ResearchPad - mechanisms-and-treatment-of-obesity-in-humans Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[OR33-07 ARNT2: A Potential Novel Candidate Gene for Monogenic Obesity in Humans]]> Introduction: Aryl hydrocarbon nuclear translocator 2 (ARNT2) is a basic helix-loop-helix (bHLH)-PAS (Per/Arnt/Sim) transcription factor shown to be critical to the development of paraventricular nucleus of the hypothalamus (PVN), key region for energy homeostasis and feeding response. In vivo and in vitro studies have shown that ARNT2 is an obligate heterodimer for SIM1, known cause of monogenic obesity. Null mutations in Arnt2 in animals are not viable, but hypomorphic mutation results in hyperphagic obesity and its associated consequences (1). Due to the critical role of ARNT2 in the development of PVN, we hypothesize that hypomorphic mutations may result in early onset obesity in humans.

Methods: The Genetics of Early Childhood Obesity (GECO) study recruits children with severe obesity (BMI > 120% of 95th percentile) of early onset (< 6 years). Whole exome sequencing (WES) was performed in a subset of proband-parent trios. The functional validation of the mutation(s) in ARNT2 is ongoing with co-transfection of tagged Arnt2 and Sim1 in HEK293 cells, with the induction of a luciferase reporter gene under the control of 6 repeats of bHLH-PAS core binding element by the Arnt2-Sim1 complex.

Results: Two adolescents from unrelated families were found to have genetic variants in ARNT2. Subject 1 has a novel de novo heterozygous coding variant in ARNT2, c.388 C>G (p.P130A, CADD 25), predicted to be deleterious by 8/12 in silico algorithms. She is a 14-year old Caucasian girl with severe early onset obesity, BMI 28.1 kg/m2 (BMIz +4.72) at 2.5 years of age that has increased to 53.54 kg/m2 (BMIz + 3.25) at 14-years, and height > 95th %tile. She is non-dysmorphic, has developmental delay, absence seizures, behavior abnormalities & glucose intolerance/dyslipidemia secondary to obesity. Using genematcher, we identified another proband with the phenotype of obesity: an African American girl (BMIz +1.9) with biallelic inherited heterozygous variants in ARNT2, c.1228T>A (p.W410R, CADD 29) and c.916G>A (p.G306S, CADD 22). An only child conceived by IVF, she is non-dysmorphic and on treatment for bilateral focal epilepsy. All 3 variants are rare, with mean allele frequency < 0.005 in population-based databases such as gNOMAD. Both the patients have early onset obesity and a significant neurological phenotype. ARNT2 is a highly constrained gene of 717 amino acids with a significant depletion of missense variants in the N-terminus (1-244 aa) and overall fewer loss of function variants in ~282,644 alleles sequenced in gNOMAD.

Conclusions: We propose that hypomorphic mutations in ARNT2 could be a potential novel cause of monogenic obesity in humans. Future studies will investigate the molecular mechanisms causing weight dysregulation in patient specific disease relevant hypothalamic neurons.

Reference: (1) Turer et al., Dis Model Mech. 2018; 11(12)

<![CDATA[OR33-02 The Treatment of Partial Lipodystrophy in the Setting of Neutralizing Antibody Against Metreleptin with Leptin Receptor Agonist REGN4461]]> Background: An 18-year-old patient with atypical partial lipodystrophy had a transient initial metabolic response to metreleptin that deteriorated when neutralizing antibodies against metreleptin developed. A therapeutic trial with setmelanotide did not result in any metabolic benefit as desired. Because her status continued to deteriorate, we attempted to treat her with REGN4461, a fully human monoclonal antibody that is an agonist to the human leptin receptor (LEPR). Clinical Case: A compassionate use protocol (IND No. 144013) was initiated to treat the patient with REGN4461. The treatment consisted of 5 mg/kg intravenous infusion followed by 300 mg weekly subcutaneous injections of REGN4461. The primary endpoint was achievement of fasting triglycerides < 500 mg/dL without the need for ongoing plasmapheresis. Treatment-emergent adverse events were also followed. Here, we report her first 21-week response to treatment with REGN4461. The treatment resulted in a reduction of triglycerides from 1288 mg/dL to 344 mg/dl and allowed her to discontinue plasmapheresis. She lost 3.4 kilograms so far, and her liver size reduced per liver span measured by physical examination. Also, the liver MRI at week 12 showed a significant reduction in liver size and fat content (from 29.9% to 16.6%). Although her glucose control is still challenging, a slight reduction in her HbA1c was observed at week 12 along with improvements in her average glucose levels and total daily insulin requirement so far. No untoward signals were detected in her safety measurements. Conclusion: To date, treatment with REGN4461 offered substantial clinical benefit by improving the metabolic abnormalities in this unique patient. This experience represents the longest human exposure with REGN4461. The improvements noted in metabolic parameters and hepatic steatosis are similar to previous observations in lipodystrophic humanized LEPR mice. Our results suggest that REGN4461 showed clinical benefit even in the presence of neutralizing antibodies to metreleptin.

<![CDATA[OR33-04 The Effect of Adiposity on the Fasting Serum Proteome in Normal Weight and Obese Men]]> In many individuals with obesity, adipose tissue is not only increased in mass but also exhibits altered function. Disordered adipokine secretion contributes to a pro-inflammatory milieu that may lead to obesity-related co-morbidities. Hypothesis-generating, high-throughput techniques can generate novel insights. Our objective was to identify proteome-wide alterations in serum proteins related to adiposity. We evaluated the fasting serum proteome in 25 men [13 normal weight (mean±SD body mass index (BMI 21.2±1.4 kg/m2) and 12 with obesity (BMI 31.5±4.8 kg/m2)]. Blood was drawn at 0, 15, 30, and 55 minutes for proteomic analysis after an overnight fast (SOMAScan, SomaLogic, Inc.). The number of proteins and pathways that significantly differed between the two groups was determined across all time points during the fasting period. Normalized protein levels were compared between adiposity groups using rank product testing. Overrepresentation of protein constituents of established biological pathways was evaluated by hypergeometric test. P-values were adjusted using the Benjamini-Hockberg method, and those with an associated false discovery rate (FDR) of <0.05 were considered statistically significant. A total of 4,785 protein isoforms were robustly identified in serum of normal weight and men with obesity, of which 226 protein isoforms were significantly higher in obesity (vs. normal weight), and 178 were significantly lower in obesity (vs. normal weight). Higher levels of leptin and lower levels of IGFBP1 and IGFBP2 were observed in individuals with obesity during fasting (all FDR < 0.019). Functional annotation using Gene Ontology indicated that the following pathways differed most between obese vs. normal weight men: complement and coagulation cascade activation, amine metabolism, phosphatase activity, cellular response to nutrients (lipids, alcohol, and vitamin D), organic acid catabolism, and regulation of inflammatory responses. The protein isoforms identified in serum likely reflect systemic tissue-level changes in metabolism that may yield insights into the pathogenesis of obesity-related comorbidities and rational targets for intervention.

<![CDATA[OR33-03 Congenital Leptin Deficiency: Clinical Insights from the First Reported US Cases]]> Background: Congenital leptin deficiency (CLD) is a rare autosomal recessive form of monogenic obesity caused by loss-of-function mutations in the leptin gene. Targeted therapy is available in the form of recombinant human leptin (metreleptin). Previous case series have reported dramatic weight loss and metabolic improvements with treatment, but metreleptin’s only FDA-approved indication is acquired generalized lipodystrophy (AGL). Metreleptin has a black box warning for risk of T-cell lymphoma, which has been reported in AGL patients, both treated and untreated with metreleptin.

Clinical Case: Two sisters ages 18 yrs (sister A; BMI 45.2 kg/m2) and 20 yrs (sister B; 45.0 kg/m2) were referred for evaluation of obesity. They are of Pakistani origin with a family history of consanguinity. Birth weight was normal, but hyperphagia and excessive weight gain developed by age 3 months. They had been seen by endocrinologists, obesity specialists, and a geneticist during childhood but work-up for monogenic obesity was not pursued. They were treated with combination OCPs in adolescence due to primary amenorrhea and hypogonadotropic hypogonadism. Sister A was diagnosed with type 2 diabetes at age 15 years. Sister B had comorbidities of hydrocephalus s/p VP shunt, developmental delay, hyponatremia, autoimmune thyroid disease, growth hormone deficiency, and prediabetes. At the time of their present evaluation, serum leptin levels were obtained and were undetectable in both sisters. After discontinuing OCPs, testing confirmed hypogonadotropic hypogonadism. Both patients were homozygous for the pathogenic variant c398delG in exon 3 of the leptin gene (LEP), which causes a frameshift/premature stop codon. On MR elastography performed for hepatic steatosis, sister B had an incidental finding of axillary lymphadenopathy. Surgical biopsy and staging work-up confirmed diagnosis of nodular lymphocyte predominant Hodgkin lymphoma (a B cell lymphoma), Stage II disease. She was treated with R-ABVD with adjuvant radiation and achieved clinical remission, prior to treatment with metreleptin. The patients were enrolled in an observational treatment protocol, and responses to metreleptin therapy will be reported in future.

Conclusion: To our knowledge, these are the first cases of CLD diagnosed in the U. S. In previous reports, CLD and other monogenic obesity disorders were prevalent among children with severe obesity in a consanguineous Pakistani population. Leptin deficiency should be considered in all patients with early onset obesity and hypothalamic amenorrhea. Furthermore, to our knowledge, this is the first report of lymphoma in a patient with CLD, occurring prior to any treatment with metreleptin. The risk for lymphoma associated with metreleptin may relate to preexisting autoimmune disease or immunologic abnormalities related to leptin deficiency rather than medication adverse effect.

<![CDATA[OR33-01 Liraglutide for Weight Management in Pubertal Adolescents with Obesity: A Randomized Controlled Trial]]> <![CDATA[OR33-05 Amino Acid Signature of Abdominal Obesity in the TwinsUK Cohort]]> <![CDATA[OR33-06 Potential Role of Mutations in TBX3 in Human Weight Regulation]]> 120% of 95th %tile of CDC reference) early onset (< 6 years) obesity. Whole exome sequencing (WES) was performed in a subset of proband-parent trios. Peripheral mononuclear cells (PBMCs) from selected families were collected to generate induced pluripotent stem cells using non-integrating Sendai virus. Differentiation into disease-relevant hypothalamic neurons was performed using the published protocol (2). Loss-of-function models & isogenic controls were created using CRISPR/Cas9 & their cellular/molecular phenotypes were obtained at several time points during the course of differentiation. Results: We have identified a family with heterozygous mutation in TBX3 (p.His205Tyr, c.613 C>T, g.115118728 G>A). The proband is an 11-year old boy with morbid obesity (BMI 43.9 kg/m2, BMIz + 3.25), advanced bone age, precocious puberty & type 2 diabetes. Trio analysis ruled out recessive & compound heterozygote causative variants, & none of the identified de novo variants were considered pathogenic. His mother suffers from severe obesity (BMI 38 kg/m2 post-bariatric surgery) supporting an autosomal dominant inheritance of the phenotype. The putative causal variant in TBX3 segregates in the proband, mother & maternal grandmother. Located in the DNA binding domain of T-box, the variant is predicted to be deleterious by 4 in silico algorithms & rare in population-based databases (mean allele frequency 0.006% in gNOMAD, absent in ClinVar). Consistent with the variable penetrance of the phenotype in UMS, neither mother nor child have the classic features, but, the mother has uterine anomalies causing 6 spontaneous abortions & was unable to breast feed due to inverted nipples. Ongoing functional studies in human hypothalamic neurons suggest that a decrease in melanocortin signaling possibly explaining the phenotype in this family. Conclusions: Mutations in TBX3 in humans may have a role as a monogenic cause of obesity and disease-relevant hypothalamic stem cells can serve as models to study them. Ref: 1) Quarta et al. Nat Metab 2019, 1(2), 222-35; 2) Wang et al. JCI, 125(2): 796-808 ]]>