Treatment Of Obesity Research Articles

7345 Study on the correlation between the levels of myokines and metabolic abnormality in obese children

Abstract Disclosure: L. Ouyang: None. M. Li: None. F. Yang: None. Objective: There are limited drug options to treat childhood obesity. Studies have found that myokines play an important role in the mechanism of exercise in the treatment of obesity. However, the correlation between myokines and metabolic abnormalities in obese children is still unclear. The purpose of this study is to analyze the correlation between the levels of myokines and metabolic abnormalities in obese children to provide the basis for the future application of myokines in childhood obesity. Methods: 41 obese children who visited the pediatric clinic of our hospital from March to October 2022 were enrolled, and 11 healthy non-obese children who had a regular physical examination in the pediatric clinic during the same period were enrolled. Basic information, anthropological indicators and biochemical indicators were collected. Human myokine magnetic bead panel was used to detect serum myokine levels including irisin, FGF21, BDNF, LIF, MSTN, IL 6, and IL 15. Difference analysis, rank sum test and Spearman analysis were used to conduct the correlation between the levels of myokines and metabolic abnormalities in obese children. Results: We found that the BMI-SDS and body fat rate of obese children with abnormal metabolism was higher than those with normal metabolism status(p<0.05). Children with abnormal glucose metabolism had an increased risk of abnormal lipid metabolism and hyperuricemia(p < 0.05), and children with abnormal lipid metabolism had an increased risk of hyperuricemia and hypertension(p<0.05). The obese children with abnormal glucose and lipid metabolism had an increased risk of abnormal purine metabolism. The levels of leukemia inhibitory factor and brain-derived neurotrophic factor in obese children were significantly higher than those in non-obese children (p<0.05), and the level of fibroblast growth factor 21 in obese children with abnormal metabolism was significantly higher than that in children with normal metabolism (p<0.05), respectively. There was a significant positive correlation between BMI-SDS and the levels of irisin, leukemia inhibitory factor and brain-derived neurotrophic factor (r=0.361, 0.368, 0.343, p=0.009, 0.007, 0.013, respectively). There was a significant positive correlation between irisin, BDNF, LIF, MSTN and IL 6, and between FGF21 and irisin, MSTN, IL 6 in children (p < 0.05). Conclusions: With the increase in BMI, the risk of metabolic abnormalities in obese children increases. Obese children with one kind of metabolic abnormality are prone to merge with other metabolic abnormalities. The levels of leukemia inhibitory factor, fibroblast growth factor 21, irisin, brain-derived neurotrophic factor, and other myokine in obese children and obese children with abnormal metabolism are different from those in non-obese children and obese children with normal metabolism respectively, and there is interaction between myokines. Presentation: 6/1/2024

6494 GLP-1/GIP/Glucagon Triagonist Improves Glycemic Control via Gαq Signaling Pathway and TRPM5 Activation

Abstract Disclosure: N. Khajavi: None. P.C. Schreier: None. P. Beyerle: None. P.S. Reinach: None. A. Breit: None. I. Boekhoff: None. T.D. Müller: Grant Recipient; Self; Novo Nordisk. Speaker; Self; Novo Nordisk. Stock Owner; Self; Novo Nordisk. T. Gudermann: None. Cutting-edge research on obesity and diabetes strives to pioneer innovative drug combinations targeting various dysfunctional metabolic regulatory pathways. The single-molecule triagonist has been developed to directly interact with the glucagon-like peptide-1 receptor (GLP-1R), glucose-dependent insulinotropic polypeptide receptor (GIPR), and the glucagon receptor (GcgR). It provides a breakthrough in the treatment of obesity and type 2 diabetes because of greater efficacy compared to conventional single-agonist therapy. While the triagonist is already undergoing phase two clinical trials, the downstream mechanism requires further study. Previously, we showed that triagonist elicits transient rises in intracellular Ca2+ concentration that augment glucose-induced rises in insulin secretion in murine (MIN6) and human (1.1B4) pancreatic β cell lines. Although Gαs signaling is known as the main mediator of both GLP-1 and GIP signaling, our research indicates that the superior effect of the triagonist on insulin secretion is not solely dependent on the activation of the classical Gαs pathway and the exchange factor activated by cAMP (EPAC) signaling. Instead, we report that the triagonist enhances glucose-induced rises in insulin secretion via Gαq signaling and its downstream effector, the TRPM5 channel. This involvement is evident, as blocking Gαq signaling with a specific blocker, YM254890, reduced triagonist-induced rises in insulin secretion in mouse pancreatic islets. Similarly, blocking TRPM5 with the TPPO blocker attenuated triagonist-induced increases in insulin secretion and Ca2+ signaling in mouse pancreatic islets. Strikingly, both blockers had no remarkable impact on GLP-1- and GIP-induced rises in insulin secretion. Our in vivo analysis demonstrates that the triagonist improves glucose tolerance in diet-induced obese wild-type mice, but this effect was absent in TRPM5 knockout mice. Notably, the triagonist augments glucose-induced insulin secretion in isolated islets of wild-type mice more than treatment with GLP1 and GIP mono-agonists. Furthermore, this enhanced response is absent in TRPM5 knockout islets. Recent studies propose that persistent membrane depolarization of β cells leads to a switch from Gαs to Gαq signaling, which is a major amplifying pathway of insulin secretion under diabetic conditions. Our study shows that the enhancing effect of the triagonist, acting as a biased agonist, on insulin secretion is dependent on TRPM5 activation through the Gαq signaling pathway. Presentation: 6/2/2024

The serotonin 1A receptor promoter polymorphism, rs6295, is associated with morphofunctional features

Introduction. The tendency to weight gain is influenced by many genetic and environmental factors (nutrition, level of physical activity, social well-being, etc.), as well as complex interactions of these factors. Studying the genetic factors of obesity can help in developing individual strategies for the prevention and treatment of this common disease. One of the most important hereditary factors is the neurotransmitter systems gene polymorphism, (including the serotonin system gene polymorphism). The aim of the investigation is to study the associations of single nucleotide polymorphism of the rs6295 locus of the serotonin receptor gene 1A HTR1A with morphofunctional features and body weight gain. Material and methods. The study used the materials of a comprehensive anthropogenetic examination of 386 men and 418 women aged 17 to 30 years. More than 20 morphofunctional indicators were measured using the traditional anthropometric method. The material for genetic analysis was genomic DNA isolated from buccal epithelium. The reliability of intergroup differences was assessed using the Mann-Whitney criterion, while canonical discriminant analysis was used to study intergroup variability. Results. For the first time, a significant correlation was shown between the polymorphism of the serotonin receptor type 1 gene HTR1A and morphofunctional features: individuals with the G/G genotype with greater body weight have lower (compared to carriers of the C/C and C/G genotypes) values of the indicators of the level of metabolic processes and specific metabolism. Conclusion. The statistically significant obtained results may be used in the development of individual strategies for the prevention and treatment of obesity, and also allow us to supplement the information on the association of serotonin system gene polymorphism with morphofunctional features and contribute to expanding our understanding of the human physique features formation and their relationships with hereditary predisposition.

6851 Rapidly Increasing Use of Anti-Obesity Medications among Veterans in the Veterans Health Administration (VA)

Abstract Disclosure: V. Vimalananda: None. S. Qian: None. R. Bolton: None. A. Hung: None. V. Smith: None. M. Maciejewski: None. Introduction: Obesity is a prevalent and costly chronic disease that compromises quality of life; increases risks of cardiometabolic disease, osteoarthritis, and several cancers; and accounts for 28% of U.S. health care costs. Anti-obesity medications (AOMs) may fill the treatment gap given the low uptake of bariatric surgery and limited effectiveness of behavioral interventions, and are guideline-recommended as part of a comprehensive obesity treatment plan. The landscape for obesity treatment has changed with introduction of the highly effective and in-demand glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dual GLP-1 + GIP receptor agonists (GIP/GLP-1 RAs). Given limited knowledge of use patterns, we describe use of AOMs among patients receiving care in the Veterans Health Administration (VA), which is the largest integrated health system in the United States. Methods: In a retrospective cohort study of VA patients from 7/1/2021-6/30/2023, we examined data from the VHA Corporate Data Warehouse separately for patients on AOMs without and with diagnosed diabetes, since the newer AOMs can be used at lower doses for the diabetes indication. Results: There were 31,106 patients without diabetes and at least one AOM prescription in the two year study period, who were 60% male and 62% White. AOM prescriptions from Year 1 to Year 2 among this group increased 215%. Overall, prescriptions were: semaglutide 34%, liraglutide 18%, orlistat 18%, phentermine/topiramate 14%, bupropion/naltrexone 12%, phentermine 4% and tirzepatide 0.03%. Prescribers were physicians 60%, LIPs 25%, and pharmacists 13%. There were 188,017 patients with diagnosed diabetes and at least one AOM prescription, and they were 92% male and 67% white. AOM prescriptions from Year 1 to Year 2 among this group increased 14% and were primarily (87%) for semaglutide. Prescribers were physicians 63%, licensed independent practitioners (LIPs) 23%, and pharmacists 10%. Conclusions AOM use is increasing in VA across all AOM classes, particularly among patients without diabetes, indicating growing interest in medical treatment of obesity. As AOM use spreads, real-world evidence on weight loss and clinical outcomes is needed among patients like those in VA who tend to be older and less healthy than the highly selected patients included in randomized clinical trials. Data is especially needed to guide practice among patients with obesity and without diabetes, given the dramatic increase in use among that group over the past 2 years. Presentation: 6/1/2024

7492 Fibroblast Growth Factor 21 In The Diagnosis And Treatment Of Metabolic Disorders

Abstract Disclosure: H.M. Heshmati: None. H.S. Abu-Lebdeh: None. Background: Fibroblast growth factor 21 (FGF21), a member of the human FGF superfamily, is a 181 amino acid peptide hormone primarily produced by the liver. The gene of FGF21, located on chromosome 19, was cloned in 2000. FGF21 is involved in the maintenance of metabolic homeostasis. This review presents an update on the relevance of FGF21 in the diagnosis and treatment of metabolic disorders including obesity, nonalcoholic fatty liver disease (NAFLD), dyslipidemia, and type 2 diabetes. Methods: A systematic search of literature was conducted using the search terms fibroblast growth factor 21, obesity, nonalcoholic fatty liver disease, dyslipidemia, and type 2 diabetes. Results: FGF21 is a stress hormone with effects on energy expenditure and metabolism of lipids and glucose. FGF21 exerts its endocrine action in the central nervous system and adipose tissue. The serum FGF21 levels in normal subjects increase with aging. Stressful conditions (e.g., fasting status, protein restriction, exercise, metabolic disorders, kidney diseases, cardiovascular diseases, and sepsis) increase FGF21 secretion. Serum FGF21 levels are increased in obesity, NAFLD, dyslipidemia, and type 2 diabetes. Some of these patients may have a state of FGF21 resistance. The resistance to FGF21 is related, at least in part, to the presence of high circulating levels of fibroblast activation protein, a protease that inactivates FGF21. It has been suggested that the exercise-induced weight loss can be due to increased FGF21 secretion and decreased FGF21 resistance in adipose tissue. Serum FGF21 level has the potential to be used as a biomarker for early diagnosis of metabolic disorders (e.g., NAFLD and type 2 diabetes). Based on different metabolic properties of FGF21, FGF21-based therapy has been considered as an attractive approach for the treatment of metabolic disorders. Since native FGF21 has poor pharmacodynamic properties (e.g., short half-life and proteolytic cleavage by proteases), long-acting FGF21 analogs (e.g., LY2405319, PF-05231023, pegozafermin, AKR-001, and LLF580) have been synthesized and tested in clinical trials for the treatment of obesity, NAFLD, dyslipidemia, and type 2 diabetes. The available results show that FGF21 analogs can reduce body weight, liver fat, blood lipids, and fasting insulin/insulin resistance. Overall, the treatment with these analogs is safe and well tolerated. Conclusion: FGF21 is a predominantly liver-derived peptide hormone regulating energy expenditure and metabolism of lipids and glucose. Serum FGF21 levels are increased in several metabolic disorders including obesity, NAFLD, dyslipidemia, and type 2 diabetes. FGF21 is an attractive target for the treatment of these metabolic disorders. Despite some promising results observed with the use of FGF21 analogs, more clinical studies are needed before recommending FGF21-based therapies in metabolic disorders. Presentation: 6/2/2024

From starvation to time-restricted eating: a review of fasting physiology.

We have long known that subjects with obesity who fast for several weeks survive. Calculations that assume the brain can only use glucose indicated that all carbohydrate and protein sources would be consumed by the brain within several weeks yet subjects with obesity who fasted for several weeks survived. This anomaly led to the determination of the metabolic role of ketone bodies. Subsequent studies transformed our understanding of ketone bodies and illustrated the value of challenging the norm and adapting theory to evidence. Although prolonged fasting is no longer a treatment for obesity, the early studies of starvation provided valuable insights about macronutrient metabolism and ketone body adaptations that fasting elicits. Intermittent fasting and its variants such as time-restricted eating are fasting models that are far less regimented than starvation and severe calorie restriction; yet they produce metabolic benefits. The mechanisms that produce the metabolic changes that intermittent fasting elicits are relatively unknown. In this article, we review the physiology of starvation, starvation adaptation diets, diet-induced ketosis, and intermittent fasting. Understanding the premise and physiology that these regimens induce is necessary to draw parallels and provoke thoughts on the mechanisms underlying the metabolic benefits of intermittent fasting and its variants.

8638 NEGR1 is a Mediator of Exercise-Induced Neuritogenesis in Subcutaneous White Adipose Tissue, Implications for Improved Systemic Metabolism

Abstract Disclosure: P. Nigro: None. N.P. Carbone: None. T. Caputo: None. M. Vamvini: None. M.M. Columbus: None. M.F. Hirshman: None. R. Middelbeek: None. L.J. Goodyear: None. Emerging research shows that exercise training results in robust and beneficial adaptions to subcutaneous white adipose tissue (scWAT), leading to improved systemic metabolism. The mechanisms for these benefits of exercise on are not fully understood, but we have recently demonstrated that training in mouse scWAT refines nerve connections in scWAT promoting neurite outgrowth (neuritogenesis). Our multi-omics and advanced microscopy data identifies Neuronal Growth Regulator 1 (NEGR1) as a potential player in this process. Here, we determine the role of NEGR1 as a mediator of scWAT neuritogenesis and regulator of systemic metabolism. Exercise training in mice for 11 days significantly increased NEGR1 protein expression by 35% (p<0.05). Next, we directly injected NEGR1 AAV into the inguinal scWAT of untrained male mice for three weeks resulting in a 43% increase in NEGR1 protein (p<0.05). Overexpression of NEGR1 led to an increase in the innervation markers tyrosine hydroxylase (+38%, p<0.01) and synaptophysin (+39%, p<0.01), and remarkably, a 16% decrease in adipocyte cell size (p<0.05), and a 15% reduction in fasting blood glucose levels (p<0.05). This suggests that NEGR1 plays a fundamental role in regulating scWAT morphology and function, adaptations that improve systemic glucose homeostasis. To determine mechanisms for exercise training-induced increases in NEGR1 expression, we used in silico and cell culture experiments and found that NEGR1 is under the regulation of the Peroxisome Proliferator-Activated Receptor gamma (PPARg) transcription factor. Given that numerous natural and synthetic PPARg ligands are lipids, we used targeted lipidomics to identify exercise-induced lipids capable of binding and inducing PPARg expression in inguinal scWAT. We identified 13-oxo-octadecadienoic acid (13-oxo-ODE), an oxylipin derived from linoleic acid, as a potent agonist and inducer of PPARg expression. Exercise training increased 13-oxo-ODE by 3-fold (p<0.05), and 13-hydroxyoctadecadienoic acid (13-HODE), the 13-oxo-ODE precursor was also increased by 3-fold (p<0.01). To validate that 13-oxo-ODE increases NEGR1, adipocytes were incubated with 2μM of 13-oxo-ODE for 48 hours. 13-oxo-ODE increased NEGR1 expression by 27-fold (p<0.0001) and NEGR1 protein by 2-fold (p<0.01). In summary, NEGR1 is a novel exercise-induced molecule that regulates neuronal refinement in scWAT. Our data also suggest that the synthesis of 13-oxo-ODE leads to PPARγ activation that in turn promotes NEGR1 expression in scWAT. NEGR1 has beneficial effects on scWAT that are associated with improved systemic metabolism, making NEGR1 a novel target for treatment of obesity and cardiometabolic diseases. Presentation: 6/1/2024

8040 Precision-Engineered Activin and GDF Ligand Trap HS235: A Novel Lean Mass-Preserving Treatment for Obesity

Abstract Disclosure: G. Schang: Employee; Self; 35Pharma. M. De Molliens: Employee; Self; 35Pharma. E. Brule: Employee; Self; 35Pharma. C. Chauvet: Employee; Self; 35Pharma. J. Denis: Employee; Self; 35Pharma. A. Sours: Employee; Self; 35Pharma. V. Ganesh: Employee; Self; 35Pharma. G. Tremblay: Employee; Self; 35Pharma. J. Schoelermann: Employee; Self; 35Pharma. M. O'Connor: Employee; Self; 35Pharma. Introduction: Novel anti-obesity medications including incretin mimetics have revolutionized the pharmacotherapy of obesity and type 2 diabetes, leading to unprecedented weight loss and clinically meaningful improvement of glucose metabolism and cardiometabolic health. However, incretins reduce body mass in a non-selective manner; both fat mass and lean mass are lost with incretin treatment. In obese patients treated with incretins, undesirable loss of lean body mass (LBM) can account for up to 40% of overall weight loss. Loss of LBM negatively impacts resting metabolic rate, leading to a weight loss plateau and often unsustainable results. Furthermore, individuals with sarcopenia, characterized by low muscle mass and strength, are at greater risk for heart failure. The preservation, or even increase, of LBM is therefore a desirable treatment goal for obesity pharmacotherapy and overall cardiometabolic health. Activins and growth differentiation factors (GDFs), which are members of the TGF-beta superfamily, are validated targets controlling body composition and metabolism. Specifically, blockade of activins and GDFs has anabolic effects in metabolically active tissues such as skeletal muscle and brown adipose tissue, while reducing white adipose tissue mass. Therefore, specific and selective blockade of activins and GDFs represents a novel anti-obesity treatment strategy which can act orthogonally to current anti-obesity medications. HS235 is an activin receptor ectodomain-based (ActR) Fc-fusion protein that has been rationally designed to attain optimal inhibition of ligands controlling body composition in obesity. Methods: A structure-assisted rational molecular engineering approach coupled with cell-based potency screening was employed to design HS235. To validate the anti-obesogenic potential of HS235, diet-induced obese (DIO) mice were injected with HS235, an incretin mimetic, or a combination of both. Fat mass, LBM, muscle weights, and biomarker readouts were assessed at the end of study. Results: In cell-based assays, HS235 potently and selectively neutralized activins and GDFs implicated in body composition. This translated to complete in vivo target engagement and pharmacodynamic response. In a DIO mouse model, both HS235 and the incretin mimetic significantly improved metabolic parameters and decreased fat mass, but only HS235 increased LBM, while incretin-based treatment led to LBM loss. Importantly, the addition of HS235 to the incretin mimetic lead to a synergistic fat mass loss and prevented loss of LBM. Conclusion: Potent and selective inhibition of activins and GDFs by HS235 represents a novel LBM preserving weight loss strategy orthogonal to incretin mimetics. Collectively, these data support the development of HS235 as a novel anti-obesity agent to complement currently approved incretin-based medications to improve quality of weight loss. Presentation: 6/3/2024

7004 Systems genetics analysis to identify candidate genes for fat distribution in BXD mice

Abstract Disclosure: N. Kim: None. D. Ryu: None. C. Oh: None. Obesity is defined as the accumulation of excess fat in the body. Although obesity is the main cause of metabolic disorders, not all obese people have metabolic disorders. Among many factors identified, the ratio of visceral (vWAT) to subcutaneous white adipose tissue (sWAT), representing body fat distribution, has been elucidated to be closely associated with metabolic health. Body fat distribution has been proposed as a possible explanation for this discrepancy. To investigate the regulation of body fat distribution, we performed a genetic analysis using the phenotype data and male subcutaneous fat microarray data from the BXD mouse genetic reference population. Our analysis identified H2-Ke6 (Hsd17b8), encoding hydroxysteroid 17-beta dehydrogenase, as a candidate target for adipose tissue plasticity. To further explore its role, we employed multiple approaches to reveal the effect of Hsd17b8 inhibition. First, lipid accumulation was attenuated in 3T3-L1 preadipocytes where Hsd17b8 was inhibited by CRISPER/Cas9 as well as lasalocid. Furthermore, we confirmed that the expression of adipogenesis-related transcription factor as well as mature adipocyte marker was decreased in terminally differentiated 3T3-L1. Specifically, CCAAT/enchancer binding protein α (Cebpa), peroxisome proliferator-activated receptor γ (Pparg), adiponectin (Adipoq), and fatty acid binding protein 4 (Fabp4) were transcriptionally downregulated. Consistently, in C. elegans, we used RNA interference (RNAi) to inhibit the expression of the Hsd17b8 ortholog, dhs-25, and observed a reduction in lipid accumulation. All these data suggest that the reduction in lipid accumulation in differentiated 3T3-L1 cells by the inhibition of Hsd17b8 is attributed to the suppression of early differentiation during the adipogenesis process. On top of that, to determine whether Hsd17b8 indeed influences body fat distribution in vitro, we utilized IngWAT Mouse Immortalized Preadipocyte Cell Line derived from subcutaneous white adipose tissue (sWAT) of a wild-type mouse. In contrast to the previous findings, we observed an increase in lipid accumulation of IngWAT when Hsd17b8 was inhibited. Surprisingly, the elevation of lipid accumulation in sWAT, as seen in gynoid obesity, has been revealed to be indicative of robust metabolic health compared to android obesity. Collectively, these data suggest that Hsd17b8 may represent a novel therapeutic target for the treatment of obesity. Our study provides valuable insights into the mechanisms underlying metabolic health in obesity and highlights the potential of Hsd17b8 as a therapeutic target for modulating adipose tissue plasticity. Presentation: 6/3/2024

7279 Survodutide and Semaglutide Both Induce Weight Loss but Show Different Effects on Food Preference and Dyslipidemia in the Free Choice Diet-induced Obese Hamster Model

Abstract Disclosure: F. Briand: Employee; Self; Physiogenix. R. Augustin: Employee; Self; Boehringer Ingelheim. K. Bleymehl: Employee; Self; Boehringer Ingelheim. T. Zimmermann: Employee; Self; Boehringer Ingelheim. T. Klöckener: Employee; Self; Boehringer Ingelheim. T. Klein: Employee; Self; Boehringer Ingelheim. Introduction: Semaglutide, a GLP-1 receptor agonist, and survodutide, a GCGR/GLP-1R dual agonist, have demonstrated significant weight loss in patients with obesity. To test whether this weight loss is associated with changes in food preference and improvement in dyslipidemia, we evaluated semaglutide and survodutide in the free choice diet-induced obese and dyslipidemic hamster, a model with a human-like lipoprotein metabolism. Methods: Obesity and dyslipidemia were induced with a 20-week free choice diet, which presents hamsters with a choice between control chow diet or high fat/cholesterol diet, and normal water or 10% fructose water. Obese hamsters were then kept on this free choice diet and treated subcutaneously once daily with vehicle, semaglutide 15 nmol/kg or survodutide 15 nmol/kg for 5 weeks. Results: Compared with vehicle, semaglutide and survodutide led to a 17% and 11% body weight reduction, respectively (both p<0.001 vs vehicle). Compared to vehicle, both chow diet and high fat diet intakes were significantly lower during the first week of semaglutide treatment, but then returned to baseline values. However, semaglutide significantly increased normal water intake and reduced fructose-enriched water intake during the whole treatment period (both p<0.001). Survodutide had a different effect, as it did not alter chow diet and normal water intakes, but significantly reduced high fat diet and fructose-enriched water intakes during the 5-week treatment period. Semaglutide and survodutide significantly reduced plasma insulin levels and the HOMA-IR index of insulin resistance (both p<0.01 vs. vehicle). Both semaglutide and survodutide significantly reduced plasma total cholesterol levels by 24% and 41%, respectively (both p<0.001). This hypocholesterolemic effect led to lower HDL-cholesterol levels (-25%, p<0.001) but unchanged LDL-cholesterol levels for hamsters treated with semaglutide. In contrast, in hamsters treated with survodutide, cholesterol lowering was observed in all lipoprotein fractions, including LDL-cholesterol (-39%, p<0.001). Conclusion: Semaglutide and survodutide both induce weight loss and lower HOMA-IR, but have different effects on food preference and dyslipidemia in the obese hamster model; such effects may be attributed to the GCGR agonism of survodutide. These preclinical data highlight the potential metabolic benefits of the GCGR/GLP-1R dual agonist survodutide for the treatment of obesity and related metabolic comorbidities. Presentation: 6/3/2024

12516 Bilateral Adrenalectomy And Bariatric Surgery For Hormonal And Metabolic Control Of Classic Congenital Adrenal Hyperplasia

Abstract Disclosure: G. Palú: None. A.M. Rodrigues: None. Background: Hyperandrogenism is sometimes difficult to control in female patients with classic congenital adrenal hyperplasia (CAH), requiring supra-physiologic glucocorticoid dose with its metabolic consequences. Clinical Case: A 25-year woman with salt-losing CAH has been followed since she was born, requiring high glucocorticoid dose (hydrocortisone dose equivalent 50-75 mg), in addition to fludrocortisone (0.1-0.15 mg/day), without control of hyperandrogenism (testosterone and androstenedione levels more than 3 times ULN). She progressively gained weight, reaching 116 kg (256 pounds) and BMI of 46 kg/m2 when she was 17 years old. Bilateral adrenalectomy was performed in 2016 for disease control and to lower glucocorticoid dose. Androgen levels were supressed, glucocorticoid dose was reduced to 5mg prednisone (hydrocortisone dose equivalent 20mg) and she lost 10 kg of weight, but she remained in class III Obesity (BMI 42.5 kg/m2). Serious adrenal crises were not reported after bilateral adrenalectomy. Pharmacologic obesity treatment was done (sibutramine plus topiramate) and she lost 16 kg of weight, reaching 90 kg and a BMI of 36 from April 2017 to February 2020. She stopped treatment during the COVID- 19 pandemic and regained weight, reaching 106 kg again. She was lost to follow-up and returned in November 2023. In May 2022, she was submitted to a gastric bypass in a country town. She achieved 71 kg with a BMI of 28. She was feeling very well, taking post-bariatric vitamins and minerals, combined oral contraceptive, prednisone 5 mg/day (hydrocortisone dose equivalent 20 mg/day) and fludrocortisone 0.1 mg/day. Until now, she did not have any adrenal crises requiring parenteral glucocorticoid use. Conclusion: Even though treatment was aggressive with two surgeries that could lead to increased risk of adrenal crises, the patient had a benign course. New medicines that block CRH or ACTH action in CAH patients could prevent excessive glucocorticoid doses and weight gain and would be a better alternative to bilateral adrenalectomy in cases such as this one. Presentation: 6/1/2024

Depression and Obesity—Do We Know Everything about It? A Narrative Review

Introduction: Due to similarities in their pathophysiology and common psychological background, depressive disorders and obesity often occur simultaneously. The treatment of obesity can reduce the symptoms of comorbid depression and, conversely, treating depression can improve weight reduction outcomes. Purpose of this study: This review aimed to analyze the available literature on the subject of various methods of treating obesity and comorbid depression and to demonstrate the mutual correlation between the therapy of depressive disorders and the therapy of obesity. Method: The Pubmed and Cochrane databases were searched for original articles on the subject of simultaneous depression and obesity that had been published between 2014 and 2024, using the key words “depression”, “depressive symptoms”, “obesity”, and “behavioral therapy”. Results and conclusions: The successful treatment of depression can help in treating obesity, especially in motivating patients to adjust their lifestyle by changing dietary habits and increasing their physical activity, which contribute to both changes in body mass index scores and reductions in depressive symptoms. Changes in self-perception, reduced daily stress, and dietary changes, as well as increased physical activity, contribute to both weight loss and the reduction of depressive symptoms. Depression and obesity should be treated as one two-dimensional disorder to achieve better long-term treatment results.

Resveratrol inhibits white adipose deposition by the ESR1-mediated PI3K/AKT signaling pathway

Excessive adipose accumulation is the primary cause of obesity. Resveratrol (RES), a natural polyphenolic compound, has garnered significant attention for its anti-obesity properties. However, the precise mechanisms by which RES influences fat deposition have not yet been explored. In this study, the aim was to identify the target proteins and associated pathways of RES in order to elucidate the mechanisms by which RES reduces fat deposition. In this study, mice were administered 400 mg/kg of RES via gavage for 12 weeks. We found that while 400 mg/kg RES had no impact on the growth of the mice, it significantly reduced the weight of various white adipose tissues, as well as the serum and liver concentrations of total cholesterol and triglycerides. Network pharmacology identified 15 potential targets of RES and highlighted the PI3K/AKT signaling pathway as a key pathway. Molecular docking and dynamic simulations suggested that ESR1 might be the target protein through which RES exerts its anti-fat deposition effects. In vitro experiments revealed that ESR1 promotes the proliferation and inhibits the differentiation of 3 T3-L1 adipocytes, and suppresses the PI3K/AKT signaling pathway. Silencing the ESR1 gene altered the ability of RES to inhibit cell differentiation via the PI3K/AKT pathway. Gene expression results in subcutaneous adipose tissue, epididymal fat tissue, and liver tissue of mice were consistent with observations in cells. In summary, RES reduces white fat deposition by directly targeting the ESR1 protein and inhibiting the PI3K/AKT signaling pathway. Our findings provide new insights into the potential use of RES in the prevention and treatment of obesity.

Effects of different intensity resistance training on fat level, energy intake, and appetite among overweight and obese female college students

This study examines how different intensity resistance exercises impact fat, energy intake, and appetite regulation in overweight and obese female college students in Jiangsu Province, China. This study used a randomized controlled trial (RCT) design that investigates resistance training intensity-target result causation. The study determines the impact of High-Intensity Interval Training (HIIT) and Moderate-Intensity Resistance Training (MIRT) on body composition, fat level/body composition, and muscle mass them. In Jiangsu Province, China, 515 overweight and obese female college students aged 18–25 were sampled. Intervention groups were assigned randomly to campus recruits based on demographic and anthropometric. This study demonstrated significant correlations between resistance training intensity, body composition, diet, and appetite regulation in overweight and obese colleagues. MIRT and HIIT outperformed Control in weight loss and diet and used valid measures like DEXA (Dual-Energy X-ray Absorptiometry), blood tests and food diaries to regulate appetite hormones. Increased protein and muscle mass minimize resistance exercise intensity-metabolic consequences. The study analyzes these impacts to show how exercise intensity, food, and metabolic health are interconnected. These findings help build evidence-based obesity prevention and treatment strategies for this demographic. Healthcare providers, legislators, and university stakeholders use this study to tackle college student obesity. The results suggest that campus wellness initiatives should focus on resistance exercise and diet to combat obesity. This research promotes exercise science and health behavior change theory for cross-cultural lifestyle interventions.

A Randomized Controlled Trial Comparing Loss versus Gain Incentives to Improve Adherence to an Obesity Treatment Intervention in Adolescents.

Adherence to pediatric obesity treatment can be challenging. Monetary incentives improve adherence to lifestyle interventions, with incentives framed as loss often more effective than those framed as gain. The objectives of this study were to determine if monetary incentives in the form of gift cards would improve adherence to an obesity treatment intervention and whether framing the incentive as either loss or gain affected adherence. Sixty adolescents with obesity (body mass index of ≥95th percentile for age and sex) were recruited from our pediatric obesity treatment program. They were randomized into one of three groups and given a monthly adherence score (AS) of up to 100 points. These points were based on completing a medical visit, reporting on diet intake, and measuring daily steps on a wearable tracker. The Gain Group (GG), N = 20, started each month with USD 0 in a virtual account and increased their monetary reward up to USD 100 depending on AS. The Loss Group (LG), N = 21, began each month with USD 100 in their virtual account, which decreased based on adherence. The Control Group (CG), N = 19, received USD 10 monthly. Adherence was highest in the GG, with 66.0 points, compared to the LG, with 54.9 points, and CG, with 40.6 points, with p < 0.01. The GG had greater adherence to their step goal (14.6) and dietary reporting (18.7) compared to the LG (10.0 and 13.9) and the CG (3.9 and 8.1), p < 0.005. Gain-framed incentives are superior to loss-framed ones in improving adherence to pediatric obesity treatments.

Influence of the consumatory behavior onto the risk of obesity and its complications in primary school children

Objective. To identify the relationship of eating behavior and clinical and metabolic status of 6–11-year-old children in order to develop effective methods for prevention and treatment of obesity and its complications. Materials and methods. 94 children aged 6 to 11 participated in the research. They formed 2 groups: group I (n = 64) – obese children (standard deviation score (SDS) of body mass index (BMI) ≥ +2.0), group II (n = 30) – children with normal body weight (SDS BMI –1.0 … +1.0). Clinical and laboratory parameters were studied and eating behavior was assessed using the Child Eating Behavior Questionnaire. Results. As a result of the study, it was determined that average values of triglycerides (TG), uric acid (UA), thyroid-stimulating hormone (TSH), fasting glycemia (FG), p = 0.001, p = 0.002, p 0.001, p 0.001 were higher in obese children. The following features of the eating behavior in obese children have been revealed: a more active reaction to food and emotional overeating, p = 0.016, p = 0.004 Statistically significant direct moderate correlations between SDS BMI and the level of TG, UA, TSH and FG under the influence of eating behavior according to the “eating approach” type were established. Conclusions. An association between the pattern of eating behavior in obese children aged 6–11 and their clinical and metabolic status, which determines the risk of atherosclerosis and cardiovascular diseases in the future was revealed. The results obtained are a justification for identifying the nature of children`s eating behavior in order to prevent the development of obesity and associated complications, as well as to increase the effectiveness of therapy.

Long-term Outcome of the Dutch Common Channel Trial (DUCATI): Preservation of Superior Weight Loss Results Without Significant Malnutrition Side Effects.

The optimal bowel limb lengths for laparoscopic Roux-en-Y gastric bypass (LRYGB) to maximize weight loss while minimizing nutritional deficiencies in severe obesity treatment remain a topic of debate. The multi-center Dutch Common Channel Trial (DUCATI) aims to compare the outcomes of a very long Roux Limb Roux-en-Y gastric bypass (VLRL-LRYGB) with a standard Roux-en-Y gastric bypass (S-LRYGB). A total of 444 patients were randomly assigned in a 1:1, double-blind manner to undergo either VLRL-RYGB or S-LRYGB. Five-year follow-up data were assessed, concentrating on weight loss, obesity-related medical conditions, complications, re-operations, and malnutrition. Both groups had comparable total alimentary lengths (RL + CC). The VLRL-LRYGB group demonstrated significantly greater %TWL (32.2% vs. 28.6%, p = 0.002) and %EWL (81.2% vs. 70.3%, p = 0.002) at 5years. Eight (3.6%) patients in the VLRL-LRYGB group versus 2 (0.9%) in the S-LRYGB group (p = 0.055) needed modification surgery for malabsorption. Suboptimal clinical response rate was significantly higher (22.0% vs. 8.3%) in S-LRYGB group. No significant differences for nutrient deficiencies in favor of the S-LRYGB group were found. A 100-cm common channel with a relatively long Roux limb provides superior, sustainable weight loss over 5years, without significantly increased rate of malabsorption-related re-operations. These results suggest that a longer Roux limb can still ensure adequate micronutrient uptake in the total alimentary tract. These findings should be considered in discussions regarding the optimal Roux-en-Y limb length for severe obesity treatment.

The endocannabinoid system in appetite regulation and treatment of obesity.

The endocannabinoid system (ECS) is a complex cell-signaling system that is responsible for maintaining homeostasis by modulating various regulatory reactions in response to internal and environmental changes. The influence of ECS on appetite regulation has been a subject of much recent research, however, the full extent of its impact remains unknown. Current evidence links human obesity to ECS activation, increased endocannabinoid levels in both central and peripheral tissues, along with cannabinoid receptor type 1 (CBR1) up-regulation. These findings imply the potential pharmacological use of the ECS in the treatment of obesity. Here, we present various pathophysiological processes in obesity involving the ECS, highlighting different pharmacological options for modulating endocannabinoid activity to treat obesity. However, the potential of those pharmacological possibilities remains under investigation and requires further research.

Assessment of clinician agreement with and knowledge of evidence-based obesity treatment in the primary care setting.

Effective, evidence-based obesity treatment is needed, which often involves use of anti-obesity medications (AOMs). Data on the breadth and quality of guideline-directed obesity treatment implementation in primary care remain limited. This study aimed to assess primary care clinicians' agreement with and knowledge of guideline-directed obesity treatment, as well as to assess the health status of persons with obesity and their use of AOMs. This multimethod study included a prospective survey of primary care clinicians, utilizing a questionnaire that measured agreement on a 5-point Likert scale and knowledge via multiple choice questions. A retrospective analysis was also performed of patient data collected between 30 June 2016 and 30 June 2020 from primary care clinics in the Midwest. Data were analyzed from 27 clinician survey responders, finding agreement toward all measured areas, however less strong for chronic AOM use and resource allocation. The survey identified multiple gaps in knowledge. Researchers assessed 5656 baseline encounters and 2941 corresponding follow-up encounters. Analysis revealed ≥50% of the total patients experienced persistently uncontrolled obesity (mean body mass index of ≥40kg/m2) and weight-related complications. Low rates (≤10%) of AOM use in clinically eligible patients were shown, with phentermine monotherapy being the most commonly used. Clinicians agree with guideline-directed obesity treatment. Persons with obesity who are poorly controlled identify an opportunity for patient care improvement.

DACRA induces profound weight loss, satiety control, and increased mitochondrial respiratory capacity in adipose tissue.

Dual amylin and calcitonin receptor agonists (DACRAs) are therapeutic candidates in the treatment of obesity with beneficial effects on weight loss superior to suppression of food intake. Hence, suggesting effects on energy expenditure by possibly targeting mitochondria in metabolically active tissue. Male rats with HFD-induced obesity received a DACRA, KBP-336, every third day for 8 weeks. Upon study end, mitochondrial respiratory capacity (MRC), - enzyme activity, - transcriptional factors, and -content were measured in perirenal (pAT) and inguinal adipose tissue. A pair-fed group was included to examine food intake-independent effects of KBP-336. A vehicle-corrected weight loss (23.4 ± 2.8%) was achieved with KBP-336, which was not observed to the same extent with the food-restricted weight loss (12.4 ± 2.8%) (P < 0.001). Maximal coupled respiration supported by carbohydrate and lipid-linked substrates was increased after KBP-336 treatment independent of food intake in pAT (P < 0.01). Moreover, oligomycin-induced leak respiration and the activity of citrate synthase and β-hydroxyacetyl-CoA-dehydrogenase were increased with KBP-336 treatment (P < 0.05). These effects occurred without changes in mitochondrial content in pAT. These findings demonstrate favorable effects of KBP-336 on MRC in adipose tissue, indicating an increased energy expenditure and capacity to utilize fatty acids. Thus, providing more mechanistic insight into the DACRA-induced weight loss.