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Abstract Objective To compare weight loss response and changes in cardiometabolic risk markers in postmenopausal women using semaglutide with and without menopause hormone therapy (HT) use. Methods Retrospective cohort study of postmenopausal women treated with semaglutide for overweight or obesity for ≥3 months. Endpoints: total body weight loss percentage (TBWL%) at 3, 6, 9, and 12 months after semaglutide initiation; and percentage of women achieving ≥5% and ≥10% TBWL and changes in cardiometabolic risk markers (glucose, blood pressure, and lipids) at 12 months. Results There were 16 women on HT and 90 on no-HT; mean age 56 ± 8 vs 59 ± 8 yr, P = 0.2 and mean BMI 36 ± 5 vs 39 ± 8 kg/m2, P = 0.1; respectively. Among women on no-HT, White race, dyslipidemia, and depression were more prevalent. Women on HT had a higher TBWL% at 3, 6, 9, and 12 months: 7 ± 3% vs 5 ± 4%, P = 0.01; 13 ± 6% vs 9 ± 5%, P = 0.01; 15 ± 6% vs 10 ± 6%, P = 0.02; and 16 ± 6% vs 12 ± 8%, P = 0.04; respectively. After adjusting for potential confounders, this association remained significant across time. At 12 months, a greater percentage of women on HT achieved ≥5% and ≥10% TBWL. Both groups experienced an improvement in cardiometabolic risk markers. Conclusion In postmenopausal women with overweight or obesity treated with semaglutide, HT use was associated with an improved weight loss response. This association was maintained when adjusted for confounders. Larger studies should be conducted to confirm these results.

AbstractBackgroundAccelerated gastric emptying (GE) is a trait seen in obesity. Mutations in the hypothalamic leptin‐melanocortin 4 receptor (Leptin‐MC4R) pathway have been associated with obesity. We sought to investigate the association of leptin‐MC4R pathway variants and GE in patients with obesity.MethodsThis is a cross‐sectional study of patients with a history of severe obesity that were genotyped and completed a GE test by scintigraphy. We evaluated the percentage of GE (GE %) at 2 and 4 h between both groups using ANCOVA with weight and sex as covariates. We subdivide patients into carriers based on the location of the identified variants (i.e., upstream or downstream of the Leptin‐MC4R pathway) and compared them with noncarriers using ANOVA. Results are presented as mean and standard deviation (± SD).Key ResultsA total of 95 patients; nine carriers (67% females; 39.78 ± 12.33 years; BMI: 49.14 ± 12.96 kg/m2) and 86 noncarriers (87% female; 49.98 ± 13.74 years; BMI: 40.75 ± 6.29 kg/m2) were included. At 2 and 4 h, carriers had a delayed GE when compared noncarriers (p = 0.03 and p = 0.005, respectively). In carriers, when compared upstream carriers vs. downstream carriers vs. noncarriers by location there was a significant difference in GE among groups at 2 h and at 4 h (p = 0.02 and p = 0.01, respectively).Conclusions & InferencesCarriers of heterozygous variants in the Leptin‐MC4R pathway had a delayed GE compared to noncarriers. These findings point the important relationship between the Leptin‐MC4R pathway and gastric motility.

Objective Multiple scores validate long-term type-2 diabetes mellitus (T2DM) remission after metabolic and bariatric surgery (MBS). However, studies comparing Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) have not adequately controlled for certain parameters, which may influence procedure selection. Methods We conducted a multicenter retrospective review of patients with T2DM who underwent RYGB or SG between 2008 and 2017. Data on demographics, clinical, laboratory, and metabolic values were collected annually for up to 14 years. Each eligible RYGB patient was individually matched to an eligible SG patient based on diabetes severity, weight loss, and follow-up duration. Results Among 1149 T2DM patients, 467 were eligible for matching. We found 97 matched pairs who underwent RYGB or SG. RYGB showed significantly higher T2DM remission rates (46.4%) compared to SG (33.0%) after matching. SG patients had higher insulin usage (35.1%) than RYGB patients (20.6%). RYGB patients also experienced greater decreases in HbA1c levels and diabetes medication usage than SG patients. Conclusions RYGB demonstrates higher efficacy for T2DM remission compared to SG, regardless of baseline characteristics, T2DM severity, weight loss, and follow-up duration. Further studies are needed to understand the long-term metabolic effects of MBS and the underlying pathophysiology of T2DM remission after MBS.

Introduction: Metabolically obese normal weight (MONW) refers to metabolic abnormalities despite normal body mass index (BMI). Hypothesis: Because obesity is generally defined by BMI, it is assumed that people with MONW do not have excessive adiposity but still have the metabolic dysregulation associated with adiposity. Methods: We included participants aged 20-65 of the National Health and Nutrition Examination Surveys from 1999-2006 and 2011-2018 with normal BMI (18.5-25 kg/m 2 ), fasting blood samples, and DEXA data. According to the AHA criteria, MONW was defined having ≥3 of the following criteria, besides a normal BMI: Hypertriglyceridemia (≥ 150 mg/dL) or treatment for elevated triglycerides; HDL cholesterol level < 40 mg/dL in men or <50 mg/dL in women or treatment for reduced HDL-C; elevated blood pressure (systolic ≥ 130 mmHg and/or diastolic ≥ 85 mmHg) or antihypertensive treatment or history of hypertension; elevated fasting plasma glucose ≥ 100 mg/dL or insulin/oral hypoglycemic treatment and central obesity by waist circumference (≥ 94 cm in men and ≥ 80 cm in women). High fat percentage was defined as ≥25% in men, ≥35% in women. Weighted logistic regression was performed to test the relation between MONW and high fat%, central obesity. Results: Of the 7,887 participants (53.6% men; mean age±SE was 39.23±0.24 years), 2433 (33.4%) had normal BMI included in the analysis. Among these, 148 had MONW (5%). Mean Fat% was 26.08±0.36% in those with MONW versus 21.90±0.17% in those without MONW for men, and 37.02±0.35% versus 33.31±0.21% for women. MONW subjects were 2.21 times more likely to have either central obesity or high fat % (OR 12.09, 95%CI: 6.18-23.67, p<0.01) and 2.18 times more likely to have high fat % (OR=2.84, 95%CI: 1.72-4.67, p<0.01) (see Figure). Conclusions: Most individuals with MONW have either increased fat content, central deposition of fat, or both. That highlights people with normal BMI may still have metabolic complications of adiposity.

Background: The role of body adiposity on metabolic dysregulation in subjects with normal body mass index (BMI) is still under debate with limited population-based evidence. Hypothesis: Body adiposity measured by dual x-ray absorptiometry (DEXA) is associated with metabolic disorders in normal-weight individuals. Methods: We evaluated a sample of adults aged 20-65 who underwent DEXA in the US National Health and Nutrition Examination Surveys from 1999-2006 and 2011-2018. We excluded those with history of cardiovascular disease, cancer, and chronic obstructive pulmonary disease. Weighted logistic regression was performed to test the association between body fat percentage (BF%) and metabolic disorders [e.g., insulin resistance (IR), metabolic syndrome (MS), dyslipidemia, type 2 diabetes mellitus (DM), hypertension]. Models were adjusted for potential confounders while considering complex survey design and were further stratified by sex and BF% as tertiles in normal-weight individuals. IR was tested as a secondary analysis to evaluate the effect on the predicted risk. Results: We included 20,613 individuals (51.5% men, 65.4% non-Hispanic whites), mean age ± SE was 39.42±0.22 years, and 6,424 were normal weight by BMI and represented our study sample. The overall BF% in these subjects measured by DEXA was 28.41±0.19%. In our cohort, metabolic disorders were prevalent in 2.1% to 40.4% of patients (Table 1). Every 10-unit % increase in total BF% was associated with a higher risk for IR, MS, dyslipidemia in the normal weight BMI group (Table 1). Metabolic disorders were associated with BF% tertiles (Figure 1). IR was significantly associated with body fat across all BF% tertiles for men and highest tertiles for women (Figure 2). Conclusion(s): Less than 1/3 of subjects in a representative national sample had a normal BMI. Even in these “normal weight” subjects, increases in body adiposity are significantly associated with increased cardiometabolic disease burden.

Goals: We aim to describe the weight loss outcomes of patients with celiac disease (CeD) taking antiobesity medications (AOMs) and compare it with the weight loss outcomes of patients without CeD taking AOMs. Background: Increasing rates of obesity and obesity-associated comorbidities have been previously reported in patients with CeD on a gluten-free diet. The effectiveness of AOMs in this population has not been previously described. Methods: In our retrospective cohort study, we matched 39 patients with treated CeD to 78 patients without CeD based on sex and AOM. We assessed the weight loss outcomes at 3, 6, and 12 months after starting the AOM in both cohorts and analyzed if there was a differential response when comparing by type of AOM [injectable glucagon-like peptide 1 (GLP-1) receptor agonists vs. oral non-GLP-1 AOMs]. Results: Both cohorts had similar baseline demographic and anthropometric characteristics. At 12 months, the CeD cohort had a nonsignificantly inferior total body weight loss percentage compared with the cohort without CeD (6.5% vs. 9.5%, P=0.13). The CeD cohort had a similar proportion of patients achieving a total body weight loss percentage of ≥5% than the cohort without CeD (72.7% vs. 72.1%, P=1.00). No significant difference was observed when comparing the weight loss outcomes of injectables (GLP-1 receptor agonists) to oral AOMs. The proportion of patients reporting side effects was similar for both groups, regardless of the type of AOM. Conclusion: Patients with CeD taking AOMs had similar weight loss outcomes to patients without CeD. Hence, AOMs can be a safe and effective therapy for weight management in patients with CeD.

AbstractBackgroundFood intake is regulated by homeostatic and hedonic systems that interact in a complex neuro‐hormonal network. Dysregulation in energy intake can lead to obesity (OB) or anorexia nervosa (AN). However, little is known about the neurohormonal response patterns to food intake in normal weight (NW), OB, and AN.Material & MethodsDuring an ad libitum nutrient drink (Ensure®) test (NDT), participants underwent three pseudo‐continuous arterial spin labeling (pCASL) MRI scans. The first scan was performed before starting the NDT after a > 12 h overnight fast (Hunger), the second after reaching maximal fullness (Satiation), and the third 30‐min after satiation (postprandial fullness). We measured blood levels of ghrelin, cholecystokinin (CCK), glucagon‐like peptide (GLP‐1), and peptide YY (PYY) with every pCASL‐MRI scan. Semiquantitative cerebral blood flow (CBF) maps in mL/100 gr brain/min were calculated and normalized (nCBF) with the CBF in the frontoparietal white matter. The hypothalamus (HT), nucleus accumbens [NAc] and dorsal striatum [DS] were selected as regions of interest (ROIs).ResultsA total of 53 participants, 7 with AN, 17 with NW (body‐mass index [BMI] 18.5–24.9 kg/m2), and 29 with OB (BMI ≥30 kg/m2) completed the study. The NW group had a progressive decrease in all five ROIs during the three stages of food intake (hunger, satiation, and post‐prandial fullness). In contrast, participants with OB showed a minimal change from hunger to postprandial fullness in all five ROIs. The AN group had a sustained nCBF in the HT and DS, from hunger to satiation, with a subsequent decrease in nCBF from satiation to postprandial fullness. All three groups had similar hormonal response patterns with a decrease in ghrelin, an increase in GLP‐1 and PYY, and no change in CCK.ConclusionConditions of regulated (NW) and dysregulated (OB and AN) energy intake are associated with distinctive neurohormonal activity patterns in response to hunger, satiation, and postprandial fullness.

The objective is to review the newer pharmacological interventions for obesity, specifically single, dual and triple incretin receptor agonists that are either available or in the pipeline for treatment of obesity. The three incretin receptor targets are glucagon like peptide‐1 (GLP‐1), glucose‐dependent insulinotropic peptide (GIP) and glucagon. There are several approved single or dual incretin agonists which can be administered subcutaneously daily (e.g., liraglutide) or weekly (e.g., semaglutide, dulaglutide, and exenatide QW), and other experimental dual or triple incretin agonists. Analogues of amylin, peptide YY and oxyntomodulin, as well as the combination of a GLP1R agonist and GIPR antagonist also are in development. Oral semaglutide (administered daily) is approved for type 2 diabetes mellitus and is on track for regulatory review for obesity. The review includes specifically perspectives on the effects of these mechanisms and pharmacological agents on gastric emptying, which contribute to satiation and weight loss, in addition to the established evidence on effects on central mechanisms controlling appetite. In the future, it is anticipated that small molecule GLP‐1 receptor agonists (e.g., oral danuglipron) will be developed for treating obesity. These pharmacological agents are having significant impact on glycaemic control and obesity and on their co‐morbidities.