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

Abstract

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.

Angiotensin AT1A receptors on leptin receptor–expressing cells control resting metabolism

“…Given the HFD results obtained above, we asked whether the RMR responses to DOCA-salt required AT 1A receptors expressed in LEPR-expressing cells and whether these cells also mediate the BP response. Control litterexpress a red fluorescent reporter after Cre-mediated recombination in LEPR-expressing cells (Lepr-Cre ROSA-stop flox -tdTomato) (12)(13)(14). We identified LEPR-and AT 1A -coexpressing cells by the colocalization of red and green fluorescence in the brain.…”

Hypothalamic Lipids: Key Regulators of Whole Body Energy Balance

“…Moreover, 2 decades after the discovery of leptin [84] , hypothalamic resistance to this hormone has been postulated as one of the main causes of obesity [85][86][87][88][89] . Indeed, several mechanisms -not necessarily exclusivehave been reported as originating leptin resistance: (1) alterations in the transport of leptin across the bloodbrain barrier [8,90] ; (2) decreased expression of the Rbleptin receptor isoform and/or increased expression of the short isoforms [91] ; (3) impaired leptin receptor trafficking to the plasma membrane [92] ; (4) impaired hypothalamic leptin receptor signalling [93] ; (5) hypothalamic inflammation [94,95] ; and (6) hypothalamic lipotoxicity and endoplasmic reticulum (ER) stress [94,[96][97][98][99] . In this sense, although it is clear that these mechanisms are involved, the molecular effector triggering them remains elusive.…”

Endospanin 1 Determines the Balance of Leptin-Regulated Hypothalamic Functions

“…The BBSome proteins BBS1 and BBS2 have been shown to interact with ObR and to control its trafficking, thus regulating energy homeostasis. In contrast to Endo1 which retains ObR inside, BBS1 transports ObR to the neuronal plasma membrane [66, 67]. The deletion of BBS1 specifically in ObRb-expressing neurons causes obesity in mice [66, 67].…”

“…In contrast to Endo1 which retains ObR inside, BBS1 transports ObR to the neuronal plasma membrane [66, 67]. The deletion of BBS1 specifically in ObRb-expressing neurons causes obesity in mice [66, 67]. The defective ObR trafficking would account for the obese phenotype seen in patients harboring mutations in BBS genes with BBS (Fig.…”