Obesity In Bardet-Biedl Syndrome Research Articles

Improved Care and Treatment Options for Patients with Hyperphagia-Associated Obesity in Bardet-Biedl Syndrome

Bardet-Biedl syndrome (BBS) is a rare, autosomal recessive multisystem disease. The pathophysiological origin is a dysfunction of the primary cilium. Clinical symptoms are heterogeneous and variable: retinal dystrophy, obesity, polydactyly, kidney abnormalities, hypogenitalism and developmental delays are the most common features. By the approval of the melanocortin 4 receptor agonist setmelanotide, a drug therapy for BBS-associated hyperphagia and obesity can be offered for the first time. Hyperphagia and severe obesity represent a considerable burden and are associated with comorbidity and increased mortality risk. Due to the limited experience with setmelanotide in BBS, a viable comprehensive therapy concept is to be presented. Therapy decision and management should be conducted in expert centers. For best therapeutic effects with setmelanotide adequate information of the patient about the modalities of the therapy (daily subcutaneous injection) and possible adverse drug events are necessary. Furthermore, the involvement of psychologists, nutritionists and nursing services (support for the application) should be considered together with the patient. The assessment of therapy response should be carried out with suitable outcome measurements and centrally reported to an adequate register.

Bardet-Biedl syndrome: A clinical overview focusing on diagnosis, outcomes and best-practice management.

Bardet-Biedl syndrome (BBS) is a genetic disorder characterized by early-onset obesity, polydactyly, genital and kidney anomalies, developmental delay and vision loss due to rod-cone dystrophy. BBS is an autosomal recessive disorder with >20 implicated genes. The genotype-phenotype relationship in BBS is not clear, and there may be additional modifying factors. The underlying mechanism is dysfunction of primary cilia. In BBS, receptor trafficking in and out of the cilia is compromised, affecting multiple organ systems. Along with early-onset obesity, hyperphagia is a prominent symptom and contributes significantly to clinical morbidity and caregiver burden. While there is no cure for BBS, setmelanotide is a new pharmacotherapy approved for treatment of obesity in BBS. The differential diagnosis for BBS includes other ciliopathies, such as Alstrom syndrome, and other genetic obesity syndromes, such as Prader-Willi syndrome. Careful clinical history and genetic testing can help determine the diagnosis and a multidisciplinary team is necessary to guide clinical management.

Burden of hyperphagia and obesity in Bardet–Biedl syndrome: a multicountry survey

BackgroundSigns and symptoms of Bardet–Biedl syndrome (BBS) occur during early childhood, progress over time, and place substantial, multifaceted burden on patients and their caregivers. Hyperphagia may be a contributing factor to early-onset obesity in BBS; however, there are limited insights into its impacts on patients and caregivers. We quantified disease burden as it relates to the physical and emotional impacts of hyperphagia in BBS.MethodsThe CAREgiver Burden in BBS (CARE-BBS) study was a multicountry, cross-sectional survey of adult caregivers of patients with BBS who have had hyperphagia and obesity. The survey consisted of questionnaires including Symptoms of Hyperphagia, Impacts of Hyperphagia, Impact of Weight on Quality of Life (IWQOL)-Kids Parent Proxy, and Patient-Reported Outcome Measurement Information System (PROMIS) v1.0-Global Health 7. In addition, clinical characteristics, medical history, and weight management questions were included. Outcomes were scored and summarized descriptively in aggregate and by country, age, and obesity severity according to weight class.ResultsThere were 242 caregivers of patients with BBS who completed the survey. Caregivers observed hyperphagic behaviors throughout the day, with negotiating for food (90%) and waking up and asking or looking for food during the night (88%) being the most frequent. Hyperphagia had at least a moderate negative impact on most patients’ mood/emotions (56%), sleep (54%), school (57%), leisure (62%), and familial relationships (51%). Hyperphagia affected concentration at school (78%), and symptoms of BBS contributed to patients missing ≥ 1 day of school a week (82%). Responses from the IWQOL-Kids Parent Proxy suggested obesity most greatly negatively affected physical comfort (mean [standard deviation (SD)], 41.7 [17.2]), body esteem (41.0 [17.8]), and social life (41.7 [18.0]). On the PROMIS questionnaire, mean (SD) global health score for pediatric patients with BBS and overweight or obesity (36.8 [10.6]) was lower than the general population (mean, 50).ConclusionsEvidence from this study suggests that hyperphagia and obesity may have broad negative impacts on the lives of patients with BBS, including physical health, emotional well-being, school performance, and personal relationships. Therapies that target hyperphagia may alleviate the extensive clinical and nonclinical impacts experienced by patients with BBS and their caregivers.

Adipose tissue function and insulin sensitivity in syndromic obesity of Bardet-Biedl syndrome.

Bardet-Biedl syndrome (BBS) is a rare autosomal recessive syndromic obesity of childhood onset among many other features. To date, the excess risk of metabolic complications of severe early-onset obesity in BBS remains controversial. In-depth investigation of adipose tissue structure and function with detailed metabolic phenotype has not been investigated yet. To investigate adipose tissue function in BBS. A prospective cross-sectional study. To determine if there are differences in insulin resistance, metabolic profile, adipose tissue function and gene expression in patients with BBS compared to BMI-matched polygenic obese controls. 9 adults with BBS and 10 controls were recruited from the national centre for BBS, Birmingham, UK. An in-depth study of adipose tissue structure and function along with insulin sensitivity was performed using hyperinsulinemic-euglycemic clamp studies, adipose tissue microdialysis, histology and RNA sequencing, and measurement of circulating adipokines and inflammatory biomarkers. Adipose tissue structure, gene expression and in vivo functional analysis between BBS and polygenic obesity cohorts were similar. Using hyperinsulinemic-euglycemic clamp and surrogate markers of insulin resistance, we found no significant differences in insulin sensitivity between BBS and obese controls. Furthermore, no significant changes were noted in an array of adipokines, cytokines, pro-inflammatory markers and adipose tissue RNA transcriptomic. Although childhood-onset extreme obesity is a feature of BBS, detailed studies of insulin sensitivity and adipose tissue structure and function are similar to common polygenic obesity. This study adds to the literature by suggesting that it is the quality and quantity of adiposity not the duration that drives the metabolic phenotype.

Setmelanotide: what does it mean for clinical care of patients with obesity?

In The Lancet Diabetes & Endocrinology, Karine Clément, Erica van den Akker, and colleagues present the results of setmelanotide in participants with three of the ultrarare genetic conditions associated with severe childhood obesity. 1 Clément K van den Akker E Argente J et al. Efficacy and safety of setmelanotide, an MC4R agonist, in individuals with severe obesity due to LEPR or POMC deficiency: single-arm, open-label, multicentre, phase 3 trials. Lancet Diabetes Endocrinol. 2020; (published online Oct 30.)https://doi.org/10.1016/S2213-8587(20)30364-8 Summary Full Text Full Text PDF Scopus (29) Google Scholar Although they occur only rarely, these conditions present enormous challenges for health-care providers, parents, and patients. The 21 participants in the setmelanotide study had biallelic variations in the prohormone pro-opiomelanocortin (POMC; n=9), proprotein convertase subtilisin and kexin type 1 (PCSK1; n=1), which is an important enzyme in activating the melanocortin 4 receptor (MC4R) pathway, or the leptin receptor (LEPR; n=11), which is essential for POMC function. These conditions produce hyperphagia and severe childhood-onset obesity and might be associated with various other endocrinopathies, such as adrenocorticotropic hormone deficiency, hypothyroidism, hypogonadism, hypopigmentation, hypoglycaemia, and others. Earlier, setmelanotide showed excellent outcomes in two patients with POMC deficiency, reversing hyperphagia and producing dramatic weight loss in both patients. 2 Kühnen P Clement K Wiegand S et al. Proopiomelanocortin deficiency treated with a melanocortin-4receptor agonist. N Engl J Med. 2016; 375: 240-246 Crossref PubMed Scopus (206) Google Scholar When given to three patients with LEPR deficiency, setmelanotide produced clinically significant reduction in both bodyweight and hyperphagia. 3 Clement K Biebermann H Farooqi IS et al. MC4R agonism promotes durable weight loss in patients with leptin receptor deficiency. Nat Med. 2018; 24: 551-555 Crossref PubMed Scopus (107) Google Scholar The drug has also been studied in seven patients with Bardet-Biedl syndrome, showing hunger reduction and mean weight loss at 1 year of –16·3% (90% CI −19·9 to−12·8). 4 Haws R Brady S Davis E et al. Effect of setmelanotide, a melanocortin-4 receptor agonist, on obesity in Bardet-Biedl syndrome. Diabetes Obes Metab. 2020; (published online July 6.)https://doi.org/10.1111/dom.14133 Crossref PubMed Scopus (13) Google Scholar Thus, the results reported herein have been eagerly anticipated. Efficacy and safety of setmelanotide, an MC4R agonist, in individuals with severe obesity due to LEPR or POMC deficiency: single-arm, open-label, multicentre, phase 3 trialsOur results support setmelanotide for the treatment of obesity and hyperphagia caused by POMC or LEPR deficiency. Full-Text PDF

Adipose tissue‐specific disruption of the BBSome cause insulin resistance

The BBSome is a protein complex composed of 8 Bardet‐Biedl syndrome (BBS) proteins including BBS1. Patients carrying mutations in any of the BBS genes display several features including obesity and type 2 diabetes mellitus. We previously demonstrated that the BBSome is required for membrane localization of the insulin receptor. We also showed that mice lacking several Bbs genes developed obesity associated with increased blood glucose, impaired glucose clearance and insulin resistance. However, the role and contribution of Bbs genes in insulin‐sensitive tissues such as adipose tissue for the development of obesity and diabetes remains unclear. To address this, we used a new conditional knockout mouse where exon 3 of the Bbs1 gene is floxed (Bbs1flox). Cre‐mediated recombination causes a frame shift resulting in a premature stop. We assessed whether deletion of the Bbs1 gene in adipocytes (by breeding Bbs1flox mice with AdiponectinCre mice) affects glucose homeostasis. Interestingly, no obesity phenotype was observed in both male and female AdipoCre/Bbs1flox mice fed either normal chow or high fat diet (45%), suggesting that development of obesity in BBS is not due to defects in adipose tissue. White fat adipose (WAT) cell size was similar between AdipoCre/Bbs1flox mice and control animals. However, mRNA and protein expression of PPARg was significantly decreased in WAT of AdipoCre/Bbs1flox mice compared to control animals (48%± 5% for mRNA and 47%± 14% for protein, respectively). In addition, fat acid synthetase (FAS) mRNA was reduced in WAT of AdipoCre/Bbs1flox mice relative to controls (34%± 10% vs control. Insulin‐induced activation of AKT was significantly decreased in the WAT, but not in the liver and skeletal muscle of AdipoCre/Bbs1flox mice versus control animals. Finally, fasting glucose level was similar between AdipoCre/Bbs1flox mice and control animals, and glucose tolerance test revealed no difference between AdipoCre/Bbs1flox mice and controls. However, insulin tolerance test uncovered impaired insulin‐induced glucose clearance in AdipoCre/Bbs1flox mice. These findings demonstrate the importance of the adipocyte BBSome for insulin sensitivity and glucose homeostasis.

Progress of research on the pathogenesis of obesity in Bardet-Biedl syndrome

Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disease characterized by retinopathy, obesity, and polydactyly. So far 21 candidate genes have been discovered, and mutations of such genes can all cause the BBS phenotype. As one of the main features of the disease, the obesity in BBS has been associated with leptin resistance and abnormal adipogenesis. However, its molecular etiology is not yet completely clear. Here the molecular mechanism of BBS-associated obesity is reviewed.

The BBSome Controls Energy Homeostasis by Mediating the Transport of the Leptin Receptor to the Plasma Membrane.

Bardet-Biedl syndrome (BBS) is a highly pleiotropic autosomal recessive disorder associated with a wide range of phenotypes including obesity. However, the underlying mechanism remains unclear. Here, we show that neuronal BBSome is a critical determinant of energy balance through its role in the regulation of the trafficking of the long signaling form of the leptin receptor (LRb). Targeted disruption of the BBSome by deleting the Bbs1 gene from the nervous system causes obesity in mice, and this phenotype is reproduced by ablation of the Bbs1 gene selectively in the LRb-expressing cells, but not from adipocytes. Obesity developed as a consequence of both increased food intake and decreased energy expenditure in mice lacking the Bbs1 gene in LRb-expressing cells. Strikingly, the well-known role of BBS proteins in the regulation of ciliary formation and function is unlikely to account for the obesogenic effect of BBS1 loss as disruption of the intraflagellar transport (IFT) machinery required for ciliogenesis by deleting the Ift88 gene in LRb-expressing cells caused a marginal increase in body weight and adiposity. Instead, we demonstrate that silencing BBS proteins, but not IFT88, impair the trafficking of the LRb to the plasma membrane leading to central leptin resistance in a manner independent of obesity. Our data also demonstrate that postnatal deletion of the Bbs1 gene in the mediobasal hypothalamus can cause obesity in mice, arguing against an early neurodevelopmental origin of obesity in BBS. Our results depict a novel mechanism underlying energy imbalance and obesity in BBS with potential implications in common forms of human obesity.

The study of a total and two hypothalamic-specific BBS10 knockout models highlights the importance of systemic inactivation in the obese phenotype in Bardet Biedl Syndrome

The autosomal recessive disorder, Bardet-Biedl syndrome (BBS) is an iconic ciliopathy, clinically characterized by obesity, retinopathy, polydactyly and renal dysfunction. To date, 19 BBS genes have been identified, with BBS10 being one of the most commonly mutated genes in human patients. The historical origin of the BBS-induced obesity has been associated with leptin resistance correlated with hyperleptinemia as well as decreased signaling in the appetite-governing arcuate nucleus neurons (ARC) of the hypothalamus. The ARC controls energy homeostasis, food intake and energy expenditure, through the detection of peripheral hormones by POMC and AgRP/NPY expressing neurons. POMC neurons are anorexigenic while NPY/AgRP are orexigenic, and both are ciliated cells. Several hormone receptors have ciliary localization, as the leptin receptor, and inactivation of the BBS proteins results in their mislocalization and signaling impairment. The present work aims at investigating the origins of obesity in the BBS by comparing the phenotype of a BBS10 total knockout (Bbs10-/-) with that of two BBS10 hypothalamic-specific KO mice: namely the POMC (Bbs10fl/fl;POMC-Cre+/-) and the AgRP (Bbs10fl/fl;AgRP-Cre+/-). Bbs10-/- mice develop obesity, together with other BBS cardinal traits, but surprisingly, both Bbs10fl/fl;AgRP-Cre+/- and Bbs10fl/fl;POMC-Cre+/- display a lean phenotype. Further characterizations of these mice highlighted the activation of compensatory mechanisms in response to the specific BBS10 inactivation probably forestalling the obese phenotype. These results indicate the complexity of the BBS-related obese phenotype, and support the need for an integrative approach that would include the contribution of other peripheral organs to better understand the origins of obesity in BBS.

Hyperphagia among patients with Bardet‐Biedl syndrome

The importance of hyperphagia as a cause for energy imbalance in humans with Bardet-Biedl syndrome (BBS) has not been established. We therefore compared hyperphagic symptoms in patients with BBS vs. controls. We studied 13 patients with BBS and 23 non-syndromic controls with similar age, sex and body mass index (BMI) z-score. A 13-item hyperphagia questionnaire was completed by patients' parents/guardians. Total hyperphagia questionnaire score was higher in BBS than controls (27.6 ± 9.0 vs. 19.1 ± 7.9, P = 0.005). Behaviour and drive subscales were higher for BBS than controls (12.5 ± 4.1 vs. 7.8 ± 3.2, P = 0.001, and 11.2 ± 4.1 vs. 8.3 ± 3.8, P = 0.04, respectively); severity was not significantly different between groups (3.8 ± 1.5 vs. 3.0 ± 1.3, P = 0.072). After adjustment for demographic variables and BMI z-score, total and behaviour subscale scores remained significantly different between groups, suggesting food-seeking activity, rather than preoccupation with food may be the main hyperphagic feature among patients with BBS. Appetite dysregulation may contribute to obesity in BBS.

Patients with Bardet-Biedl Syndrome Have Hyperleptinemia Suggestive of Leptin Resistance

Bardet-Biedl syndrome (BBS) is a genetically heterogeneous disorder of the primary cilium associated with obesity. In BBS mouse models, ciliary dysfunction leads to impaired leptin signaling and hyperleptinemia before obesity onset. To study the pathophysiology of obesity in BBS, we compared patients with BBS and body mass index Z-score (BMI-Z)-matched controls. Fifty patients with BBS were matched 2:1 by age, sex, race, and BMI-Z with 100 controls. Patients with BBS and controls were compared for differences in body composition (dual-energy x-ray absorptiometry, abdominal magnetic resonance imaging), blood pressure Z-score (BP-Z; standardized for age, sex, and height), and fasting concentrations of leptin, lipids, insulin, and glucose. Patients with BBS were also compared by genotype. Leptin, triglycerides, intraabdominal fat mass, and diastolic BP-Z were significantly greater in patients with BBS than in the controls. BBS1 (27%) and BBS10 (30%) mutations were the most prevalent. Patients with BBS10 mutations had significantly higher BMI-Z, greater visceral adiposity, and greater insulin resistance than those with BBS1 mutations. Patients with BBS had higher leptin than expected for their degree of adiposity, consistent with the notion that ciliopathy-induced leptin signaling dysfunction is associated with leptin resistance. The preferential deposition of fat intraabdominally in patients with BBS may indicate a predisposition for metabolic complications, including hypertension and hypertriglyceridemia. The observation of disparate results in the BBS10 vs. BBS1 mutation groups is the first demonstration of physiological differences among patients with BBS caused by mutations in distinct genes. These results suggest that the obesity of BBS is distinct from nonsyndromic obesity.

Transient ciliogenesis involving Bardet-Biedl syndrome proteins is a fundamental characteristic of adipogenic differentiation

Bardet-Biedl syndrome (BBS) is an inherited ciliopathy generally associated with severe obesity, but the underlying mechanism remains hypothetical and is generally proposed to be of neuroendocrine origin. In this study, we show that while the proliferating preadipocytes or mature adipocytes are nonciliated in culture, a typical primary cilium is present in differentiating preadipocytes. This transient cilium carries receptors for Wnt and Hedgehog pathways, linking this organelle to previously described regulatory pathways of adipogenesis. We also show that the BBS10 and BBS12 proteins are located within the basal body of this primary cilium and inhibition of their expression impairs ciliogenesis, activates the glycogen synthase kinase 3 pathway, and induces peroxisome proliferator-activated receptor nuclear accumulation, hence favoring adipogenesis. Moreover, adipocytes derived from BBS-patients' dermal fibroblasts in culture exhibit higher propensity for fat accumulation when compared to controls. This strongly suggests that a peripheral primary dysfunction of adipogenesis participates to the pathogenesis of obesity in BBS.