Hypothalamic Leptin Resistance: From BBB to BBSome.

In 1969, Douglas Coleman joined the bodies of an obese and a normal mouse by a procedure called parabiosis. Days later, the normal mouse starved. Something had taken away its desire to eat [1]. It was not until almost 25 years later that the true nature of what Coleman then called "satiety factor" was revealed. In 1994, Jeffrey Friedman identified the adipocytic hormone leptin [2,3] and it was made official: obesity has a genetic background. Leptin binds and activates a receptor of the cytokine receptor family. Alternative mRNA splicing and posttranslational processing result in several receptor isoforms (LRa, LRb, LRc, LRe, and LRf); the long isoform, LRb, is implicated in signal transduction. The other isoforms may act as leptin sequesters and transporters, binding leptin without signal transduction. LRb possesses a long intracellular domain that binds to Janus kinase 2 (JAK2) and to signal transducers and activators of transcription (STAT)-3 and STAT-5. Plasma leptin crosses the blood– brain barrier (BBB) via a saturable process, reaching the hypothalamus, where LRb is widely expressed. Acting in the hypothalamic arcuate nucleus (ARC), leptin inhibits the expression of orexigenic neuropeptides (e.g., agouti-related protein [AgRP], and neuropeptide Y [NPY]) and increases the expression of anorexigenic neuropeptides (e.g., proopiomelanocortin [POMC]), which decreases feeding and increases energy expenditure [4,5]. The role of leptin in human obesity remains poorly understood. Leptin deficiency and mutations in leptin receptor cause morbid obesity; however, these defects are extremely rare [6]. On the contrary, the majority of obese humans have high levels of leptin, suggesting leptin insensitivity or resistance [4]. Central leptin resistance may develop via different mechanisms (Fig 1), such as (1) impairment in the function of the saturable leptin transporters in the BBB [7]; (2) deficient leptin signaling [4,5,7,8]; (3) lipotoxicity and endoplasmic reticulum (ER) stress, as well as (4) inflammatory signals that have also been shown to modulate leptin responsiveness [9]. Despite this evidence, recent data questioned that obesity may be a result of leptin resistance [10]. In a recent publication in PLOS Genetics, Kamal Rahmouni and colleagues describe a novel mechanism that promotes leptin resistance. They show that neuronal Bardet-Biedl Syndrome (BBS) proteins influence energy homeostasis through the control of cell surface expression of the leptin receptor [11]. BBS is a rare and highly pleiotropic autosomal recessive disorder characterized by retinal dystrophy, polydactyly, renal and gonadal anomalies, cognitive impairment, and obesity [12,13]. BBS is part of an emerging class of diseases named ciliopathies that are characterized by disorders of the cellular cilia, anchoring structures, basal bodies, or impaired ciliary function [12]. At least 20 genes (BBS1-BBS20), when mutated, lead to defective cilia and result in BBS [12,13]. Eight of the BBS proteins (BBS1, BBS2, BBS4, BBS5, BBS7,