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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 -
Advances in Nutrition (Bethesda, Md.) Jul 2023Epidemiologic evidence supports a positive association between ultraprocessed food (UPF) consumption and body mass index. This has led to recommendations to avoid UPFs... (Review)
Review
Epidemiologic evidence supports a positive association between ultraprocessed food (UPF) consumption and body mass index. This has led to recommendations to avoid UPFs despite very limited evidence establishing causality. Many mechanisms have been proposed, and this review critically aimed to evaluate selected possibilities for specificity, clarity, and consistency related to food choice (i.e., low cost, shelf-life, food packaging, hyperpalatability, and stimulation of hunger/suppression of fullness); food composition (i.e., macronutrients, food texture, added sugar, fat and salt, energy density, low-calorie sweeteners, and additives); and digestive processes (i.e., oral processing/eating rate, gastric emptying time, gastrointestinal transit time, and microbiome). For some purported mechanisms (e.g., fiber content, texture, gastric emptying, and intestinal transit time), data directly contrasting the effects of UPF and non-UPF intake on the indices of appetite, food intake, and adiposity are available and do not support a unique contribution of UPFs. In other instances, data are not available (e.g., microbiome and food additives) or are insufficient (e.g., packaging, food cost, shelf-life, macronutrient intake, and appetite stimulation) to judge the benefits versus the risks of UPF avoidance. There are yet other evoked mechanisms in which the preponderance of evidence indicates ingredients in UPFs actually moderate body weight (e.g., low-calorie sweetener use for weight management; beverage consumption as it dilutes energy density; and higher fat content because it reduces glycemic responses). Because avoidance of UPFs holds potential adverse effects (e.g., reduced diet quality, increased risk of food poisoning, and food wastage), it is imprudent to make recommendations regarding their role in diets before causality and plausible mechanisms have been verified.
Topics: Humans; Obesity; Food; Diet; Body Weight; Energy Intake; Food Handling; Fast Foods
PubMed: 37080461
DOI: 10.1016/j.advnut.2023.04.006 -
Nature Jul 2023Caloric restriction that promotes weight loss is an effective strategy for treating non-alcoholic fatty liver disease and improving insulin sensitivity in people with...
Caloric restriction that promotes weight loss is an effective strategy for treating non-alcoholic fatty liver disease and improving insulin sensitivity in people with type 2 diabetes. Despite its effectiveness, in most individuals, weight loss is usually not maintained partly due to physiological adaptations that suppress energy expenditure, a process known as adaptive thermogenesis, the mechanistic underpinnings of which are unclear. Treatment of rodents fed a high-fat diet with recombinant growth differentiating factor 15 (GDF15) reduces obesity and improves glycaemic control through glial-cell-derived neurotrophic factor family receptor α-like (GFRAL)-dependent suppression of food intake. Here we find that, in addition to suppressing appetite, GDF15 counteracts compensatory reductions in energy expenditure, eliciting greater weight loss and reductions in non-alcoholic fatty liver disease (NAFLD) compared to caloric restriction alone. This effect of GDF15 to maintain energy expenditure during calorie restriction requires a GFRAL-β-adrenergic-dependent signalling axis that increases fatty acid oxidation and calcium futile cycling in the skeletal muscle of mice. These data indicate that therapeutic targeting of the GDF15-GFRAL pathway may be useful for maintaining energy expenditure in skeletal muscle during caloric restriction.
Topics: Animals; Humans; Mice; Appetite Depressants; Caloric Restriction; Diabetes Mellitus, Type 2; Diet, High-Fat; Eating; Energy Metabolism; Growth Differentiation Factor 15; Muscle, Skeletal; Non-alcoholic Fatty Liver Disease; Receptors, Adrenergic, beta; Weight Loss
PubMed: 37380764
DOI: 10.1038/s41586-023-06249-4 -
Drugs Jul 2023Fenfluramine (Fintepla) is an oral anti-seizure medication (ASM) with a novel mechanism of action consisting of activity in the serotonergic system coupled with positive... (Review)
Review
Fenfluramine (Fintepla) is an oral anti-seizure medication (ASM) with a novel mechanism of action consisting of activity in the serotonergic system coupled with positive allosteric modulation effects at sigma-1 receptors. Originally approved for use at high doses as an appetite suppressant, it was subsequently withdrawn after being linked to valvular heart disease (VHD) and pulmonary arterial hypertension (PAH), before being investigated for use at low doses as an adjunctive ASM in patients with developmental epileptic encephalopathies, including Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) who have pharmacoresistant seizures. In clinical trials, treatment with adjunctive fenfluramine markedly reduced convulsive seizure frequency in patients with DS that were sustained for up to 3 years, and reduced drop seizure frequency in patients with LGS that were sustained for up to 1 year. Notably, fenfluramine was also associated with clinically meaningful improvements in aspects of everyday executive functioning (EF) not entirely explainable by seizure reduction alone. Furthermore, it was generally well tolerated with, importantly, no reports of VHD or PAH. Thus, adjunctive fenfluramine is a novel and effective treatment for pharmacoresistant seizures associated with DS and LGS that may also improve aspects of everyday EF in some patients.
Topics: Humans; Lennox Gastaut Syndrome; Fenfluramine; Epilepsies, Myoclonic; Treatment Outcome; Seizures; Anticonvulsants
PubMed: 37316680
DOI: 10.1007/s40265-023-01881-w -
Diabetes, Obesity & Metabolism Aug 2023To investigate the hypothesis that weight loss with the glucagon-like peptide-1 receptor agonist (GLP-1RA) liraglutide alone would lead to a greater reduction in the... (Randomized Controlled Trial)
Randomized Controlled Trial
Effect of the glucagon-like peptide-1 receptor agonist liraglutide, compared to caloric restriction, on appetite, dietary intake, body fat distribution and cardiometabolic biomarkers: A randomized trial in adults with obesity and prediabetes.
AIMS
To investigate the hypothesis that weight loss with the glucagon-like peptide-1 receptor agonist (GLP-1RA) liraglutide alone would lead to a greater reduction in the proportion of fat to lean tissue mass when compared to caloric restriction (CR) alone, as well as when compared to treatment with sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, that also enhances GLP-1 activity - to determine the independent effects of each treatment.
METHODS
A total of 88 adults with obesity and prediabetes were randomized to 14 weeks of intervention with CR (-390 kcal/d), liraglutide (1.8 mg/d), or the dipeptidyl peptidase-4 inhibitor sitagliptin (100 mg/d) as a weight-neutral comparator. Changes between groups in appetite and hunger ratings measured via visual analogue scales, dietary intakes, body weight, body composition via dual energy x-ray absorptiometry, and resting energy expenditure via indirect calorimetry were assessed using the Kruskal-Wallis test or Pearson's chi-squared test.
RESULTS
Weight loss ≥5% of baseline body weight occurred in 44% of participants in the CR group, 22% of the liraglutide group and 5% of the sitagliptin group (p = 0.02). The ratio of fat to lean mass decreased by 6.5% in the CR group, 2.2% in the liraglutide group, and 0% in the sitagliptin group (p = 0.02). Visceral fat reduced by 9.5% in the CR group, 4.8% in the liraglutide group, and 0% in the sitagliptin group (p = 0.04). A spontaneous reduction in dietary simple carbohydrates in the CR group was associated with improved homeostatic model assessment of insulin resistance score (HOMA-IR).
CONCLUSIONS
Although both liraglutide and CR are valuable strategies for cardiometabolic risk reduction, CR was associated with greater weight loss and more favourable improvements in body composition than treatment with liraglutide alone. Differences in the response to each of these interventions enables patients to be stratified to the most optimal intervention for their personal risk factors.
Topics: Humans; Adult; Liraglutide; Glucagon-Like Peptide-1 Receptor; Prediabetic State; Caloric Restriction; Appetite; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Sitagliptin Phosphate; Obesity; Dipeptidyl-Peptidase IV Inhibitors; Body Weight; Eating; Body Fat Distribution; Weight Loss; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Cardiovascular Diseases
PubMed: 37188932
DOI: 10.1111/dom.15113