Background: The primary research goal was to identify brain alterations reliably associated with obesity using coordinate-based metaanalysis. A secondary goal was to compare brain alterations in ...metabolically healthy (MHO) and unhealthy (MUO) obesity. Methods: Source data were peer-reviewed studies reporting locations of gray-matter alterations in group-average, case-control contrasts (obese vs. non-obese) cohorts, performed in a whole-brain, voxel-wise manner. Both voxel-based morphometry and voxel-based physiology studies were included. Three coordinate-based meta-analyses were performed: Pooled (MUO + MHO), MHO, and MUO. Results: Thirty-two studies reporting a total of 50 case-control contrasts (MHO, 23; MUO, 27) met inclusion criteria, representing 3368 participants (obese, 1781; non-obese, 1587). The pooled analysis yielded eight cerebral foci (3 nuclear, 5 cortical) in regions implicated in reward-seeking, cognitive, and interoceptive behaviors. MHO yielded 7 cerebral foci (4 nuclear, 3 cortical), partially overlapping Pooled results, with similar behavioral loadings. The MUO pattern was distinct, with 3 cerebellar and 1 occipital foci. Conclusions: Brain alterations occurred reliably in obesity. The dominant pattern (Pooled & MHO) involved cerebral reward-system circuits, evident even in metabolically healthy obesity. Cerebellar alterations occurred exclusively in metabolically unhealthy obesity, a pattern previously reported in metabolic syndrome.
Background: According to CDC, Obesity in the US affects 100.1 million (41.9%) adults and 14.7 million (19.7%) children and accounts for approximately $147 billion in annual healthcare costs. As per ...WHO, obesity has tripled in the world between 1975 and 2016. As obesity is increasing at such a profound pace, so is the use of medications for its management. Thus, It is equally important to know the safety profile of these medications, specifically in the form of post-marketing surveillance from realworld data. Cardiovascular (CV) comorbidities are very commonly associated with obesity because of common risk factors. Unfortunately, limited data is available describing the CV safety profile of these anti-obesity medications, hence we attempted to study this. Methods: We queried the Food and Drug Administration (FDA)'s Adverse Event Reporting System (FAERS) database for various different Adverse Events (AE) of Orlistat, Phenteramine-topiramate, Tirzepatide, and semaglutide along with CV AEs including hypertension, arrhythmia, heart failure, ventricular hypertrophy, and so forth. The data on these AEs were collected, analyzed, and compared for all four drugs using descriptive statistics. Results: We found a total of 915 CV AEs reported combining all the Anti-obesity medications mentioned above. Out of all the AEs reported for Tirzepatide, there were only 0.71% (35) AEs related to the CV system, compared to Phenteramine-Topiramate, which had the highest CV AEs reported as 3.3% (111) out of all AEs reported. CV AEs associated with Orlistat and Semaglutide were found to be 1.51% (446) and 1.99% (323) respectively. Conclusions: Tirzepatide has 4.5 times less associated CV AEs as compared to phentermine-Topiramate and about 2 times less associated CV AEs compared to Semaglutide and Orlistat. Hence, Tirzepatide followed by Orlistat can be relatively safer to use for patients with Cardiovascular comorbidities as compared to other medications used for the management of Obesity among patients with CV comorbidities. Our study will help clinicians to select appropriate anti-obesity medication among patients with certain comorbidities. With, the increasing use of anti-obesity medications, further clinical studies are required to establish the CV and overall safety profile of these medications especially among patients with certain comorbidities.
Background: Monoacylglycerol acyltransferase 2 (MGAT2) is an enzyme involved in triglyceride resynthesis of small intestinal epithelial cells. Although some reports indicate that inhibition of MGAT2 ...would be a promising target for anti-obesity treatment, there are few MGAT2 inhibitors that show a highly effective profile. Therefore, we identified S-309309, which is an oral MGAT2 small molecule inhibitor, and examined its anti-obesity effect and mechanisms in non-clinical study. Methods: In vitro activity of S-309309 was tested using mouse and human MGATs and diacylglycerol acyltransferase (DGATs) enzymes. In vivo anti-obesity effect of S-309309 was evaluated in high fat diet induced obese (DIO) mice by comparison with liraglutide or combination of phentermine/topiramate, which used in clinical for obesity. In addition, combination studies with liraglutide or semaglutide and mechanism study of S-309309 anti-obesity effect were also conducted in DIO mice. Results: S-309309 had potent inhibitory activity for human and mouse MGAT2 with IC50 values of <30 nM. On the other hand, IC50 values of S-309309 on human MGAT3, DGAT1 and DGAT2 were more than 100 pM. S-309309 showed a potent and dose-dependent anti-obesity effect in DIO mice, and the effect was stronger than that of liraglutide and combination of phentermine/topiramate. When combination with liraglutide or semaglutide, the combinations exhibited stronger anti-obesity effect than single-agent therapy of liraglutide, semaglutide or S-309309 in DIO mice. Furthermore, we demonstrated that S-309309 had multiple mechanisms of action such as suppression of feeding, delayed lipid absorption into the body and increased energy expenditure. Conclusions: S-309309 showed a significant and selective inhibitory activity on human and mouse MGAT2 in vitro and a potent antiobesity effect with multiple mechanisms in DIO mice. These results suggest the attractive therapeutic potential of S-309309 for obesity treatment.
Background: Medication Possession Ratio (MPR) measures adherence and persistence on anti-obesity medication (AOM). Previous studies have shown poor compliance to AOM. An MPR of 80% historically ...suggests acceptable level of adherence. The aim of our study was to illustrate MPR rate in our MOVE! Program at VA Greater Los Angeles Healthcare System (VAGLAHS). Methods: Patients were identified if they filled any FDA approved AOM (phentermine/topiramate, naltrexone/bupropion, orlistat, liraglutide, or lorcaserin) from January 2006 to June 2020. Patients were excluded if they only filled AOM once. MPR was calculated as the sum of day supply of medication for all fills over number of days from first fill to last fill. Data was extracted from VAs Corporate Data Warehouse. Results: A total of 280 Veterans were included in our MPR calculation. MPR for orlistat was the least at 56% (n=160, range 5-200%), followed by low dose phentermine/topiramate at 76% (n=97, range 15-130%), liraglutide at 82% (n=73, range 35-153%), high dose phentermine/topiramate at 83% (n=38, range 17-162%), lorcaserin at 85% (n=35, range 33-120%), and lastly naltrexone/bupropion with the highest MPR at 92% (n=16, range 34-200%). Average days between first and last fill in order from shortest to longest duration were 184 days on naltrexone/bupropion, 249 days on lorcaserin, 323 days on high dose phentermine/topiramate, 333 days on low dose phentermine/topiramate, 364 days on liraglutide, and 445 days on orlistat. Conclusions: There were varying ranges of MPR of each medication, however we saw a high percentage of adherence, which would conflict with existing poor adherence studies, except for orlistat, in our MOVE! Program at our institution. We had a relatively long duration of therapy as well on AOMs suggesting efficacy and tolerability as we move forward in treating obesity as a chronic disease state.
Background: The melanocortin-4 receptor (MC4R) pathway is critical for the regulation of energy balance. Variants within genes comprising this pathway, including POMC, PCSK1, LEPR, SH2B1, and NCOA1 ...(also known as SRC1), have a well-established association with severe obesity. However, the frequency of variants in these genes has not been assessed systematically in a clinically relevant US population. Methods: We sequenced POMC, PCSK1, LEPR, SH2B1, and NCOA1 exons and intron-exon boundaries in 45,866 US individuals with severe obesity (<18 years old, >97th percentile BMI for age; >18 years old, BMI >40kg/m2). This cohort is comprised of individuals sequenced across multiple initiatives, including the Uncovering Rare Obesity® diagnostic genetic testing program. In the current analysis, we included rare variants classified as pathogenic/likely pathogenic (P/LP) or as a variant of uncertain significance (VUS) according to ACMG criteria. Results: 8.2% of individuals with severe obesity carried >1 rare variants in >1 of the 5 studied genes, including 0.3% who carried a P/LP variant and 7.9% who carried a VUS variant. Within the context of a community-focused clinical diagnostic tool, Uncovering Rare Obesity® results demonstrated a higher frequency of P/LP of 0.6% and a 10.0% frequency of VUS genotypes. Conclusions: Overall, in our large US-based cohort of individuals with severe, early-onset obesity, ~8% of individuals carry >1 potentially clinically relevant rare variants in the 5 MC4R pathway genes POMC, PCSK1, LEPR, SH2B1, and NCOA1. Understanding the role of these variants in the pathophysiology of obesity may improve the clinical care of individuals living with these rare genetic diseases of obesity.
Background: Registered dietitians (RDs) are an important part of the interdisciplinary team required for effective obesity care. However, the extent of obesity training for RDNs has not been studied. ...The objective of this study was to benchmark the inclusion and perceived importance of obesity-related competencies in US dietetic supervised practice (SP) programs, which are a required part of clinical training for all RDs. Methods: This cross-sectional survey study was modeled after previous studies of obesity-related medical training. The survey was based on the 2017 interprofessional Provider Competencies on the Prevention and Management of Obesity and was emailed to all 319 SP directors in the US. Participants were asked to rate the extent to which each of the 31 competencies are incorporated into their program using a 4-pt Likert scale. The survey also included questions about barriers. Results: We received 34 responses, representing 10% of SP directors. 55% (n=21) indicated that teaching students about the prevention or treatment of obesity is an intentional program objective. The most commonly included competencies were 'evaluate BMI' and 'perform effectively in an interprofessional team', reported as being covered to a "great extent" by 82% and 71% of respondents, respectively. Very few programs reported "not at all incorporated" for any competencies; the most frequent were 'potential role of genetics/epigenetics' (15%, n=5) and 'physiology/pathophysiology of obesity' (12%, n=4). 'Perform effectively in an interprofessional team' and 'discuss obesity in a non-judgmental manner' were considered "very important" by 94% and 88% of respondents, respectively. The most frequently reported barriers were lack of room in the curriculum and lack of obesity-related rotation sites, reported as a moderate or large barrier by 68% and 53% of respondents, respectively. Conclusions: This study is the first step to understanding the degree to which RDs are trained in obesity, and the perceived importance of obesity training. Some competencies are integrated to a high degree, while others are incorporated very little due to various barriers.
Background: Obesity is a complex disease characterized by dysregulation in energy intake. The reward circuitry of the central nervous system is essential in food intake regulation. However, the ...effects of a short- and long-term fast on reward activity and subsequent caloric intake are not well understood. Methods: The neuroimaging food paradigm consisted of three pseudo-continuous arterial spin labeling (pCASL) MRI scans during an ad libitum nutrient drink (Ensure®) test (NDT) (drinking until maximal fullness). The first scan was performed before starting the NDT (Hunger) after a >12-hr (long-term) overnight fast or a 4-hr (short-term fast) after a 380-kcal standard breakfast, the second scan after reaching maximal fullness (Satiation), and the third scan 30-min after satiation (Satiety). Semiquantitative cerebral blood flow (CBF) maps in mL/100 gr brain/min were calculated from the pCASL data. Brain regions of interest (right and left caudate, putamen, and nucleus accumbens NAc) were segmented from T2 volumes using Freesurfer (run_first_all) and used to mask CBF maps to determine the average CBF in each region. Changes in CBF were used as a proxy of neural activity. Results: A total of 43 patients with obesity (mean±SD age 37±10 years, body-mass index BMI 35.1±4.4kg/m2, 72% females) completed the study, 29 in the long-term fast and 14 in the short-term fast group. The long-term fast group consumed 1306±125 kcal in the NDT compared with 1125±301 kcal in the short-term fast (p=0.1). The short-term fast group had a significantly lower activity (CBF) in the left and right NAc, and left and right caudate nucleus during hunger, satiation, and satiety, and in the left and right putamen only at hunger. Conclusions: Recent (<4hrs) caloric intake decreases reward neural activity but not ad libitum energy intake in patients with obesity.
Background: Obesity is a complex multifactorial disease associated with debilitating chronic comorbidities and increased healthcare costs. Due to an array of factors such as weight bias and ...discrimination, patients with obesity are also more likely to be unemployed and to earn less than their counterparts without obesity. This study aimed to evaluate patterns of financial toxicity among patients with obesity. Methods: Using the National Health Interview Survey from 2013 to 2018, patient demographics and self-reported financial metrics were collected or calculated for patients with obesity (body mass index of 30 or greater), including financial hardship from medical bills, financial distress, food insecurity, and cost-related medication (CRM) non-adherence. Multivariable logistic regression was used to assess factors associated with increased financial hardship. Results: 72,254 patients with obesity were included in this study. 22.3% faced some financial hardship due to medical bills, of which 55.8% could not pay these bills. Obesity was associated with higher odds of financial hardship from medical bills (odds ratio OR 1.27, 95% confidence interval CI 1.23-1.32) with similar trends for financial distress (OR 1.13, 95% CI 1.09-1.17), food insecurity (OR 1.19, 95% CI 1.14-1.24)=, and CRM non-adherence (OR 1.23, 95% CI 1.18-1.28, p<0.001 for all). Financial hardship among patients with obesity was also associated with being male (OR 1.28, 95% CI 1.21-1.35), Black (OR 1.31, 95% CI 1.22-1.41), uninsured (OR 2.11, 95% CI 1.96-2.27), and in poor self-reported health (AOR 5.88, 95% CI 5.18-6.67, p<0.001 for all). Conclusions: A substantial proportion of adults with obesity struggle with paying their medical bills and suffer from high rates of financial distress, food insecurity, and CRM non-adherence. Further research into the causal and potentially actionable mechanisms that lead patients with obesity to experience financial toxicity should be pursued. Public policy reform may represent a critical lever to ease the burden of financial hardship for these patients.
Background: The potent and long-acting novel human glucagon-like peptide 1 receptor (GLP-1R) agonist (GLP-1RA); GL0034, selectively activates GLP-1R. Based on the anti-obesogenic and metabolic ...benefits of GLP-1RAs, we evaluated the efficacy of GL0034 in diet induced-obesity (DIO) mouse model. Methods: C57BL6/J mice (age 7 weeks) were fed with high fat pelleted diet for 12 weeks to induce obesity and glucose intolerance. DIO mice were administered placebo or GL0034 (6.25 pg/kg or 25 pg/kg) or semaglutide (50pg/kg) every alternate day (q2d) for 4 weeks. On day 29, biochemical parameters, liver lipid and histology were evaluated. NAS-score was calculated as the sum of the scores for steatosis (0-3), lobular inflammation (0-3), and ballooning (0-2), with a total range of 0 to 8. Statistical evaluation was performed using Prism 5 software, where ·p<0.05, ··p<0.01 and ···p<0.001 vs. placebo and #p<0.05, ##p<0.01 and ###p<0.001 vs. semaglutide. Semaglutide was synthesized in-house. Results: DIO mice treated with GL0034 (6.25 pg/kg and 25 pg/kg) and semaglutide (50 pg/kg) demonstrated reduction in body weight of 0.4%, 10.4%··· and 14.9%··· and concomitant fat mass 11.0%, 29.8%··· and 39.1%··· respectively. Insulin levels were decreased from 10.7 (±2.0) ng/mL to 10.4 (±1.3), 6.0··· (±0.6), and 5.7··· (±1.0) ng/mL. Triglycerides levels were reduced from 40.9(±3.5) mmol/kg to 31.1··· (±3.3), 20.1··· (±1.3), and 18.0··· (±1.8) mmol/ kg respectively and low-density lipoprotein cholesterol were reduced from 1.34(±0.27) mmol/kg to 0.91·· (±0.17), 0.64··· (±0.05), and 0.57··· (±0.06) mmol/kg, respectively. The circulating levels of alanine aminotransferase (ALT) were significantly more reduced with GL0034 than with semaglutide treatment: 56%···#, 54%···# and 34% ···, respectively, for the three treatment groups vs. the placebo group. Further steatosis score was 1.0···, 0.3··· and 0.1··· as against 1.9 of placebo. Lobular inflammation grade of 0.7#, 0.4···### and 1.3 was observed vs. 0.9 of placebo. The observed NAS total score of 1.7···, 0.7···# and 1.4··· respectively vs. 2.7 of placebo. Conclusions: Our study demonstrates that, GL0034, even at lower doses, improves plasma and liver biochemical markers and histopathological changes. The efficacy of GL0034 was similar or superior to semaglutide at 2-8-fold lower doses in ameliorating the steatohepatic condition.
