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Cardiovascular Research Feb 2024Obesity is a chronic disease associated with serious complications and increased mortality. Weight loss (WL) through lifestyle changes results in modest WL long-term...
Obesity is a chronic disease associated with serious complications and increased mortality. Weight loss (WL) through lifestyle changes results in modest WL long-term possibly due to compensatory biological adaptations (increased appetite and reduced energy expenditure) promoting weight gain. Bariatric surgery was until recently the only intervention that consistently resulted in ≥ 15% WL and maintenance. Our better understanding of the endocrine regulation of appetite has led to the development of new medications over the last decade for the treatment of obesity with main target the reduction of appetite. The efficacy of semaglutide 2.4 mg/week-the latest glucagon-like peptide-1 (GLP-1) receptor analogue-on WL for people with obesity suggests that we are entering a new era in obesity pharmacotherapy where ≥15% WL is feasible. Moreover, the WL achieved with the dual agonist tirzepatide (GLP-1/glucose-dependent insulinotropic polypeptide) for people with type 2 diabetes and most recently also obesity, indicate that combining the GLP-1 with other gut hormones may lead to additional WL compared with GLP-1 receptor analogues alone and in the future, multi-agonist molecules may offer the potential to bridge further the efficacy gap between bariatric surgery and the currently available pharmacotherapies.
Topics: Humans; Diabetes Mellitus, Type 2; Obesity; Glucagon-Like Peptide 1; Appetite; Weight Loss; Glucagon-Like Peptide-1 Receptor; Hypoglycemic Agents
PubMed: 36448672
DOI: 10.1093/cvr/cvac176 -
Acta Diabetologica Aug 2023The purpose of this review is to explore the interconnected pathways of the microbiota-gut-brain axis (MGBA), focusing on the roles of the vagus nerve and glucagon like... (Review)
Review
AIMS
The purpose of this review is to explore the interconnected pathways of the microbiota-gut-brain axis (MGBA), focusing on the roles of the vagus nerve and glucagon like peptide-1 in appetite control, and in the development of obesity and diabetes.
METHODS
Type 2 diabetes mellitus (T2DM) and obesity are metabolic disorders whose prevalence has significantly increased in recent decades and is expected to increase every year, to pandemic proportions. These two pathologies often coexist and have substantial public health implications. The term "diabesity" defines the pathophysiological connection between overweight and T2DM. The gut microbiota affects many aspects of the host. Beyond the regulation of intestinal functions and the activation of immune responses, the gut microbiota plays a role in central nervous system functions (i.e., mood, and psychiatric conditions associated with stress and memory) and is a central regulator of metabolism and appetite.
RESULTS
The MGBA involves pathways such as the autonomic and enteric nervous systems, the hypothalamic- pituitary-adrenal axis, the immune system, enteroendocrine cells, and microbial metabolites. Notably, the vagus nerve plays an essential role in eating behavior by modulating appetite and learning nutritional preferences.
CONCLUSIONS
Because of its enteroendocrine cell-mediated interaction with the gut microbiota, the vagus nerve may provide a potential pathway through which gut microorganisms influence host feeding behavior and metabolic control of physiological and pathological conditions.
Topics: Humans; Gastrointestinal Microbiome; Diabetes Mellitus, Type 2; Brain-Gut Axis; Brain; Obesity; Vagus Nerve
PubMed: 37058160
DOI: 10.1007/s00592-023-02088-x -
International Journal of Obesity (2005) Feb 2024Obesity is a chronic disease associated with increased risk of obesity-related complications and mortality. Our better understanding of the weight regulation mechanisms... (Review)
Review
Obesity is a chronic disease associated with increased risk of obesity-related complications and mortality. Our better understanding of the weight regulation mechanisms and the role of gut-brain axis on appetite has led to the development of safe and effective entero-pancreatic hormone-based treatments for obesity such as glucagon-like peptide-1 (GLP-1) receptor agonists (RA). Semaglutide 2.4 mg once weekly, a subcutaneously administered GLP-1 RA approved for obesity treatment in 2021, results in 15-17% mean weight loss (WL) with evidence of cardioprotection. Oral GLP-1 RA are also under development and early data shows similar WL efficacy to semaglutide 2.4 mg. Looking to the next generation of obesity treatments, combinations of GLP-1 with other entero-pancreatic hormones with complementary actions and/or synergistic potential (such as glucose-dependent insulinotropic polypeptide (GIP), glucagon, and amylin) are under investigation to enhance the WL and cardiometabolic benefits of GLP-1 RA. Tirzepatide, a dual GLP-1/GIP receptor agonist has been approved for glycaemic control in type 2 diabetes as well as for obesity management leading in up to 22.5% WL in phase 3 obesity trials. Other combinations of entero-pancreatic hormones including cagrisema (GLP-1/amylin RA) and the triple agonist retatrutide (GLP-1/GIP/glucagon RA) have also progressed to phase 3 trials as obesity treatments and early data suggests that may lead to even greater WL than tirzepatide. Additionally, agents with different mechanisms of action to entero-pancreatic hormones (e.g. bimagrumab) may improve the body composition during WL and are in early phase clinical trials. We are in a new era for obesity pharmacotherapy where combinations of entero-pancreatic hormones approach the WL achieved with bariatric surgery. In this review, we present the efficacy and safety data for the pipeline of obesity pharmacotherapies with a focus on entero-pancreatic hormone-based treatments and we consider the clinical implications and challenges that the new era in obesity management may bring.
PubMed: 38302593
DOI: 10.1038/s41366-024-01473-y -
Current Opinion in Endocrinology,... Jun 2024Various gut hormones interact with the brain through delicate communication, thereby influencing appetite and subsequent changes in body weight. This review summarizes... (Review)
Review
PURPOSE OF REVIEW
Various gut hormones interact with the brain through delicate communication, thereby influencing appetite and subsequent changes in body weight. This review summarizes the effects of gut hormones on appetite, with a focus on recent research.
RECENT FINDINGS
Ghrelin is known as an orexigenic hormone, whereas glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), cholecystokinin (CCK), postprandial peptide YY (PYY), and oxyntomodulin (OXM) are known as anorexigenic hormones. Recent human studies have revealed that gut hormones act differently in various systems, including adipose tissue, beyond appetite and energy intake, and even involve in high-order thinking. Environmental factors including meal schedule, food contents and quality, type of exercise, and sleep deprivation also play a role in the influence of gut hormone on appetite, weight change, and obesity. Recently published studies have shown that retatrutide, a triple-agonist of GLP-1, GIP, and glucagon receptor, and orforglipron, a GLP-1 receptor partial agonist, are effective in weight loss and improving various metabolic parameters associated with obesity.
SUMMARY
Various gut hormones influence appetite, and several drugs targeting these receptors have been reported to exert positive effects on weight loss in humans. Given that diverse dietary and environmental factors affect the actions of gut hormones and appetite, there is a need for integrated and largescale long-term studies in this field.
Topics: Humans; Gastrointestinal Hormones; Appetite Regulation; Obesity; Cholecystokinin; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Peptide YY; Oxyntomodulin; Animals; Ghrelin; Appetite
PubMed: 38511400
DOI: 10.1097/MED.0000000000000859 -
Philosophical Transactions of the Royal... Oct 2023Genetic disruption of key molecular components of the hypothalamic leptin-melanocortin pathway causes severe obesity in mice and humans. Physiological studies in people... (Review)
Review
Genetic disruption of key molecular components of the hypothalamic leptin-melanocortin pathway causes severe obesity in mice and humans. Physiological studies in people who carry these mutations have shown that the adipose tissue-derived hormone leptin primarily acts to defend against starvation. A lack of leptin causes an intense drive to eat and increases the rewarding properties of food, demonstrating that human appetite has a strong biological basis. Genetic studies in clinical- and population-based cohorts of people with obesity or thinness continue to provide new insights into the physiological mechanisms involved in weight regulation and identify molecular targets for weight loss therapy. This article is part of a discussion meeting issue 'Causes of obesity: theories, conjectures and evidence (Part II)'.
Topics: Humans; Animals; Mice; Leptin; Thinness; Obesity; Adipose Tissue; Mutation
PubMed: 37661743
DOI: 10.1098/rstb.2022.0205 -
Archives of Medical Research Dec 2023Obesity is one of the most prevalent diseases in the world. Based on hundreds of clinical and basic investigations, its etiopathogenesis goes beyond the simple imbalance... (Review)
Review
Obesity is one of the most prevalent diseases in the world. Based on hundreds of clinical and basic investigations, its etiopathogenesis goes beyond the simple imbalance between energy intake and expenditure. The center of the regulation of appetite and satiety lies in the nuclei of the hypothalamus where peripheral signals derived from adipose tissue (e.g., leptin), the gastrointestinal tract, the pancreas, and other brain structures, arrive. These signals are part of the homeostatic control system (eating to survive). Additionally, a hedonic or reward system (eating for pleasure) is integrated into the regulation of appetite. This reward system consists of a dopaminergic circuit that affects eating-related behaviors influencing food preferences, food desires, gratification when eating, and impulse control to avoid compulsions. These systems are not separate. Indeed, many of the hormones that participate in the homeostatic system also participate in the regulation of the hedonic system. In addition, factors such as genetic and epigenetic changes, certain environmental and sociocultural elements, the microbiota, and neuronal proinflammatory effects of high-energy diets also contribute to the development of obesity. Therefore, obesity can be considered a complex neuroendocrine disease, and all of the aforementioned components should be considered for the management of obesity.
Topics: Humans; Appetite Regulation; Obesity; Brain; Adipose Tissue; Endocrine System Diseases; Energy Metabolism
PubMed: 37945442
DOI: 10.1016/j.arcmed.2023.102896 -
Cell Dec 2023The hedonic value of salt fundamentally changes depending on the internal state. High concentrations of salt induce innate aversion under sated states, whereas such...
The hedonic value of salt fundamentally changes depending on the internal state. High concentrations of salt induce innate aversion under sated states, whereas such aversive stimuli transform into appetitive ones under sodium depletion. Neural mechanisms underlying this state-dependent salt valence switch are poorly understood. Using transcriptomics state-to-cell-type mapping and neural manipulations, we show that positive and negative valences of salt are controlled by anatomically distinct neural circuits in the mammalian brain. The hindbrain interoceptive circuit regulates sodium-specific appetitive drive , whereas behavioral tolerance of aversive salts is encoded by a dedicated class of neurons in the forebrain lamina terminalis (LT) expressing prostaglandin E2 (PGE2) receptor, Ptger3. We show that these LT neurons regulate salt tolerance by selectively modulating aversive taste sensitivity, partly through a PGE2-Ptger3 axis. These results reveal the bimodal regulation of appetitive and tolerance signals toward salt, which together dictate the amount of sodium consumption under different internal states.
Topics: Animals; Neural Pathways; Sodium; Taste; Mice; Gene Expression Profiling
PubMed: 37989313
DOI: 10.1016/j.cell.2023.10.020