Anti-obesity Research Articles

Pharmacologic Management of Obesity in Neuro-oncology: A Case Report

Introduction: Brain tumors are the most common solid tumors in pediatric oncology. Advances in the treatment of childhood brain tumors have led to increased survival; however, treatment-related morbidity remains high. The risk of developing overweight/obesity or significant weight gain is commonly observed in children with a brain tumor often due to hypothalamic damage as a result of radiation therapy, surgery, or the tumor itself. This may be accompanied by endocrinopathies such as diabetes insipidus and central precocious puberty in survivors of a childhood brain tumor. Lifestyle intervention strategies are often ineffective in preventing and managing obesity. Patients have difficulty with adherence to dietary interventions due to prolonged exposure to high-dose steroids, compromised physical health due to the disease process, or limitations in mobility as a result of excessive weight gain or the sequelae of the tumor management. There are no effective interventions to prevent or manage obesity in this patient population. Case Presentation: We describe a case report of a 11-year-old female who underwent treatment for a ganglioglioma, WHO grade 1 and, simultaneously, experienced nearly 100-kilogram weight gain. After several unsuccessful attempts at lifestyle interventions, she was referred to endocrinology and prescribed a GLP-1 receptor agonist, semaglutide. Following treatment with semaglutide, significant weight loss was observed. Importantly, the patient reported enhanced quality of life and social activity. Conclusion: Anti-obesity medications are promising treatment options for this vulnerable patient group. Additional research is warranted to examine their use for the prevention and treatment of obesity in children with a brain tumor.

Oral GLP-1 Receptor Agonists for Weight Loss

With the increasing prevalence of obesity and the advent of new and highly effective antiobesity medications, there is renewed interest in novel antiobesity pharmacotherapy. Currently, the most effective medications for obesity are injectable medicines. There is a need to develop equally efficacious oral drugs to increase availability to patients. Oral semaglutide was approved by the Food and Drug Administration for type 2 diabetes in 2019. Herein, we review the current literature regarding the use of oral GLP-1 receptor agonists specifically for obesity including semaglutide, danuglipron, and orforglipron, with a focus on oral semaglutide as it is Food and Drug Administration-approved, although not for obesity alone. We also examine the future directions and impacts it will have on patients with obesity and overweight related to weight loss and cardiovascular disease.

Evaluation of Functional Properties and the Lipase Inhibitory Activity of Proteins from Amaranthus cruentus Seeds

Aims/Background: Obesity is characterized by excessive body fat and is a chronic and complex disease. The medications used to date for the treatment of obesity have exhibited various side effects. Thus, new substances must be sought from alternative sources as anti-obesity drugs. Recently, there has been increased interest in the study of bioactive peptides generated from plant proteins for functional food development. Plant proteins have exhibited pancreatic lipase inhibitory activity and can be potentially studied as sources of anti-obesity drugs for long-term use. Amaranthus cruentus seeds are very nutritious, with high protein con-tent and medicinal properties. Hence, this study focuses on pancreatic lipase inhibitory activity and functional properties of Amaranthus cruentus seed protein isolates. Materials and Methods: Proteins were isolated using conventional and thermal isoelectric pre-cipitation methods. The protein's ability to inhibit lipases was assessed using both synthetic and natural substrates. The functional properties, such as nitrogen solubility, foaming test, emulsi-fication test, and water and oil holding abilities, were evaluated. The protein isolates were char-acterized by SDS-PAGE and DSC. Cell line studies were performed on 3T3-L1 cell lines to determine the cytotoxicity and anti-adipogenic activity of protein isolates. Results: Proteins 1, 2, 3, and 4 were found to have high protein yield and protein content. SDS-PAGE characterization showed protein bands at different molecular weights (kDa). Protein iso-lates demonstrated good functional properties and antilipase activity as compared to flour. In the cell line experiments, protein 1 exhibited a dose-dependent reduction in the lipid content. Conclusion: A. cruentus seed protein could pave the way for the development of nutraceutical formulation in the treatment of obesity.

Molecular Modeling Studies of β-aminoacyl containing Homopiperazine derivatives as DPP4 Inhibitors

Dipeptidyl peptidase IV (DPP4) is a promising target for developing novel anti-diabetic and anti-obesity drugs. Pharmacophore based three dimensional quantitative structure activity relationship studies (3D-QSAR) and molecular docking were performed on a series of 56 β-aminoacyl-containing homopiperazine derivatives of DPP4 inhibitors to find out the structural relationship with the activity. The best predictive 3D-QSAR model with pharmacophore based alignment resulted in R2 (training set) value of 0.9407, Q2 (internal test set) value of 0.9053, Pearson-R value of 0.9517 and root mean square error (RMSE) 0.2838. The information rendered by pharmacophore based 3D-QSAR models and docking studies may afford valuable clues to optimize the lead and design of potent, selective inhibitors.

Deep phenotyping obesity using EHR data: Promise, Challenges, and Future Directions.

Obesity affects approximately 40% of adults and 15-20% of children and adolescents in the U.S, and poses significant economic and psychosocial burdens. Currently, patient responses to any single anti-obesity medication (AOM) vary significantly, making obesity deep phenotyping and associated precision medicine important targets of investigation. To evaluate the potential of EHR as a primary data source for obesity deep phenotyping, we conduct an in-depth analysis of the data elements and quality available from obesity patients prior to pharmacotherapy, and apply a multi-modal longitudinal deep autoencoder to investigate the feasibility, data requirements, clustering patterns, and challenges associated with EHR-based obesity deep phenotyping. We analyzed 53,688 pre-AOM periods from 32,969 patients with obesity or overweight who underwent medium- to long-term AOM treatment. A total of 92 lab and vital measurements, along with 79 ICD-derived clinical classifications software (CCS) codes recorded within one year prior to AOM treatment, were used to train a gated recurrent unit with decay based longitudinal autoencoder (GRU-D-AE) to generate dense embeddings for each pre-AOM record. principal component analysis (PCA) and gaussian mixture modeling (GMM) were applied to identify clusters. Our analysis identified at least nine clusters, with five exhibiting distinct and explainable clinical relevance. Certain clusters show characteristics overlapping with phenotypes from traditional phenotyping strategy. Results from multiple training folds demonstrated stable clustering patterns in two-dimensional space and reproducible clinical significance. However, challenges persist regarding the stability of missing data imputation across folds, maintaining consistency in input features, and effectively visualizing complex diseases in low-dimensional spaces. In this proof-of-concept study, we demonstrated longitudinal EHR as a valuable resource for deep phenotyping the pre-AOM period at per patient visit level. Our analysis revealed the presence of clusters with distinct clinical significance, which could have implications in AOM treatment options. Further research using larger, independent cohorts is necessary to validate the reproducibility and clinical relevance of these clusters, uncover more detailed substructures and corresponding AOM treatment responses.

New AHA/ASA Stroke Guidelines Focus on Prevention, Pregnancy Risks and the New Weight-loss Drugs

New AHA/ASA Stroke Guidelines Focus on Prevention, Pregnancy Risks and the New Weight-loss Drugs

Single-cell transcriptomics of human organoid-derived enteroendocrine cell populations from the small intestine.

Gut hormones control intestinal function, metabolism and appetite, and have been harnessed therapeutically to treat type 2 diabetes and obesity. Our understanding of the enteroendocrine axis arises largely from animal studies, but intestinal organoid models make it possible to identify, genetically modify and purify human enteroendocrine cells (EECs). This study aimed to map human EECs using single-cell RNA sequencing. Organoids derived from human duodenum and ileum were genetically modified using CRISPR-Cas9 to express the fluorescent protein Venus driven by the chromogranin-A promoter. Fluorescent cells from CHGA-Venus organoids were purified by flow cytometry and analysed by 10X single-cell RNA sequencing. Cluster analysis separated EEC populations, allowing an examination of differentially expressed hormones, nutrient-sensing machinery, transcription factors and exocytotic machinery. Bile acid receptor GPBAR1 was most highly expressed in L-cells (producing glucagon-like peptide 1 and peptide YY), long-chain fatty acid receptor FFAR1 was highest in I-cells (cholecystokinin), K-cells (glucose-dependent insulinotropic polypeptide) and L-cells, short-chain fatty acid receptor FFAR2 was highest in ileal L-cells and enterochromaffin cells, olfactory receptor OR51E1 was notably expressed in ileal enterochromaffin cells, and the glucose-sensing sodium glucose cotransporter SLC5A1 was highly and differentially expressed in K- and L-cells, reflecting their known responsiveness to ingested glucose. The organoid EEC atlas was merged with published data from human intestine and organoids, with good overlap between enteroendocrine datasets. Understanding the similarities and differences between human EEC types will facilitate the development of drugs targeting the enteroendocrine axis for the treatment of conditions such as diabetes, obesity and intestinal disorders. KEY POINTS: Gut hormones regulate intestinal function, nutrient homeostasis and metabolism and form the basis of the new classes of drugs for obesity and diabetes. As enteroendocrine cells (EECs) comprise only ∼1% of the intestinal epithelium, they are under-represented in current single-cell atlases. To identify, compare and characterise human EECs we generated chromogranin-A labelled organoids from duodenal and ileal biopsies by CRISPR-Cas9. Fluorescent chromogranin-A positive EECs were purified and analysed by single-cell RNA sequencing, revealing predominant cell clusters producing different gut hormones. Cell clusters exhibited differential expression of nutrient-sensing machinery including bile acid receptors, long- and short-chain fatty acid receptors and glucose transporters. Organoid-derived EECs mapped well onto data from native intestinal cell populations, extending coverage of EECs.

Weight loss drugs: what do I tell patients if they ask about them?

Weight loss drugs: what do I tell patients if they ask about them?

Seven unanswered questions about blockbuster weight-loss drugs.

Seven unanswered questions about blockbuster weight-loss drugs.

Molecular connectomics reveals a glucagon-like peptide 1-sensitive neural circuit for satiety.

Liraglutide and other glucagon-like peptide 1 receptor agonists (GLP-1RAs) are effective weight loss drugs, but how they suppress appetite remains unclear. One potential mechanism is by activating neurons that inhibit the hunger-promoting Agouti-related peptide (AgRP) neurons of the arcuate hypothalamus (Arc). To identify these afferents, we developed a method combining rabies-based connectomics with single-nucleus transcriptomics. Here, we identify at least 21 afferent subtypes of AgRP neurons in the mouse mediobasal and paraventricular hypothalamus, which are predicted by our method. Among these are thyrotropin-releasing hormone (TRH)+ Arc (TRHArc) neurons, inhibitory neurons that express the Glp1r gene and are activated by the GLP-1RA liraglutide. Activating TRHArc neurons inhibits AgRP neurons and feeding, probably in an AgRP neuron-dependent manner. Silencing TRHArc neurons causes overeating and weight gain and attenuates liraglutide's effect on body weight. Our results demonstrate a widely applicable method for molecular connectomics, comprehensively identify local inputs to AgRP neurons and reveal a circuit through which GLP-1RAs suppress appetite.

Glucagon-like peptide-1 receptor agonists in peri-operative care: Dispelling myths and unveiling insights with essential considerations for anaesthesiologists.

With the growing use of glucagon-like-peptide-1 (GLP-1) receptor (GLP-1R) agonists as anti-obesity medication it is becoming increasingly important to examine its consequences in the peri-operative period. GLP-1R agonists are known for their glucose-lowering and gastroparetic effects of which the latter causes some safety concerns regarding induction of anaesthesia, more specifically the risk of pulmonary aspiration. This article gathers the available evidence on this subject in addition to the already established guidelines. Current evidence makes us assume there is indeed an increased level of gastroparesis, but there are no studies to date with evidence of a presumed elevated risk of pulmonary aspiration. Future perspectives should focus on the actual risk of pulmonary aspiration and the possible implementation of ultrasound in the preoperative assessment.

Eligibility for Anti-Obesity Medications through Medicare for Older Adults with Overweight or Obesity

Medicare covered anti-obesity medications (AOMs) only for type 2 diabetes until March 2024, when the agency announced that AOMs with additional indications will be covered under Medicare Part D. Consequently, Medicare beneficiaries with overweight or obesity can be eligible for AOMs if they concurrently have type 2 diabetes or cardiovascular disease (CVD). To assess the potential impact of Medicare's March guidance, we estimated the number of US adults aged ≥65 years with overweight or obesity who were eligible for Medicare coverage of AOMs before and after Medicare's March 2024 guidance, stratified by sociodemographic status. We pooled data from the National Health and Nutrition Examination Survey from January 2011 to March 2020, including participants aged ≥65 years with a BMI ≥27 kg/m2. The study sample included 3,385 participants aged ≥65 with overweight or obesity, representing 26,552,194 adults. Among this population, 45.8% (95% CI, 43.4-48.2) or 12.2 million people had diabetes or cardiovascular disease and were eligible for AOMs through Medicare post-March 2024. In contrast, 33.8% (95% CI, 31.6-36.0%) or 9.0 million people had diabetes and were eligible for AOMs through Medicare pre-March 2024. Older age, male sex, and White race were associated with greater expansion in AOM eligibility due to Medicare's March guidance. Older age, male sex, identifying as a minority race/ethnicity, lower income, and less education were associated with greater AOM eligibility rates post-March 2024. These findings demonstrate that across sociodemographic groups Medicare's guidance significantly expanded the population of beneficiaries eligible for AOMs, but about half of older adults with overweight or obesity remain ineligible for AOMs through Medicare.

Structural characterization of polysaccharide isolated from Inonotus hispidus and its anti-obesity effect based on regulation of the interleukin-17-mediated inflammatory response.

A heteropolysaccharide (IHP3) with a molecular weight of 22.0 kDa was isolated from Inonotus hispidus (Bull.: Fr.) P. Karst using column chromatography purification from water extraction. Its backbone was predominantly composed of →6)-α-D-Galp-(1→, →2,6)-α-D-Galp-(1→,→6)-α-D-O-Me-Galp-(1→, →3)-α-D-Manp-(1→, and →3,4,6) -β-D-Galp-(1 → residues, branched at C2 of partial α-D-Galp, or C3 and C4 of β-D-Galp, and terminated by α-D-Manp, and α-L-Fucp. In high-fat diet (HFD)-fed obese mice, IHP3 effectively suppressed body weight and plasma glucose gain, decreased fat accumulation, ameliorated lipid metabolism, and protected liver function from HFD-induced damage. Combining the analysis of gut microbiota metabolomics, hepatic proteomics and biochemical detection revealed, IHP3 significantly altered cecum fecal metabolite abundances, inhibited the phosphorylation of peroxisome proliferator-activated receptor gamma, and promoted the browning of white adipose tissue and the activation of brown adipose tissue. These changes collectively contributed to alleviating obesity symptoms by suppressing the interleukin (IL)-17-mediated inflammatory response in obese mice. Therefore, these findings suggest that IHP3 could be a potential candidate for the development of anti-obesity drugs.

HTA367 Is There an Opportunity for Reimbursement of Anti-Obesity Drugs in Central and Eastern Europe?

HTA367 Is There an Opportunity for Reimbursement of Anti-Obesity Drugs in Central and Eastern Europe?

CO98 The Impact of Approved Anti-Obesity Medications on the Incidence of Osteoarthritis, Healthcare Resource Use and Costs Among Patients With Obesity: A Retrospective Cohort Study

CO98 The Impact of Approved Anti-Obesity Medications on the Incidence of Osteoarthritis, Healthcare Resource Use and Costs Among Patients With Obesity: A Retrospective Cohort Study

CO8 A Retrospective Analysis of the Impact of Approved Anti-Obesity Medications on Cardiovascular Disease Risk Among Patients With Obesity

CO8 A Retrospective Analysis of the Impact of Approved Anti-Obesity Medications on Cardiovascular Disease Risk Among Patients With Obesity

CO134 The Impact of Approved Anti-Obesity Medications on the Incidence of Obstructive Sleep Apnea, Healthcare Resource Utilization and Costs Among Patients, with Obesity: A Retrospective Cohort Study

CO134 The Impact of Approved Anti-Obesity Medications on the Incidence of Obstructive Sleep Apnea, Healthcare Resource Utilization and Costs Among Patients, with Obesity: A Retrospective Cohort Study

Targeting Dlat-Trpv3 pathway by hyperforin elicits non-canonical promotion of adipose thermogenesis as an effective anti-obesity strategy

IntroductionPromoting adipose thermogenesis is considered as a promising therapeutic intervention in obesity. However, endeavors to develop anti-obesity medications by targeting the canonical thermogenesis regulatory pathway, particularly β3-adrenergic receptor (β3-AR)-dependent mechanism, have failed due to the off-target effects of β3-AR agonists, exacerbating the risk of cardiovascular disease. Hyperforin (HPF), a natural compound extracted from the traditional herbal St. John’s Wort, binds to Dihydrolipoamide s-acetyltransferase (Dlat) and exerts effective anti-obesity properties through promoting adipose thermogenesis. ObjectivesThe objective of this study was to investigate the oral efficacy and pharmacokinetics profile of HPF, and explore the detailed mechanism by which Dlat modulates HPF-mediated adipose thermogenesis. MethodsTo assess the anti-obesity efficacy of orally administered HPF in vivo, Dlat heterozygous knockout (Dlat+/-) mice and wild-type (WT) mice, both fed a high-fat diet (HFD), underwent a validation process that involved the use of metabolic cages, NMR analysis, and infrared imaging. Sprague Dawley rats were employed to determine the pharmacokinetic parameters of HPF. Seahorse assays, JC-1 staining, qPCR, and immunoblotting were performed to evaluate cellular thermogenic efficacy of HPF and Dlat in vitro. ResultsOur study uncovered a non-canonical thermogenesis pathway involving Dlat, transient receptor potential vanilloid 3 (Trpv3, a calcium channel) and AMPK. Dlat interacted with Trpv3 to activate it, resulting in an increase in intracellular calcium (Ca2+) and the activation of Camkkβ. Camkkβ then stimulated AMPK, leading to elevated Ucp1 expression and initiating adipose thermogenesis. HPF promoted thermogenesis in adipose tissues through enhancing the Dlat-Trpv3 interaction independently of β3­AR, causing minimal cardiac side effects. Notably, HPF’s thermogenic effects were reduced in Dlat+/- mice. Moreover, HPF exerted favorable oral bioavailability, a relatively long half-life, and extensive distribution within adipose tissues. ConclusionIn summary, our study demonstrates that HPF targets a novel mechanism for promoting adipose thermogenesis and exhibits potent and safe anti-obesity efficacy.

EE58 The Impact of Approved Anti-Obesity Medications on the Incidence of Cardiovascular Disease, Healthcare Resource Use, and Costs Among Patients With Obesity: A Retrospective Cohort Study

EE58 The Impact of Approved Anti-Obesity Medications on the Incidence of Cardiovascular Disease, Healthcare Resource Use, and Costs Among Patients With Obesity: A Retrospective Cohort Study

CO53 The Impact of Approved Anti-Obesity Medications on the Risk of Obstructive Sleep Apnea in Patients With Obesity: A Retrospective Cohort Study

CO53 The Impact of Approved Anti-Obesity Medications on the Risk of Obstructive Sleep Apnea in Patients With Obesity: A Retrospective Cohort Study