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 SRC1, ...have a well-established association with severe obesity. However, the frequency of variants in these genes have not been assessed systematically in a clinically relevant US population. Methods: We sequenced POMC, PCSK1, LEPR, SH2B1, and SRC1 exons and intron-exon boundaries in 35,276 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 (URO) 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. We additionally included one non-rare variant, PCSK1 p.N221D, which for which published functional and population studies suggests a potential contribution to obesity. Results: 10.2% of individuals with severe obesity carried >1 rare variants in >1 of the 5 studied genes, including 0.7% who carry a P/ LP variant and 9.5% who carry a VUS variant. An additional 5.4% carried the PCSK1 p.N221D variant. Within the context of a community focused clinical diagnostic tool, URO demonstrated a slightly higher frequency of P/LP and PCSK1 N221D genotypes, 1.2% and 6.9%, respectively, and a 9.8% frequency of VUS genotypes. Conclusions: Overall, in our large US-based cohort of individuals with severe early-onset obesity, 15.6% of individuals carry a potentially clinically relevant variant in the MC4R pathway genes POMC, PCSK1, LEPR, SH2B1, and SRC1. 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: Variants on the FTO gene increase obesity risk. FTO has been previously associated with alterations in brain structure, but less is known about the influence of FTO on brain structure in ...children. Methods: We examined differences in grey matter volume (GMV) and cortical thickness (CT) between FTO SNP rs9939609 allele carriers in 2 to 15 year old children. Structural MRI data were drawn from a longitudinal study of healthy brain development (Resonance). We cross-sectionally analyzed differences in GMV and CT in typically developing children grouped by FTO risk alleles: AA high risk, n = 53, age = 7.4 ± 2.9 y, 26M,27F, BMIz = 0.32 ± 1.13; AT moderate risk, n = 142, age = 7.31 ± 2.98 y, 77M,65F, BMIz = 0.25 ± 1.21; TT low risk, n = 89, age = 7.26 ± 3.1 y, 56M,33F, BMIz = -0.0035 ± 1.38. GMV and CT measurements were obtained using FreeSurfer. Preliminary multivariate GLM analysis was performed in SPSS to assess group differences (Bonferroni corrected for multiple comparisons, P < 0.05), where GMV and CT were adjusted for age, sex and BMIz, with additional total intracranial volume adjustments for GMV. Results: The AT vs. TT group demonstrated alterations in left amygdala, right cerebellum, left superior temporal sulcus and left fusiform gyrus (lower GMV); right superior parietal cortex (higher CT). The AA vs. TT group showed alterations in left caudal anterior cingulate cortex and right cerebellum (lower GMV), right frontal pole (higher GMV+CT), and left lateral occipital cortex (higher CT). Conclusions: Structural brain alterations associated with FTO risk alleles could predict future obesity. Future longitudinal analyses will examine effects of FTO variants on brain development and weight trajectories, with potential implications for neurobehaviorally targeted obesity prevention.
Background: Adults with obesity exhibit a restrictive pattern, whereas children with obesity exhibit an obstructive pattern. However, the transition process remains unclear. Methods: We performed a ...systematic search for studies reporting on body mass index and pulmonary function in children. The main outcomes were forced expiratory volume in 1 second (FEVj.), forced vital capacity (FVC), and their ratio (FEV1/FVC). We compared individuals with overweight or obesity with individuals with normal weight. Random-effects models were used to calculate pooled estimates. Results: A total of 17 studies were included. Individuals with obesity had a lower FEVj/FVC ratio (mean difference MD = -3.61%; 95% confidence interval CI = -4.58%, -2.64%) and a higher percent-predicted FVC (MD = 3.33%; 95% CI = 0.79%, 5.88%) than those with normal weight. Obesity impaired pulmonary function in the obstructive pattern during childhood to young adulthood, and the maximum obstruction was observed at the age of 16 years in boys and 20 years in girls. The effects attenuated at approximately 30 years and then shifted to the restrictive pattern after 35 years of age in men and 40 years in women. Conclusions: The effects of obesity on pulmonary function change from the obstructive pattern in childhood to the restrictive pattern in adulthood.
Background: Single Minded-1 (SIM1) is a transcription factor involved in development and function of the hypothalamic paraventricular nucleus, a site critical for the body weight regulating function ...of the melanocortin-4 receptor (MC4R) pathway. Consistent with its MC4R pathway involvement, rare loss-of-function (LOF) variants in SIM1 are associated with severe early-onset obesity and hyperphagia, hallmark features of rare genetic diseases of obesity. To better understand the contribution of SIM1 variants to severe clinical obesity, we performed functional biochemical characterization of rare SIM1 variants in Rhythm's database of approximately 40,000 individuals with severe obesity. Methods: Functional impact of SIM1 missense variants was assessed using a well-established and controlled hypoxia response element(HRE-) luciferase reporter gene assay. Results: In total, 189 missense SIM1 variants were identified in individuals with severe obesity; 80 have not been previously described, while 176 have not been functionally assessed. Biochemical characterization of all 189 SIM1 variants was performed to determine impact on protein function. Of the 189 variants, 2 exhibited complete LOF, 85 exhibited moderate LOF, and 102 exhibited WT-like activity. Thus, nearly half of the rare SIM1 missense variants, including 36 novel variants, observed in obese individuals exhibit LOF in a biochemical assay. Conclusions: These findings provide important insights into the SIM1 variant landscape and may help in the future diagnosis and treatment of individuals with SIM1 deficiency obesity.
Background: Obesity is associated with a dysbiotic gut microbiome characterized by low microbial diversity and a loss of Christensenella minuta, which are low abundance human gut dwelling anaerobic ...bacteria. A newly isolated strain of C. minuta DSM 33407 was recently demonstrated to carry a strong anti-obesity potential in diet-induced obesity mouse models. In a human ex vivo model of obese gastrointestinal tract, the same strain demonstrated a keystone effect as it increased the diversity of the gut microbiota and stimulated the production of short chain fatty acids, indicating that this specific strain was able to repair some functions of the obese dysbiotic microbiome. To develop the strain for clinical applications, a gastroresistant capsule containing 109 CFU of C. minuta DSM 33407 was prepared for daily oral use. Here are presented the results of the first clinical trial ever evaluating safety and tolerability of a christensenellabased biotherapy to treat obesity Methods: The trial included two study arms: one open label arm included 8 healthy volunteers (HV) with BMI withing the normal range (18-24.9); one randomized double-blind placebo-controlled arm included 30 metabolically unhealthy overweight volunteers (OV) with elevated BMI (27-34.9). All HV received the investigational product (IP) while twenty OV received the IP and 10 received the placebo. Treatment period was 12 weeks followed by a 4-week wash-out period. Adverse events were monitored during the entire study period. Fecal samples were collected at baseline, week 2, 8, 12 and 16 to monitor persistence of C. minuta DSM 33407 in stools using targeted qPCR. Results: Twenty-eight patients were enrolled in the study and only one withdrew for personal reasons. No Serious Adverse Events (SAEs) were reported in both study groups. A single HV reported an adverse event (active stomach), while four adverse events were recorded for the OV group. C. minuta DSM 33407 were not detected in stools at baseline but were detected in all samples during the treatment period. Only 3 HV still displayed a low level signal after 4 weeks of wash-out. Conclusions: C. minuta DSM 33407 demonstrated good safety and tolerability in both HV and OV, opening a new path towards development of microbiome-based biotherapies to treat obesity and associated metabolic disorders.
The American Society for Metabolic and Bariatric Surgery Pediatric Committee updated their evidence-based guidelines published in 2012, performing a comprehensive literature search (2009-2017) with ...1387 articles and other supporting evidence through February 2018. The significant increase in data supporting the use of metabolic and bariatric surgery (MBS) in adolescents since 2012 strengthens these guidelines from prior reports. Obesity is recognized as a disease; treatment of severe obesity requires a life-long multidisciplinary approach with combinations of lifestyle changes, nutrition, medications, and MBS. We recommend using modern definitions of severe obesity in children with the Centers for Disease Control and Prevention age- and sex-matched growth charts defining class II obesity as 120% of the 95th percentile and class III obesity as 140% of the 95th percentile. Adolescents with class II obesity and a co-morbidity (listed in the guidelines), or with class III obesity should be considered for MBS. Adolescents with cognitive disabilities, a history of mental illness or eating disorders that are treated, immature bone growth, or low Tanner stage should not be denied treatment. MBS is safe and effective in adolescents; given the higher risk of adult obesity that develops in childhood, MBS should not be withheld from adolescents when severe co-morbidities, such as depressed health-related quality of life score, type 2 diabetes, obstructive sleep apnea, and nonalcoholic steatohepatitis exist. Early intervention can reduce the risk of persistent obesity as well as end organ damage from long standing co-morbidities.
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