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.