Molecular basis of the obesity associated with Bardet-Biedl syndrome

Abstract

Bardet-Biedl Syndrome (BBS) is a rare human hereditary disorder associated with several features including obesity, retinopathy, renal defects, polydactyly, learning disabilities and hypogenitalism. This article discusses the abnormalities accounting for energy imbalance leading to obesity in BBS, with emphasis on the recent evidence pointing to aberrations in hypothalamic action of leptin. Indeed, BBS proteins have emerged as important mediators of leptin receptor trafficking, and loss of BBS genes results in leptin resistance that could be due to abnormal leptin receptor handling in a subset of leptin-responsive neurons. These recent discoveries hold promise for improved clinical management of BBS patients. The relevance of these findings to non-syndromic common obesity is also discussed.

Figure 1

BBS proteins and ciliary function. A) Abnormal ependymal cell cilia in BBS mice. Analysis by transmission electron microscopy of ependymal cell cilia (indicated by the arrow) lining the ventral portion of the third ventricle (adjacent to the arcuate nucleus of the hypothalamus) in BBS1 M290R mutant and wild type (WT) mice demonstrates enlargement of the distal region of cilia in BBS1 mutant animals. These results are representative of data published elsewhere (ref. 32). B) Schematic illustration depicting the cilium structure and the function of various BBS proteins. The BBS chaperonin complex mediate the assembly of the BBSome core which then interact with BBS3 at the base of the cilium to sort and mediate the trafficking of cargos including receptors to cilia and/or cell membrane.

Figure 2

Obesity phenotype in BBS mice. Representative MRI images demonstrating the increased fat mass in a BBS2 mutant mouse relative to a wild-type littermate control. Coronal (top panels) and axial abdominal (bottom panels) sections of are shown. Fat appears white whereas lean mass appears gray or black; (+) indicate subcutaneous fat and (*) visceral fat pads. These results are representative of data published elsewhere (ref. 50).

Figure 3

Schematic illustration of the leptin-sensitive neuronal populations in the hypothalamic arcuate nucleus; those activated (catabolic pathway represented by proopiomelanocortin (POMC) neurons) and those inhibited (anabolic pathway represented by the neuropeptide Y (NPY) neurons which also express agouti related protein, AgRP). In POMC neurons, leptin increases neuronal firing and POMC gene expression promoting the secretion of alpha-melanocyte stimulating hormone (α-MSH), an agonist of the melanocortin 3 and 4 receptors (MC3/4-R) located in the second order neurons. Conversely, in NPY neurons, leptin inhibits neuronal firing rate and decreases the expression and secretion of NPY and AgRP (antagonist of the MC3/4-R), promoting activation of MC3/4-R and inhibition of NPY-R, respectively. Leptin suppression of the NPY anabolic pathway and stimulation the POMC catabolic pathway reduce food intake and promote thermogenesis (resulting in decrease in body weight). BBS appears to be associated with a specific defect in leptin action in POMC neurons, but not NPY neurons.