and mental health when prescribing treatments. Specifically, balance and awareness of the factors involved in the variable abuse potentials of these prescribed medications is paramount. A cursory review of weight loss medications commonly used is performed with attention to FDA status, mechanism of action, and abuse potential. Concurrent strategies to minimize risk such as drug screening, ruling out doctor shopping, temporal considerations, monitoring for signs and symptoms of abuse and/or dependency, and a safety-tiered prescribing approach is also discussed in order to optimize best treatment practice . As the understanding of these disorders progresses along with the evolution of agreed nomenclature and awareness of compulsive behavioral disorders in general, greater safety and more appropriate interventions may be achieved. Further areas of research will help to elucidate nuances of the coocurrance and treatment of these disorders and perhaps guide drug research and development in the area of drug treatments of obesity.

The development of new phamacological treatments for obesity has been challenging. In part, the lack of early diagnosis, early detection, early intervention and treatment has meant that more cases progress to life-threatening co-morbidities and surgical options. Pharmacological treatment of obesity has been limited. Self medication with drugs of abuse and tobacco has been successful for some patients, but abuse and addiction make this approach quite dangerous. The advent of trendy ‘diets du jour’ has apparently made obesity and eating disorders more likely rather than less likely. Trials of novel anti-obesity compounds have generally compared the new medication and placebo to a dietary counseling intervention. Interventions for patients who are not obese enough for gastric banding or bariatric surgery are quite similar to those given to alcoholics in the 1970s, “drink less or stop drinking”. We need to consume less in a modern life of desk and computer work, driving, and even internet shopping. However, we are driven and reinforced to consume and easily fall prey to television and other cues and messages driving this relationship to eating. This paper , after briefly reviewing the consensus on consumption and exercising suggests that new treatments may be developed by increasing exercise adherence and even increasing the reinforcing value or power of exercise itself. Food, sex, and drugs of abuse are highly valued and reinforced in our brains, so why not exercise?

as obesity, type 2 diabetes (T2DM) and the metabolic syndrome sweep across the research and the clinical landscape of medical care, effective pharmacologic remedies for the treatment of obesity have become imperative. The complexities of nutrient impact on neurotransmitter and endocrine modulating chemistry have become increasingly better characterized as have the basic neurochemical pathways that mediate their effects. Food addiction has emerged as an important phenomenon that may help to explain and improve our capabilities of rendering bench lab research into impactful clinical intervention. Against this challenging backdrop of current research and study we introduce the notion that food may, itself, represent a type of drug. In this review of food as a drug, we outline some of the emerging science that argues how proteins, carbohydrates and fats operating on three basic levels of organismic functioning may constitute the most powerful drugs we have available to effectuate weight loss or weight gain over time. In addition, certain foods may not only be more addictive than others, but may actually have a direct effect on pro-inflammatory mediators that determine both metabolic dysfunction as well as overall neuropsychiatric function and well-being.

Obesity among adults, children and adolescents has markedly increased regardless of gender, age, ethnicity or educational level, and has become a national health threat and a major public health challenge. This obesity epidemic can be attributed to excess energy intake and decreased energy expenditure experienced in Westernized countries. Unfortunately, there is no single solution to prevent or treat obesity that will be inclusive of everyone. Often times, treatment of obesity may include a combination of diet, exercise, behavior modification, medication, and sometimes weight-loss surgeries. Hence, bariatric surgery has evolved over the last four decades and has been shown to be effective in reducing obesity related comorbidities, improve the quality of life, number of sick days, monthly medication costs, and overall mortality. With the increasing rates of weight loss surgical procedures, the quality, efficacy and surgical outcomes have improved with the creation of Bariatric Centers of Excellence designated by the American Society of Metabolic and Bariatric Surgery or American College of Surgeons. The benefits of bariatric procedures in morbidly obese patients outweigh the risks. With the advent of minimally invasive surgical procedures, bariatric surgery is a reasonable treatment option in those who strongly desire substantial weight loss and have life-threatening comorbid conditions.

The contemporary American food environment makes energy-dense, nutrient-poor foods and beverages the “default” option for most consumers. Economic interventions like taxes can shift the relative prices of unhealthy foods to nudge consumers towards healthier options. Beverages with added sugar are a good starting point for food taxation; they constitute over 10 percent of caloric intake nationwide and provide little or no nutritional value. Current levels of taxation on sugar-sweetened beverages (SSBs) are too low to affect consumer behavior, but the implementation of a penny-per-ounce excise tax could lead to substantial public health benefits. Current estimates predict that a tax that raised the cost of SSBs by 20 percent could lead to an average reduction of 3.8 pounds per year for adults, causing the prevalence of obesity to decline from 33 to 30 percent. SSB taxes would also generate considerable revenue for public health and obesity prevention programs. Although the beverage industry is fighting such taxes with massive lobbying and public relations campaigns, support for the policies is increasing, especially when revenue is earmarked for obesity prevention.