bluuebunny/crossref_metadata_2025_split huggingface dataset:
ODP605 Body Mass Index and Weight Reductions in Patients With SRC1 Genetic Variant Obesity After 1 Year of Setmelanotide
Authors: Martos-Moreno Gabriel Á , Argente Jesús , Scimia Cecilia , Ohayan Olga , Yuan Guojun , Farooqi Sadaf 
Published: November 2022

Abstract

Background
The melanocortin-4 receptor (MC4R) pathway is a key regulator of energy balance. Steroid receptor coactivator 1 (SRC1; also known as NCOA1) is a transcriptional coactivator that regulates proopiomelanocortin (POMC) expression in the MC4R pathway. Certain SRC1 variants impair MC4R signaling and are associated with hyperphagia (pathologic insatiable hunger) and early-onset, severe obesity. Treatment with setmelanotide, an MC4R agonist, resulted in weight and hunger reductions after 3 months in patients with SRC1 variant obesity in a Phase 2 study. This analysis is the first to assess the continued efficacy of 1 year of setmelanotide treatment in patients with SRC1 variant obesity.

Methods
Patients with SRC1 variant obesity aged ≥6 years were eligible for this long-term extension (LTE) trial (NCT03651765) if they completed an index trial in which they received setmelanotide and demonstrated clinical benefit on the basis of efficacy and acceptable safety as determined by the investigator. Patients received a minimum of 4 months of setmelanotide treatment as part of the index trial and began the LTE immediately following completion. Study visits occurred approximately every 3 months. Study objectives included evaluating changes in weight-related measures and tolerability. The current analysis reports outcomes after 1 year of setmelanotide treatment across the index and LTE trials, relative to index trial baseline.

Results
As of October 29, 2021, 30 patients (20 ≥18 years old and 10 &lt;18 years old) with SRC1 variant obesity enrolled in the index trial. Seventeen patients entered the LTE; at the time of analysis, 16, 11, and 8 patients had received at least 6, 9, and 12 months of treatment, respectively. At index trial baseline, mean (standard deviation [SD]) body mass index (BMI) for all patients was 45.4 (11.3) kg/m2, body weight in patients ≥18 years old was 139.7 (25.1) kg, and BMI Z score in patients &lt;18 years old was 2.99 (0.63). After 6, 9, and 12 months of treatment, mean (SD) percent change in BMI was −5.7% (5.6%; n=16), −7.8% (5.8%; n=11), and −10.1% (9.4%; n=8), respectively. Mean (SD) percent change in body weight in patients ≥18 years old at 6, 9, and 12 months was −6.7% (6.1%; n=11), −9.9% (7.4%; n=8), and −11. 0% (8.6%; n=7), respectively. The mean (SD) change in BMI Z score was −0.35 (0.35; n=7), −0.42 (0.23; n=5), and −0.67 (0.57; n=3) after 6, 9, and 12 months, respectively. No new safety concerns emerged during long-term treatment, and no patients discontinued because of an adverse event.

Conclusions
One year of setmelanotide treatment led to clinical weight benefits in patients with SRC1 variant obesity. These data support the continued investigation of setmelanotide in this population, which is underway in the Phase 3 EMANATE trial (NCT05093634).
Presentation: No date and time listed
ODP607 Long-term Efficacy of Setmelanotide in Patients With POMC or LEPR Deficiency Obesity
Authors: Clément Karine , Wabitsch Martin , Van den Akker Erica , Argente Jesús , Scimia Ceclila , Srinivasan Madhura , Yuan Guojun , Kühnen Peter 
Published: November 2022

Abstract
The melanocortin-4 receptor (MC4R) pathway in the brain is responsible for energy regulation, affecting appetite and body weight. Impairments of this pathway can result in hyperphagia (insatiable hunger) and obesity. The MC4R can be impacted by the POMC, PCSK1, or LEPR genes. Variants in these genes that are inherited from both parents (biallelic) can result in MC4R pathway signaling deficiencies. Setmelanotide is a drug that activates the MC4R. In earlier Phase 3 studies, setmelanotide was shown to improve hunger and reduce weight in patients with POMC, PCSK1, and LEPR biallelic deficiency. The present study aims to examine the long-term efficacy of ∼3 years of setmelanotide treatment in patients with POMC, PCSK1, and LEPR biallelic deficiency in a long-term extension after a previous trial. Setmelanotide treatment continued to provide sizable reductions in body weight and body mass index while being generally well tolerated. These findings provide strong support of the safe and effective long-term use of setmelanotide to treat obesity in patients with POMC, PCSK1, and LEPR biallelic deficiency.
Presentation: No date and time listed
OR23-1 FXR Regulates the Expansion and Metabolic Function of Adipose Tissue upon Caloric Excess
Authors: Akinrotimi Oludemilade , Anakk Sayeepriyadarshini , Dadlani Neal , Zhou Weinan 
Published: November 2022

Abstract
Obesity is a major risk factor for developing metabolic diseases. Adipose tissue stores excess calories during obesity. Nuclear receptor Farnesoid X receptor (FXR) is expressed in various tissues and transcriptionally regulates lipid and glucose metabolism. However, the role of FXR in regulating adipose expansion is unknown. We showed that Fxr transcript is expressed in mature adipocytes isolated from both white (WAT) and brown (BAT) adipose tissues. In adipocyte-specific Fxr knockout (Ad-FxrKO) mice, we found enlarged adipocytes and decreased expression of lipolytic genes upon 60% high fat diet (HFD) or high fat/high sucrose western diet challenge. Transcriptomic analysis of WAT from Ad-FxrKO and control mice upon chow or HFD revealed that many genes involved in glucose and lipid homeostasis are misregulated in Ad-FxrKO mice with distinct patterns under normal and obese conditions. Since WAT stores fat and BAT generates heat, we examined both these depots in Ad-FxrKO mice and found reductions in the expression of mitochondrial genes and energy expenditure. Intriguingly, we found ectopic fat accumulation in the liver and systemic glucose intolerance in Ad-FxrKO compared to the control mice during obesity. Overall, these findings implicate that FXR may regulate lipid metabolism and mitochondrial functions in the adipose tissue, which consequently impacts whole-body energy homeostasis.
Presentation: Monday, June 13, 2022 11:15 a.m. - 11:30 a.m.
PSUN114 Correlation of Percent Body Fat From Two-Electrode Bioelectric Impedance Analysis and Dual-Energy X-Ray Absorptiometry
Authors: Roongjiraroj Thanasate , Siriwan Chonpiti , Suwannahitatorn Picha 
Published: November 2022

Abstract

Background
The diagnosis of obesity by measuring body mass index (BMI) is limited in some populations. Moreover, BMI does not reflect body fat levels, which are the main factors causing metabolic-related disorders, including cardiovascular disease. There are various methods for measuring percent body fat, such as using a two-electrode bioelectric impedance analysis (BIA), which is considered a portable and easy-to-use tool. In Thailand, the studies on BIA compared to standard method, dual-energy X-ray absorptiometry (DEXA scan) are still limited.

Objective
To study a correlation of percent body fat from two-electrode BIA and DEXA scan Methods: In this cross-sectional study, percent body fat were measured using three of two-electrode BIA and DEXA scan within the same week. The subjects were categorized into 3 groups according to their BMI: normal group (18.5 - 22.9 kg/m2), overweight and obese group (23 - 29.9 kg/m2) and extreme obesity group (≥ 30 kg/m2).

Results
A total of 30 study participants, with an average age of 28.07 ± 5.81 years, correlation of percent body fat as measured two-electrode BIA and DEXA scan were Omron®HBF-222T = 0.801, Tanita®BC-730 = 0.922, and Xiaomi®Body Composition Scale 2 = 0.884. All three correlations were strong (r 3 0.75) and statistically significant (p-value &lt;0.001). Moreover, the percent body fat measured by three of two-electrode BIA were no different (p-value = 0.167).

Conclusion
The percent body fat measured by three of two-electrode BIA and DEXA scan is highly correlated and not statistically difference between three brands. Therefore, two-electrode BIA can be used as alternative method to DEXA scan to measure percent body fat.
Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
PSUN119 Obesity As An Independent Factor In Outcome Of SIADH Hospitalizations
Authors: Maghari Ibrahim , Abusalim Abdul-rahman , Ojemolon Pius , Abusalim Abdul-rahman , Shaka Hafeez , Laswi Hisham 
Published: November 2022

Abstract

Introduction
Several comorbidities have been associated with the syndrome of inappropriate anti-diuretic hormone secretion (SIADH). However, not much literature documents an association between SIADH and obesity, and there is a marked paucity of research documenting the impact of obesity on outcomes in patients hospitalized with SIADH.

Method
We extracted data from the US Nationwide Inpatient Sample (NIS) for 2019. The NIS contains hospital discharge information estimating yearly US hospitalizations. We included hospitalizations with a principal discharge diagnostic code for SIADH using the ICD-10-CM code (E22.2). The study excluded hospitalizations of patients less than 18 years. This cohort was divided based on the secondary diagnosis of obesity.
Outcomes included comparing inpatient mortality rates, mean length of hospital stay (LOS), mean hospitalization cost (THC), rates of septic shock, acute myocardial infarction (AMI), acute respiratory failure (ARF), acute renal failure (AKI), acute pulmonary edema (PE) between the subgroups. An adjustment was made for age, sex, race, primary payer, median household income by zip code, Carlson Comorbidity Index (CCI), hospital location, bed-size, and teaching status using multivariate regression analysis. Statistical significance was set at a p-value &lt; 0.05.

Results
In 2019, a total of 39,110 hospitalizations involved patients with SIADH as the reason for the admission and 7.7% of these admissions had comorbid obesity. A higher proportion of hospitalizations involved females, with more of the obese cohort being females (65.7 vs 61.4%, p=0.034). Patients with obesity comparatively had a lower mean age (67.9±13.1 vs 73±13.3 years, p&lt;0.001), a higher proportion of CCI &gt;2, and a higher proportion of Whites.
In patients with SIADH, obesity was associated with no difference in mortality (1.1 vs 1.3%, p=0.589) or THC, but patients with obesity had higher odds of increased LOS (5.6 vs 4.9 days, p=0.007), AKI (20 vs 11.3%, aOR: 1.88, p&lt;0.001), and ARF (11.2 vs 7%, aOR: 1.53, p=0.003). There was no significant difference in CVA, PE, septic shock or AMI odds.

Conclusions
Comorbid obesity was associated with higher LOS and odds of AKI and ARF, but there was no difference in mortality, THC, CVA, PE, septic shock or AMI compared to SIADH hospitalizations without obesity.
Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
PSUN82 The Gut Microbiome Regulates Healthy Adipose Tissue Expansion via the Action of FFA2
Authors: Nnyamah Christine , Wicksteed Barton , Layden Brian 
Published: November 2022

Abstract
The obesity pandemic is a major health concern driving Type 2 Diabetes (T2D) and cardiovascular disease (CVD). One novel pathogenetic factor of obesity is the gut microbiome (GM), that is the microbes that reside in the digestive tract. Changes in the GM have profound effects on the obesity. These symbiotic microbes break down dietary fiber that are otherwise indigestible, releasing nutrients (in particular, short chain fatty acids, SCFAs). Free Fatty Acid Receptor 2 (FFA2) is a G-protein coupled receptor (GPCR) that senses SCFAs and influences secretion of the appetite-regulating proteins GLP-1 and PYY from enteroendocrine cells. However, its role in adipose tissue is less clear. While highly expressed in adipose tissue, research using global knockouts (KOs) of FFA2 in mouse models has observed conflicting phenotypic results. Here, we use adipocytes isolated from FFA2-KO and WT mice and SCFA-supplemented media to demonstrate that acetate, a primary ligand of FFA2, leads to increased adipogenesis. This expansion of total adipocyte population rather than individual size has been shown to greatly decrease metabolic health complications in highly obese individuals. Our ongoing research aims to explore the in vitro effects of FFA2 on lipogenesis, lipolysis, and secretion of adipokines. Primarily, we are exploring these outcomes in vivo using novel adipose-specific FFA2 KO (AdFFA2-KO) mice which we show have no congenital defects and are metabolically similar to FFA2 floxxed control mice on a normal chow diet. Our ongoing research challenges the mice with obesogenic diets to observe the effects of metabolic strain on FFA2 function specifically in adipose tissue.
Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
PSUN83 Exploring the Role of PARP1-mediated ADP-ribosylation in Diet-induced Obesity
Authors: Lee Kraus W , Whitaker Amy 
Published: November 2022

Abstract
Poly(ADP-ribosyl)ation (PARylation) is a posttranslational modification that regulates various cellular processes, including the differentiation of preadipocytes. PARylation involves the covalent attachment of a chain of ADP-ribose units to proteins by poly(ADP-ribose) polymerases (PARPs), mainly PARP1. We previously found that PARP1 activity decreases precipitously upon differentiation of preadipocytes, including 3T3-L1 cells, a preadipocyte cell line. Upon knockout or knockdown of Parp1, or chemical inhibition of PARP1, adipogenesis is dramatically increased. We have previously used a mouse lineage tracing model to show that knockout of Parp1 in preadipocytes promotes adipogenesis by expanding the pool of precursors, ultimately leading to accumulation of fat. PARP1 controls adipogenesis, in part, by PARylating two sites (E135A and E139A) in the regulatory domain of C/EBPβ, a proadipogenic transcription factor. Mutation of these sites enhances chromatin binding and transcriptional activity of C/EBPβ, as well as promotes a proadipogenic gene expression program and differentiation, in 3T3-L1 cells. However, we still do not know the role of PARP1-mediated site-specific PARylation in diet-induced obesity. We recently created a set of PAR-Trackers (PAR-Ts) that can detect changes in PAR levels during physiological processes in cells. We used PAR-T NanoLuc to observe dynamic changes in PAR levels during the differentiation of 3T3-L1 cells. We are now modifying the system to investigate PAR levels in the tissues of live animals. To investigate the physiological impact of loss of C/EBPβ PARylation in adipocytes, we have generated a knock-in mouse model for inducible tissue-specific expression of a C/EBPβ PARylation site mutant (Cebpb/E135A/E139A or C/EBPβ PAR mut). Using this model, we will investigate the impact of site-specific PARylation of C/EBPβ in mice fed a high fat diet. With these studies, we hope to reveal the specific roles of PARP1-mediated ADP-ribosylation in diet-induced obesity.
Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
PSUN84 Chronic Adrenergic Stimulation in Humans Increases Plasma Bile Acids and Expression of Bile Acid Synthesis Enzymes in White Adipose Tissue
Authors: Zhu Alexander R , Pierce Anne E , Katz Jacqueline M , Cero Cheryl , Cypess Aaron M 
Published: November 2022

Abstract
Bile acids (BAs) are classically known as facilitators of fat digestion. Moreover, they are now known to be ligands for receptors involved in glucose and lipoprotein metabolism. BA synthesis was originally thought to be exclusive to hepatic tissue, but emerging evidence in rodents has demonstrated the expression of BA transporters and de novo synthetic enzymes in murine adipose tissue. We previously showed that chronic activation of brown adipose tissue (BAT) and white adipose tissue (WAT) in adult women via the β3-adrenergic receptor (ADRB3) agonist mirabegron increases total plasma BA levels. The largest increases were seen with primary unconjugated BAs. Overall, these data suggest that chronic adrenergic stimulation may increase the synthesis and activity of BA synthesis enzymes in human adipose tissue, which contributes to the increase in total plasma BAs. To confirm this hypothesis, we measured expression levels of BAT and BA synthesis enzymes in liver and adipose tissues collected from healthy patients and those with pheochromocytoma (pheo) who experienced chronic adrenergic activation. As expected, expression of thermogenic UCP1 and ADRB3 was higher in pheo peri-renal BAT than in liver tissue (76,000x, P&lt;0.001; and 6,000x, P=0.02, respectively) or either healthy subcutaneous WAT or pheo subcutaneous WAT (≥1500x, P&lt;0.001 for UCP1). Conversely, expression of the rate-determining enzyme in BA synthesis CYP7A1 was similar in liver and both WAT depots (P&gt;0.05), and liver had slightly higher expression than BAT (3x, P=0.03). Otherwise, most of the principal BA synthesis genes’ expression levels demonstrated the following stepwise pattern: liver tissue &gt; pheo WAT = subcutaneous WAT &gt; BAT (CYP8B1, CYP27A1, AKR1D1, and BAAT). These results suggest that BA production in humans is not limited to the liver. Rather, human WAT in particular may contribute to the BA pool and could serve as a target for producing BA-mediated improvements in glucose and lipoprotein metabolism.
Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
RF10 | PMON205 LH/CG Receptor Activation Protects Mice from Diet-Induced Obesity and Modifies Adipose Tissue Immune Response
Authors: Lizneva Daria , Ievleva Kseniia , Gumerova Anisa , Shelly Eleanor , Korkmaz Funda , Muradova Valeriia , Netto Jessica , Kuo Tanchun , Sultana Farhath , Kumar Pushkar , Kramskiy Natan , Ryu Vitaly , Padilla Ashley , Hutchison Susan , Yuen Tony , Zaidi Mone 
Published: November 2022

Abstract
Menopause is associated with the loss of LH ovulatory surges and enhanced visceral adiposity. Visceral fat depots increase from 5-8% at premenopause to 15-20% of total body fat at postmenopause. Here, we report that high-dose LH, hCG, or small molecule LH/CGR agonist ORG43553 injected twice-a-week into 14-weeks-old C57BL/6 male mice protects them from diet-induced obesity. Testosterone levels were elevated in mice treated with LH or hCG, but not with ORG43553. Notably, the anti-obesity action of LH/hCG is independent of testosterone, as blocking the androgen receptor using flutamide yielded similar results. Importantly, male Lhcgr knockout mice on a high-fat diet treated with LH failed to display a reduction in adiposity, confirming the in vivo specificity of action. Furthermore, our data phenocopied Lhcgr haploinsufficiency in mice. We confirmed the presence of Lhcgr in mouse genital and inguinal fat pads, adipose-derived stromal vascular cells, as well as in differentiated and undifferentiated 3T3-L1 murine adipocytes by qPCR, RNAscope in situ hybridization, and immunohistochemistry. Sanger sequencing showed that the extracellular domain of Lhcgr in genital fat depot was identical to the ovarian receptor. Similarly, we identified LHCGR in human subcutaneous and visceral fat depots. Binding of intraperitoneally injected AlexaFluor-488-labeled hCG was found not only in mouse ovary, but also in genital and subcutaneous fat pad, further confirming the presence of LHCGR in adipose tissue. This binding could be competitively displaced in 3T3-L1 cells using unlabeled hCG. LH, hCG and ORG43553 activated ERK1/2 in a dose-dependent manner in undifferentiated and differentiated 3T3-L1 cells, suggesting that the adipose LHCGR is fully functional. LH, hCG, and ORG43553 reduced adipogenic differentiation in 3T3-L1 cells, which is further confirmed by RNA sequencing. Moreover, we observed, that LH and hCG also alters several aspects of immune response in adipose tissue, including inflammatory response and adaptive immunity. In conclusion, we demonstrated that LH/CG receptors are present and fully functional in adipose tissue, and that high-dose intermittent activation of LHCGR in mouse fat depots protects mice from diet-induced obesity and modifies adipose tissue immune response.
Presentation: Saturday, June 11, 2022 1:42 p.m. - 1:47 p.m., Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.
RF12 | PSUN80 A Novel DXA Algorithm to Aid in the Diagnosis of Familial Partial Lipodystrophy
Authors: Harris Charles , Zheng Wenjun , Brown Rebecca 
Published: November 2022

Abstract

Familial partial lipodystrophy (FPLD) is a rare and heterogenous disease without gold-standard diagnostic criteria. The heterogeneity applies to fat distribution, symptomatology, metabolic complications, and genetic etiology. Disease heterogeneity has contributed to the lack of standardized diagnostic criteria, an obstacle to understanding both the natural history of the disease and response to therapies. We have assessed whether DXA data can aid in disease diagnosis.
DXA scans quantify fat and lean mass in the whole body, arms, legs, and trunk. An increased ratio of fat percentage in the trunk to the legs (termed "trunk-leg ratio", TLR) has been proposed as an objective method to detect FPLD. Using large sets of DXA data from control subjects, along with data from FPLD subjects, we sought to improve upon TLR. We hypothesized that TLR might change as a function of overall adiposity (total body fat, TF). Females were studied first because of the high female: male ratio of disease prevalence observed in FPLD. In 2713 control females with DXA measurements within the UKBiobank (UKB), TLR increased linearly as a function of TF until a TF of ∼36% and then the TLR plateaued with higher TF. We analyzed published DXA data of FPLD subjects from the USA (n=55).1 FPLD subjects had higher TLRs than controls at each level of adiposity. Due to the non-linear relationship between total adiposity and TLR, two linear fits were generated to best discriminate controls from FPLD subjects for a given adiposity. For females with body fat &lt;36%, the algorithm predicts FPLD if TLR &gt;TF*0.0311+0.232. For females with body fat ≥36%, the algorithm predicts FPLD if TLR &gt;1.353. After training on this UKB data set, we tested the algorithm on independent data sets of control females from NHANES (n=2347) and FPLD subjects (n=37, from the NIH). The algorithm had a sensitivity of 92–97% and a specificity of 99.3%. This degree of specificity is still not sufficient for implementation of rare disease screening in the general population, but could be useful in a population with increased pre-test probability of having FPLD such as non-obese individuals with Type 2 diabetes and/or hypertriglyceridemia. Because race and ethnicity are possible modifiers of body fat distribution, we examined the relationship between TF and TLR across ethnic and racial groups in NHANES. Mexican-Americans (n=659), Hispanic-other (n=81), White (n=871), Black (n=612), and other/biracial (n=124) subjects from NHANES had a similar relationship between adiposity and TLR. Therefore, the same DXA criteria can be applied across these ethnicities. In summary, the relationship between adiposity and TLR may be used to aid in the diagnosis of FPLD in females.

Reference
Meral R, et al. Diabetes Care. 2018;41,2255–2258.
Presentation: Saturday, June 11, 2022 1:06 p.m. - 1:11 p.m., Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.