Regulation of appetite to treat obesity (original) (raw)
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Appetite Suppressants for The Treatment of Obesity: Advances And Challenges
2014
Obesity is a global health problem and has reached pandemic proportions. It arises as a consequence of energy imbalance, and a lot of research efforts have been carried out to understand the molecular mechanisms underlying the regulation of energy balance. A number of endogenous mediators including pancreatic, gut and adipose derived hormones and neuropeptides involved in appetite regulation and thereby energy balance, have provided the potential sites for the designing of anti-obesity medications. The present review focuses around the mediators involved in appetite regulation, the advances and challenges encountered in the development of appetite suppressants.
Current trends in targeting the hormonal regulation of appetite and energy balance to treat obesity
Expert Review of Endocrinology & Metabolism, 2010
With the eruption of the obesity pandemic over the past few decades, much research has been devoted to understanding the molecular mechanisms by which the human body regulates energy balance. These studies have revealed several mediators, including gut/pancreatic/adipose hormones and neuropeptides that control both short-and long-term energy balance by regulating appetite and/or metabolism. These endogenous mediators of energy balance have been the focus of many anti-obesity drug-development programs aimed at either amplifying endogenous anorexigenic/lipolytic signaling or blocking endogenous orexigenic/lipogenic signaling. Here, we discuss the efficacy and safety of targeting these pathways for the pharmacologic treatment of obesity.
Pharmacological management of appetite expression in obesity
Nature Reviews Endocrinology, 2010
| For obese individuals, successful weight loss and maintenance are notoriously difficult. Traditional drug development fails to exploit knowledge of the psychological factors that crucially influence appetite, concentrating instead on restrictive criteria of intake and weight reduction, allied to a mechanistic view of energy regulation. Drugs are under development that may produce beneficial changes in appetite expression in the obese. These currently include glucagon-like peptide-1 analogs such as liraglutide, an amylin analog davalintide, the 5-HT 2C receptor agonist lorcaserin, the monoamine re-uptake inhibitor tesofensine, and a number of combination therapies such as pramlintide and metreleptin, bupropion and naltrexone, phentermine and topiramate, and bupropion and zonisamide. However, the effects of these treatments on eating behavior remain poorly characterized. Obesity is typically a consequence of overconsumption driven by an individual's natural sensitivity to food stimuli and the pleasure derived from eating. Intuitively, these processes should be effective targets for pharmacotherapy, and behavioral analysis can identify drugs that selectively affect desire to eat, enjoyment of eating, satiation or postmeal satiety. Rational interventions designed specifically to modulate these processes could limit the normally aversive consequences of caloric restriction and maximize an individual's capacity to successfully gain control over their appetite.
Emerging Therapeutic Strategies for Obesity
Endocrine Reviews, 2006
The rising tide of obesity is one of the most pressing health issues of our time, yet existing medicines to combat the problem are disappointingly limited in number and effectiveness. Fortunately, a recent burgeoning of mechanistic insights into the neuroendocrine regulation of body weight provides an expanding list of molecular targets for novel, rationally designed antiobesity pharmaceuticals. In this review, we articulate a set of conceptual principles that we feel could help prioritize among these molecules in the development of obesity therapeutics, based on an understanding of energy homeostasis. We focus primarily on central targets, highlighting selected strategies to stimulate endogenous catabolic signals or inhibit anabolic signals. Examples of the former approach include methods to enhance central leptin signaling through intranasal leptin delivery, use of superpotent leptin-receptor agonists, and mechanisms to increase leptin sensitivity by manipulating SOCS-3, PTP-1B, ciliary neurotrophic factor, or simply by first losing weight with traditional interventions. Techniques to augment signaling by neurochemical mediators of leptin action that lie downstream of at least some levels of obesity-associated leptin resistance include activation of melanocortin receptors or 5-HT2C and 5-HT1B receptors. We also describe strategies to inhibit anabolic molecules, such as neuropeptide Y, melanin-concentrating hormone, ghrelin, and endocannabinoids. Modulation of gastrointestinal satiation and hunger signals is discussed as well. As scientists continue to provide fundamental insights into the mechanisms governing body weight, the future looks bright for development of new and better antiobesity medications to be used with diet and exercise to facilitate substantial weight loss. (Endocrine Reviews 27: 779-793, 2006) I. The Obesity Crisis II. Neuroendocrine Regulation of Body Weight III. Principles for the Design of Antiobesity Therapeutics IV. Stimulators of Catabolic Pathways A. Leptin and leptin-receptor agonists B. Strategies to overcome obesity-related leptin resistance C. Second-and higher-order targets of leptin action: melanocortins D. Ciliary neurotrophic factor E. Subtype-selective serotonin-receptor agonists V. Inhibitors of Anabolic Neuropeptides A. Neuropeptide Y and its many receptors B. Melanin-concentrating hormone VI. Gastrointestinal Peptides That Regulate Food Intake A. Glucagon-like peptide-1 B. Peptide-YY 3-36 C. Oxyntomodulin D. Amylin E. Ghrelin VII. Bringing It All Together: Cannabinoid-1 Receptor Antagonism VIII. Closing Comments I. The Obesity Crisis
Future Medicinal Chemistry, 2020
In recent decades, obesity has become a pandemic disease and appears to be an ultimate medical and social problem. Existing antiobesity drugs show low efficiency and a wide variety of side effects. In this review, we discuss possible mechanisms underlying brain–gut–adipose tissue axis, as well as molecular biochemical characteristics of various neurochemical regulators of body weight and appetite. Multiple brain regions are responsible for eating behavior, hedonic eating and food addiction. The existing pharmacological targets for treatment of obesity were reviewed as well.
Gut-Brain Endocrine Axes in Weight Regulation and Obesity Pharmacotherapy
Journal of Clinical Medicine, 2014
In recent years, the obesity epidemic has developed into a major health crisis both in the United States as well as throughout the developed world. With current treatments limited to expensive, high-risk surgery and minimally efficacious pharmacotherapy, new therapeutic options are urgently needed to combat this alarming trend. This review focuses on the endogenous gut-brain signaling axes that regulate appetite under physiological conditions, and discusses their clinical relevance by summarizing the clinical and preclinical studies that have investigated manipulation of these pathways to treat obesity.
Hypothalamic Neuropeptide Systems as Targets for Potential Anti-Obesity Drugs
Mini-Reviews in Medicinal Chemistry, 2007
Food intake and energy homeostasis are controlled by peripheral humoral signals, afferent neuronal pathways to the brain and central signals, represented, in particular, by neuropeptides. This review reports the status of development of novel compounds targeting some hypothalamic neuropeptide systems which are currently viewed as potential targets to treat obesity.
Centrally Acting Agents for Obesity: Past, Present, and Future
Drugs, 2018
For many years obesity was believed to be a condition of overeating that could be resolved through counseling and short term drug treatment. Obesity was not recognized as a chronic disease until 1985 by the scientific community and 2013 by the medical community. Pharmacotherapy for obesity has advanced remarkably since the first class of drugs, amphetamines, were approved for short-term use. Most amphetamines were removed from the obesity market due to adverse events and potential for addiction, and it became apparent that obesity pharmacotherapies were needed that could safely be administered over the long-term. This review of central nervous system (CNS) acting anti-obesity drugs evaluates current therapies such as phentermine/topiramate which act through multiple neurotransmitter pathways to reduce appetite. In the synergistic mechanism of bupropion/ naltrexone, naltrexone blocks the feedback inhibitory circuit of bupropion to give greater weight loss. Lorcaserin, a selective agonist of a serotonin receptor that regulates food intake, and the glucagon-like-peptide-1 (GLP-1) receptor agonist liraglutide are reviewed. Future drugs include tesofensine, a potent triple reuptake inhibitor in phase III trials for obesity and semaglutide, an oral GLP-1 analog approved for diabetes and currently in trials for obesity. Another potential new pharmacotherapy, setmelanotide, is a melanocortin-4 receptor agonist which is still in an early stage of development. As our understanding of the communication between the CNS, gut, adipose tissue, and other organs evolves, it is anticipated that obesity drug development will move toward new centrally acting combinations and then to drugs acting on peripheral target tissues.
Progress and challenges in anti-obesity pharmacotherapy
The Lancet Diabetes & Endocrinology, 2017
Obesity is a serious and growing worldwide health challenge. Healthy lifestyle choices are the foundation of obesity treatment. However, weight loss can lead to physiological adaptations that promote weight regain. As a result, lifestyle treatment alone typically produces only modest weight loss that is difficult to sustain. In other metabolic diseases, pharmacotherapy is an accepted adjunct to lifestyle. Several anti-obesity drugs have been approved in the USA, European Union, Australia, and Japan including sympathomimetics, pancreatic lipase inhibitors, GABA A receptor activators, a serotonin 2C receptor agonist, opioid antagonist, dopamine-norepinephrine reuptake inhibitor, and glucagon-like peptide-1 (GLP-1) receptor agonists. These drugs vary in their efficacy and side-effect profiles but all provide greater weight loss than do lifestyle changes alone. Even though obesity is widespread and associated with adverse health consequences, and anti-obesity drugs can help people to lose weight, very few patients use these drugs partly because of concerns about safety and efficacy, but also because of inadequate health insurance coverage. Despite great advances in our understanding of the biology of weight regulation, many clinicians still believe that patients with obesity should have the willpower to eat less. The tendency to hold the patient with obesity responsible for their condition can be a barrier to greater acceptance of anti-obesity drugs as appropriate options for treatment. Physicians should be comfortable discussing the risks and benefits of these drugs, and health insurance companies should provide reasonable coverage for their use in patients who are most likely to benefit. Although few promising antiobesity medications are in the drug-development pipeline, the most promising drugs are novel molecules that are co-agonists for multiple gut hormones including GLP-1, glucagon, and gastric inhibitory peptide.
Appetite Regulatory Hormones – A Novel Target for Prevention, Management, and Treatment of Obesity
Clinical Medicine Reviews in Therapeutics, 2016
The World Health Organization has described obesity as one of the today's most neglected public health problems worldwide. The main factor contributing to excessive weight gain is the impaired balance between energy intake and expenditure. This review aims to highlight the role of appetite regulatory hormones in obesity and to discuss a few evidence-based researches dealing with interventions targeting these hormones. Appetite regulatory hormones such as leptin and ghrelin are known to affect the development of obesity by influencing food intake, fat metabolism, and gastrointestinal function. Interventional studies conducted across the globe targeting these appetite regulatory hormones have proven to be impactful in altering the serum concentrations of these hormones and thus improve appetite regulation, thereby regulating energy homeostasis leading to desirable weight loss. Within this framework, it is expected that exploiting the body's own appetite regulatory signals through a conceptual strategy involving lifestyle, behavioral, public health, and medical interventions would appear to be a promising platform in prevention, management, and treatment of obesity.