Weight-lowering Effects Research Articles

Glucagon-Like Peptide 1 Receptor Agonists Are Not Associated With an Increased Risk of Ileus or Intestinal Obstruction in Patients with Inflammatory Bowel Disease-A Danish Nationwide Cohort Study.

There is a global increase in the prevalence of obesity, including among individuals with inflammatory bowel disease (IBD). Glucagon-like peptide 1 receptor agonists (GLP-1RAs) are potential anti-obesity medications due to their weight-lowering effects. However, concerns exist regarding ileus and intestinal obstruction as a severe side effect. This nationwide Danish cohort study evaluates the risk of ileus and intestinal obstruction in patients with IBD receiving GLP-1RAs. Patients with IBD and their exposure to GLP-1RAs were identified using Danish health registries. Cox regression analysis was used to estimate hazard ratios for the risk of ileus and intestinal obstruction adjusted for age at diagnosis of IBD, sex, type of IBD, prior ileus or intestinal obstruction, diabetes status, steroid use, and small bowel or colon surgery. This study found that GLP-1RA exposure was not associated with an increased risk of ileus or intestinal obstruction in patients with IBD. This study suggests that GLP-1RAs do not increase the risk of ileus or intestinal obstruction in patients with IBD.

A Metabolome Wide Association Study of Fruit and Vegetable Consumption and Associations with Cardiovascular Disease Risk Factors: The International Study of Macro-/Micronutrients and Blood Pressure (INTERMAP) Study

BackgroundEpidemiologic evidence linking blood pressure (BP) and body weight-lowering effects with fruit and vegetable consumption mostly relies on self-reported dietary assessment prone to misreport and under- or overestimation of relationships. We characterized objective 24-h urinary metabolites and a derived metabolite score associated with fruit and vegetable intake and assessed their associations with BP and BMI, with validation across cohorts. Objectives. MethodsWe used untargeted proton nuclear magnetic resonance spectroscopy (1H NMR) of 2 timed repeated 24-h urine collections from free-living participants from the US (n = 2032) and the UK (n = 449) of the cross-sectional International Study of Macro-/Micronutrients and Blood Pressure (INTERMAP). We evaluated correlations between fruit and vegetable intake assessed by 24-h dietary recalls with 7100 1H NMR features, adjusted for confounders and multiple testing. We related identified metabolites and a metabolite score with BP and BMI using extensively adjusted multiple linear regression models. ResultsWe characterized 11 1H NMR-derived 24-h urinary metabolites related to fruit and vegetable intake, reproducible across multiple 24-h urine collections of both cohorts. Proline betaine, citrate, N-methylproline, scyllo-inositol, 2-hydroxy-2-(4-methyl cyclohex-3-en-1-yl) propoxyglucuronide, and proline were associated with fruit intake, specifically with Rutaceae intake, whereas S-methyl-L-cysteine sulfoxide and S-methyl-L-cysteine sulfoxide metabolite were associated with Brassicaceae intake. The metabolite score, explaining 39.8% of fruit and vegetable intake, was inversely associated with systolic BP [−1.65 mmHg; 95% confidence interval (CI): −2.68, −0.62; P < 0.002] and BMI (−1.21 kg/m2; 95% CI: −1.62, −0.78; P < 0.0001). These associations were, to a large extent, explained by urinary citrate excretion. ConclusionsWe identified 1H NMR-derived urinary metabolites associated with fruit and vegetable consumption, consistent and reproducible between urine collections and across populations. A higher fruit and vegetable-related metabolite score showed associations with lower systolic BP and BMI, mainly mediated by citrate, but would need confirmation in further studies.

GLP-1R-positive neurons in the lateral septum mediate the anorectic and weight-lowering effects of liraglutide in mice.

Liraglutide, a glucagon-like peptide-1 (GLP-1) analog, is approved for obesity treatment, but the specific neuronal sites that contribute to its therapeutic effects remain elusive. Here, we show that GLP-1 receptor-positive (GLP-1R-positive) neurons in the lateral septum (LSGLP-1R) play a critical role in mediating the anorectic and weight-loss effects of liraglutide. LSGLP-1R neurons were robustly activated by liraglutide, and chemogenetic activation of these neurons dramatically suppressed feeding. Targeted knockdown of GLP-1 receptors within the LS, but not in the hypothalamus, substantially attenuated liraglutide's ability to inhibit feeding and lower body weight. The activity of LSGLP-1R neurons rapidly decreased during naturalistic feeding episodes, while synaptic inactivation of LSGLP-1R neurons diminished the anorexic effects triggered by liraglutide. Together, these findings offer critical insights into the functional role of LSGLP-1R neurons in the physiological regulation of energy homeostasis and delineate their instrumental role in mediating the pharmacological efficacy of liraglutide.

Lac-Phe mediates the effects of metformin on food intake and body weight.

Metformin is a widely prescribed anti-diabetic medicine that also reduces body weight. There is ongoing debate about the mechanisms that mediate metformin's effects on energy balance. Here, we show that metformin is a powerful pharmacological inducer of the anorexigenic metabolite N-lactoyl-phenylalanine (Lac-Phe) in cells, in mice and two independent human cohorts. Metformin drives Lac-Phe biosynthesis through the inhibition of complex I, increased glycolytic flux and intracellular lactate mass action. Intestinal epithelial CNDP2+ cells, not macrophages, are the principal in vivo source of basal and metformin-inducible Lac-Phe. Genetic ablation of Lac-Phe biosynthesis in male mice renders animals resistant to the effects of metformin on food intake and body weight. Lastly, mediation analyses support a role for Lac-Phe as a downstream effector of metformin's effects on body mass index in participants of a large population-based observational cohort, the Multi-Ethnic Study of Atherosclerosis. Together, these data establish Lac-Phe as a critical mediator of the body weight-lowering effects of metformin.

Targeting postsynaptic glutamate receptor scaffolding proteins PSD-95 and PICK1 for obesity treatment.

Human genome-wide association studies (GWAS) suggest a functional role for central glutamate receptor signaling and plasticity in body weight regulation. Here, we use UK Biobank GWAS summary statistics of body mass index (BMI) and body fat percentage (BF%) to identify genes encoding proteins known to interact with postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-d-aspartate (NMDA) receptors. Loci in/near discs large homolog 4 (DLG4) and protein interacting with C kinase 1 (PICK1) reached genome-wide significance (P < 5 × 10-8) for BF% and/or BMI. To further evaluate the functional role of postsynaptic density protein-95 (PSD-95; gene name: DLG4) and PICK1 in energy homeostasis, we used dimeric PSD-95/disc large/ZO-1 (PDZ) domain-targeting peptides of PSD-95 and PICK1 to demonstrate that pharmacological inhibition of PSD-95 and PICK1 induces prolonged weight-lowering effects in obese mice. Collectively, these data demonstrate that the glutamate receptor scaffolding proteins, PICK1 and PSD-95, are genetically linked to obesity and that pharmacological targeting of their PDZ domains represents a promising therapeutic avenue for sustained weight loss.

Metformin improves obesity-related oligoasthenospermia via regulating the expression of HSL in testis in mice

Researches have proposed that obesity might contribute to development of oligoasthenospermia. This study was performed to confirm whether obesity contributes to oligoasthenospermia as well as the underlying mechanisms in mice fed with a high fat diet (HFD). Meanwhile, the actions of metformin, a drug of well-known weight-lowering effect, on sperm quality in obese mice were investigated. Our results showed that HFD feeding reduced sperm quality and steroid hormone levels in mice, associated with disruptions in testicular histomorphology and spermatogenesis. Moreover, obesity increased sperm apoptosis. These effects could be prevented by metformin treatment in HFD-fed mice. Mechanistically, an increasement in lipid contents associated with decreased hormone-sensitive lipase (HSL) protein expression in testes in HFD-fed mice was observed, which could be improved by metformin treatment. Then, the model of TM4 mouse Sertoli cells stimulated with palmitic acid (PA) was used to investigate the potential effect of lipid retention on testicular apoptosis and sperm quality reduction. In consistent, PA exposure elevated lipid contents as well as apoptosis in TM4 cells, which could also be improved by metformin treatment. Of note, the protein expression of HSL was reduced stimulated by PA in TM4 cells, also rescued by metformin. Then, anti-apoptosis effect of metformin would be lost with the deficiency of HSL. In summary, our study propose that obesity contributes to oligoasthenospermia by increasing sperm apoptosis induced by impaired lipid hydrolysis due to HSL down-regulation, which could be prevented with metformin treatment via regulating the expression of HSL in testis in mice.

FRI068 Gender Differences In Smoking Cessation? Results Of A Randomized Controlled Trial Of Dulaglutide-assisted Smoking Cessation

Abstract Disclosure: F. Baur: None. D. Coynel: None. C. Atila: None. S. Lengsfeld: None. T. Burkard: None. A. Meienberg: None. C. Bathelt: None. M. Christ-Crain: None. B.F. Winzeler: None. Introduction: Smoking harms women more than men and women seem to be less successful in quitting. Greater concerns about post-cessational weight in women and gender differences in craving and reward processing have been postulated as possible explanations. Our group recently showed that the GLP-1 analogue dulaglutide reduces post-cessational weight gain. We hypothesize that women compared to men might profit more from the weight-lowering effects of dulaglutide in terms of abstinence rates. Methods: This is a predefined secondary analysis of a placebo-controlled, double-blind, single-center randomized trial including 255 daily smokers (155 women, 100 men). Participants received weekly dulaglutide (1.5mg) or placebo (0.9% sodium chloride) subcutaneous injections for 12 weeks in addition to standardized smoking cessation care. Smoking status was self-reported and confirmed by end-expiratory carbon monoxide measurement. We analyzed gender differences after 12 weeks of dulaglutide / placebo treatment in weight change, abstinence rates and craving assessed by a visual analogue scale (VAS, minimum 1, maximum 10). Additionally, fMRI was performed in a subset of participants and craving and neuronal activity in response to smoking cue videos were examined for gender differences. Results: Median [IQR] age at inclusion was 42 [32,53] years in females and 44 [34,53] years in males. Mean (SD) BMI was 26.0 (5.0) kg/m² and 28.9 (4.9) kg/m², respectively. After 12 weeks, 61% of females in the dulaglutide and 65% in the placebo group were abstinent, compared to 66% and 64% of male participants. Among quitters, there were no gender differences in absolute or percentual weight change neither on dulaglutide (difference: 0.2 kg, 95%-CI [-1.2, 1.6]; p=0.762 / 0.7%, 95%-CI [-0.9, 2.3]; p= 0.382) nor on placebo treatment (difference: 0.0 kg, 95%-CI [-1.0, 1.0]; p=0.954 / -0.6 %, 95%-CI [-1.8, 0.6]; p=0.340).There is no evidence for either a direct association of gender with change in craving (mean difference females vs. males: 0.05 points, 95%-CI [-1.34, 1.43], p= 0.947) or that the effect of gender on change in craving might depend on dulaglutide treatment (interaction term: p=0.712). Smoking cessation was directly associated with a decline in craving (mean difference quitters vs. persistent smokers: -3.07 points, 95%-CI [-4.67, -1.47], p&amp;lt;0.001); however, this did not depend on gender (interaction term: p=0.380). Data of the fMRI substudy are currently being analyzed and will be presented at the congress. CONCLUSION: Our data showed similar abstinence rates, post-cessational weight changes and craving intensity in females and males. Presentation: Friday, June 16, 2023

Activation of brown adipose tissue by a low-protein diet ameliorates hyperglycemia in a diabetic lipodystrophy mouse model

Long-term ad libitum dietary restrictions, such as low-protein diets (LPDs), improve metabolic health and extend the life span of mice and humans. However, most studies conducted thus far have focused on the preventive effects of LPDs on metabolic syndromes. To test the therapeutic potential of LPD, we treated a lipodystrophy mouse model IRFKO (adipose-specific insulin receptor knockout) in this study. We have previously shown that IRFKO mice have profound insulin resistance, hyperglycemia, and whitening of interscapular brown adipose tissue (BAT), closely mimicking the phenotypes in lipoatrophic diabetic patients. Here, we demonstrate that 14-day of LPD (5.1% kcal from protein) feeding is sufficient to reduce postprandial blood glucose, improve insulin resistance, and normalize glucose tolerance in the IRFKO mice. This profound metabolic improvement is associated with BAT activation and increase in whole body energy expenditure. To confirm, we showed that surgical denervation of BAT attenuated the beneficial metabolic effects of LPD feeding in IRFKO mice, including the ‘browning’ effects on BAT and the glucose-ameliorating results. However, BAT denervation failed to affect the body weight-lowering effects of LPD. Together, our results imply a therapeutic potential to use LPD for the treatment of lipoatrophic diabetes.

Body weight lowering effect of glucose-dependent insulinotropic polypeptide and glucagon-like peptide receptor agonists is more efficient in RAMP1/3 KO than in WT mice

The glucose-dependent insulinotropic polypeptide (GIPR) and glucagon-like peptide (GLP-1R) receptor agonists are insulin secretagogues that have long been shown to improve glycemic control and dual agonists have demonstrated successful weight loss in the clinic. GIPR and GLP-1R populations are located in the dorsal vagal complex where receptor activity-modifying proteins (RAMPs) are also present. According to recent literature, RAMPs not only regulate the signaling of the calcitonin receptor, but also that of other class B G-protein coupled receptors, including members of the glucagon receptor family such as GLP-1R and GIPR.The aim of this study was to investigate whether the absence of RAMP1 and RAMP3 interferes with the action of GIPR and GLP-1R agonists on body weight maintenance and glucose control. To this end, WT and RAMP 1/3 KO mice were fed a 45% high fat diet for 22 weeks and were injected daily with GLP-1R agonist (2 nmol/kg/d; NN0113-2220), GIPR agonist (30 nmol/kg/d; NN0441-0329) or both for 3 weeks.While the mono-agonists exerted little to no body weight lowering and anorectic effects in WT or RAMP1/3 KO mice, but at the given doses, when both compounds were administered together, they synergistically reduced body weight, with a greater effect observed in KO mice. Finally, GLP-1R and GIP/GLP-1R agonist treatment led to improved glucose tolerance, but the absence of RAMPs resulted in an improvement of the HOMA-IR score. These data suggest that RAMPs may play a crucial role in modulating the pharmacological actions of GLP-1 and GIP receptors.

Perspectives in weight control in diabetes – BI 456906

Glucagon-like peptide-1 receptor (GLP-1R) agonists are approved treatments for Type 2 diabetes mellitus, with liraglutide and semaglutide also approved for the treatment of obesity. The natural gut hormone oxyntomodulin is a weak dual agonist of the glucagon receptor (GCGR) and GLP-1R. Development of poly-agonists mimicking oxyntomodulin, such as the novel dual GCGR/GLP-1R agonist BI 456906, represents an important step towards a more effective treatment for people with Type 2 diabetes mellitus and obesity. BI 456906 is a 29-amino acid peptide derived from glucagon, with the incorporation of potent GLP-1 activities. It contains a C18 diacid which mediates binding to albumin, thereby prolonging the half-life to enable once-weekly subcutaneous dosing. The utilisation of GCGR agonism aims to enhance body weight-lowering effects by increasing energy expenditure in addition to the anorectic action of GLP-1R agonists. Glucose-lowering efficacy of BI 456906 has been demonstrated in a Phase II trial in patients with Type 2 diabetes mellitus and obesity and was associated with clinically meaningful body weight loss. These data highlight the potential of dual GCGR/GLP-1R agonism for reducing glycated haemoglobin and body weight in patients with Type 2 diabetes mellitus, and for greater therapeutic efficacy compared with GLP-1R agonism alone.

TAAR1 Agonist Ulotaront Improves Glycemic Control and Reduces Body Weight in Rodent Models of Diabetes, Obesity, and Iatrogenic Weight Gain

AbstractIntroductionPreclinical evidence has identified the trace amine-associated receptor 1 (TAAR1) as a novel regulator of metabolic control. Ulotaront is a TAAR1 and 5-HT1A agonist currently in Phase 3 clinical trials for the treatment of schizophrenia. Here we summarize preclinical results assessing the effects of ulotaront on weight and metabolic parameters.MethodsEffects of ulotaront administration were evaluated on oral glucose tolerance (oGTT), gastric emptying, and in rodent models of weight gain (high-fat diet [HFD]-, corticosterone-, and olanzapine-induced).ResultsFollowing 15-day oral administration of ulotaront, rats on HFD showed dose-dependent reduction in body weight, food intake, and liver triglyceride content compared to controls. In addition, a more rapid reversal of olanzapine-induced weight gain and food intake was observed in rats switched to ulotaront (vs. vehicle). Consistent with weight-lowering effects in rats, chronic ulotaront treatment normalized corticosterone-induced weight gain in mice. Assessment of oGTT showed a dose-dependent reduction of glucose excursion in response to acute ulotaront administration in naive and diabetic db/db mice. Ulotaront administration also delayed gastric emptying in mice—a likely mechanism driving reductions in glucose excursions during the oGTT. Whole-brain c-fos imaging of ulotaront-treated mice revealed increased neuronal activity in several brain regions associated with regulation of food intake and metabolic signals.ConclusionsThe data indicate that ulotaront not only lacks metabolic liabilities typically associated with antipsychotics but can reduce body weight and improve glucose tolerance in rodent models. The underlying mechanisms may include TAAR1-mediated peripheral effects on glucose homeostasis and/or direct modulation of homeostatic and hedonic neurocircuits regulating energy balance. The beneficial metabolic effects of ulotaront may suggest a substantially improved risk-benefit profile compared to established antipsychotics.FundingSunovion Pharmaceuticals Inc. and Otsuka Pharmaceutical Development &amp; Commercialization, Inc.

Expression of Neurotensin and Its Receptors Along the Intestinal Tract in Type 2 Diabetes Patients and Healthy Controls.

Enteroendocrine N cells secrete neurotensin (NTS). NTS reduces food intake in rodents and may increase insulin release. In humans, postprandial NTS responses increase following Roux-en-Y gastric bypass, associating the hormone with the glucose- and body weight-lowering effects of these procedures. We looked at N cell density and mucosal messenger RNA (mRNA) expression profiles of NTS and NTS receptors in type 2 diabetes (T2D) patients and healthy controls. Using double-balloon enteroscopy, 12 patients with T2D and 12 sex-, age-, and body mass index-matched healthy controls had mucosa biopsies taken from the entire length of the small intestine (at 30-cm intervals) and from 7 anatomically well-defined locations in the large intestine. Biopsies were analyzed using immunohistochemistry and mRNA sequencing. N cell density and NTS mRNA expression gradually increased from the duodenum to the ileum, while negligible NTS-positive cells and NTS mRNA expression were observed in the large intestine. NTS receptor 1 and 2 mRNA expression were not detected, but sortilin, a single-pass transmembrane neuropeptide receptor of which NTS also is a ligand, was uniformly expressed in the intestines. Patients with T2D exhibited lower levels of NTS-positive cells and mRNA expression than healthy controls, but this was not statistically significant after adjusting for multiple testing. This unique intestinal mapping of N cell density and NTS expression shows increasing levels from the small intestine's proximal to distal end (without differences between patients with T2D and healthy controls), while negligible N-cells and NTS mRNA expression were observed in the large intestine. Sortilin was expressed throughout the intestines in both groups; no NTS receptor 1 or 2 mRNA expression were detected.

An Evidence-Based Review of Anti‐Obesity and Weight Lowering Effects of &lt;i&gt;Zingiber officinale&lt;/i&gt; Roscoe and &lt;i&gt;Terminalia chebula&lt;/i&gt; Retz

Since time immemorial, the Indian medical system, particularly Ayurveda and Siddha, has prioritised prevention and health over symptoms and drugs. Siddha, an Indian system of medicine, originated in ancient Thamilakam (currently Tamil Nadu, India). The combination of Inji (Zingiber officinale Roscoe), Sukku (Zingiber officinale Roscoe) and Kadukkai (Terminalia chebula Retz) as herbal therapy with numerous chemical constituents can be considered a better pharmacological approach than consuming individual ingredients and/or chemical constituents. This review is an attempt to summarize the evidence related to the anti-obesity and weight-lowering effects of ginger and T. chebula. The overall view shows an anti-hyperlipidemic effect of Zingiber officinale and Terminalia chebula.

The weight-lowering effect of low-intensity endurance training targeted at the level of maximal lipid oxidation (LIPOX max) lasts for more than 8 years, and is associated with improvements in body composition and blood pressure

The weight-lowering effect of low-intensity endurance training targeted at the level of maximal lipid oxidation (LIPOX max) lasts for more than 8 years, and is associated with improvements in body composition and blood pressure

The Anti-Obesity Effect of Porous Silica Is Dependent on Pore Nanostructure, Particle Size, and Surface Chemistry in an In Vitro Digestion Model.

The potential for porous silica to serve as an effective anti-obesity agent has received growing attention in recent years. However, neither the exact pharmacological mechanism nor the fundamental physicochemical properties of porous silica that drive its weight-lowering effect are well understood. Subsequently, in this study, an advanced in vitro digestion model capable of monitoring lipid and carbohydrate digestion was employed to elucidate the effect of porous silica supplementation on digestive enzyme activities. A suite of porous silica samples with contrasting physicochemical properties was investigated, where it was established that the inhibitory action of porous silica on digestive enzyme functionality was strongly dependent on porous nanostructure, particle size and morphology, and surface chemistry. Insights derived from this study validate the capacity of porous silica to impede the digestive processes mediated by pancreatic lipase and α-amylase within the gastrointestinal tract, while the subtle interplay between porous nanostructure and enzyme inhibition indicates that the anti-obesity effect can be optimized through strategic particle design.

The GDF15-GFRAL pathway is dispensable for the effects of metformin on energy balance.

Metformin is a blood-glucose-lowering medication with physiological effects that extend beyond its anti-diabetic indication. Recently, it was reported that metformin lowers body weight via induction of growth differentiation factor 15 (GDF15), which suppresses food intake by binding to the GDNF family receptor α-like (GFRAL) in the hindbrain. Here, we corroborate that metformin increases circulating GDF15 in mice and humans, but we fail to confirm previous reports that the GDF15-GFRAL pathway is necessary for the weight-lowering effects of metformin. Instead, our studies in wild-type, GDF15 knockout, and GFRAL knockout mice suggest that the GDF15-GFRAL pathway is dispensable for the effects of metformin on energy balance. The data presented here question whether metformin is a sufficiently strong stimulator of GDF15 to drive anorexia and weight loss and emphasize that additional work is needed to untangle the relationship among metformin, GDF15, and energy balance.

Effects of saffron (Crocus sativus L.) on anthropometric and cardiometabolic indices in overweight and obese patients: A systematic review and meta-analysis of randomized controlled trials.

The worldwide prevalence of obesity is approximately tripled between 1975 and 2016 according to World Health Organization; therefore, obesity is now considered a global pandemic that needs academic and clinical focus. In search of antiobesity agents, Crocus sativus, known widely as saffron, has been praised for its beneficial effects. Several randomized controlled trials (RCTs) have been conducted to investigate the weight lowering effect of saffron. Following PRISMA guidelines, several medical databases were comprehensively searched for RCTs with a population consisting of obese individuals. A random-effects meta-analysis was used to pool estimates across studies, and standardized mean difference (SMD) was used to synthesize quantitative results. Twenty-five RCTs met the inclusion criteria. Meta-analysis showed a nonsignificant decrease for weight (-0.32 kg; CI: -3.15, 2.51; p=0.82), BMI (-0.06 kg/m2 ;CI:-1.04,0.93; p=.91), waist circumference (-1.23 cm; CI: -4.14, 1.68; p=.41), and hip circumference (-0.38 cm; CI: -5.99, 5.23; p=.89) and a significant decrease of waist-to-hip ratio (SMD=-0.41; CI: -0.73, -0.09; p=.01; I2 = 0%). The mean difference in fasting blood sugar showed a significant reduction in patients with metabolic syndrome (SMD=-0.30; 95% CI: -0.63, 0.03; p=.07; I2 = 0.37%) but a nonsignificant change in the HbA1C level (WMD=0.05; 95% CI: 0.32, 0.41; p=.79). Despite bearing several limitations, mainly as a result of heterogeneity among included studies, the available evidence indicates saffron supplementation shows promising effects on some cardiometabolic factors among overweight to obese patients; however, further investigations and high-quality evidence are required for more generalizable and comprehensive results.

Is Nigella sativa an Effective Bodyweight Lowering Agent and a Mitigator of Obesity Risk? A Literature Review.

Obesity is one of the major health-threatening conditions nowadays. Nigella sativa (NS) is a medicinal plant that demonstrates multiple therapeutic effects. In the current review, we aim to evaluate the weight lowering effect of NS in both clinical trials and experimental studies and to explore the possible reported mechanisms of this effect. We searched PubMed and Web of science and retrieved 14 clinical trials and 5 experimental studies that justify our inclusion criteria. After the analysis of these articles, we can conclude that long-term administration of NS for 6–12 weeks can significantly lower bodyweight and other anthropometric indices. NS-oil is more potent than NS-powder in lowering bodyweight probably due to the higher concentration of fatty acids and thymoquinone. The weight lowering effect of NS is not a toxic effect, it conversely and preferably lowers the elevated liver enzymes in condition of fatty liver. It is also frequently accompanied by positive metabolic modifications, such as enhancement of lipid profile, lowering blood glucose and improving insulin resistance. Possible mechanisms for NS-bodyweight lowering effect might include an appetite-suppression effect, lowering caloric-intake and inhibition of intestinal glucose absorption. However, further experimental evidence is required to support these mechanisms or unveil new ones.

235-LB: YH34160, a Novel Long-Acting GDF15 Fusion Protein, Exerts Potent and Sustained Body Weight Loss in Rodent Obesity Models

Growth differentiation factor 15 (GDF15) is a multifunctional protein associated with energy homeostasis and body weight regulation. GDF15 has emerged as an attractive therapeutic target to treat obesity-related metabolic disorders. GDF15 reduces food intake with a unique mode of action via its receptor GDNF family receptor α-like (GFRAL) and the co-receptor RET. YH34160 is an engineered GDF15 variant-Fc fusion protein to have extended half-life and potent functional activity by enhancing binding affinity to GDF15 receptors (GFRAL/RET) . Based on rodent and monkey pharmacokinetic (PK) data, YH34160 is expected to have an optimal PK profile for once-weekly dosing in humans. In efficacy studies using obese mouse models, YH34160 demonstrated a potent and sustained weight-lowering effect. After a single subcutaneous injection in diet-induced obese (DIO) mice, YH34160-treated groups showed sustained and dose-dependent body weight (BW) reduction compared to long-acting glucagon like peptide-1 receptor agonist (GLP-1RA) . Following a 6-week multiple-dose study in DIO mice, YH34160-treated groups exhibited a greater and more prolonged BW loss compared to the group of GLP-1RA. Marked BW reduction and improved lipid profile by YH34160 were also proved in leptin-deficient (ob/ob) mice compared to GLP-1RA. In addition, YH34160 caused significantly better anti-obesity effects, and a much more improved metabolic profile than that of albumin-GDF15, and dual GLP-1/Glucagon receptor agonist. Interestingly, YH34160 in combination with GLP-1RA or dual GLP-1/glucose-dependent insulinotropic polypeptide receptor agonist (GIPRA) achieved more potent and greater BW loss compared to each mono-treated group. Overall, these findings indicate that YH34160 would be a promising therapeutic candidate, as well as in combination with GLP-1-based therapeutics, for the treatment of obesity and obesity-related comorbidities. Disclosure S. Lim: None. D. Kim: None. J. Yang: None. M. Ju: None. S. Kim: None. B. Sim: None. J. Kim: None. S. Oh: Employee; Yuhan, Stock/Shareholder; Yuhan.

720-P: Change in Body Weight from Baseline with Tirzepatide: Sex Subgroup Analysis of the SURPASS Studies

Five Phase 3 SURPASS trials have shown robust efficacy of novel dual GIP/GLP-1 receptor agonist, tirzepatide, in glycaemic control and body weight (BW) loss in adults with Type 2 Diabetes (T2D) . A key secondary endpoint investigated the effect of tirzepatide (5, 10, and 15 mg) versus placebo or active comparators on mean BW change from baseline to endpoint. To determine whether weight-lowering effects of tirzepatide depend on the sex of study participants, we conducted a post-hoc subgroup analysis of SURPASS (S) -1 to -5 trials. BW change in the sex subgroups was assessed in patients while on treatment without rescue medication (efficacy estimand) in the modified intention-to-treat (mITT) population, defined as all randomized patients who received at least one dose of study drug. All tirzepatide doses significantly reduced BW compared to placebo or active comparators regardless of the sex of study participants (S-1 to -5 p&amp;lt;0.001) . The most frequent AEs were mild-to-moderate, GI-related, and occurred during the dose-escalation period. Disclosure A.W.Plat: None. N.Rasouli: Advisory Panel; Eli Lilly and Company, Novo Nordisk, Sanofi, Research Support; Allergan, Eli Lilly and Company, Novo Nordisk. J.Peleshok: Employee; Eli Lilly and Company, Eli Lilly and Company. H.Sapin: Employee; Eli Lilly and Company. J.Wilding: Advisory Panel; Alnylam Pharmaceuticals, Inc., AstraZeneca, Eli Lilly and Company, Mundipharma, Novo Nordisk A/S, Rhythm Pharmaceuticals, Inc., Sanofi, Research Support; AstraZeneca, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Novo Nordisk A/S, Takeda Pharmaceutical Company Limited. Funding Eli Lilly and Company