Rahmouni, K. et al. Leptin resistance contributes to obesity and hypertension in mouse models of Bardet-Biedl syndrome. J. Clin. Invest. 118, 1458-1467

Department of Internal Medicine, Center on Functional Genomics of Hypertension, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA.
Journal of Clinical Investigation (Impact Factor: 13.22). 05/2008; 118(4):1458-67. DOI: 10.1172/JCI32357
Source: PubMed


Bardet-Biedl syndrome (BBS) is a heterogeneous genetic disorder characterized by many features, including obesity and cardiovascular disease. We previously developed knockout mouse models of 3 BBS genes: BBS2, BBS4, and BBS6. To dissect the mechanisms involved in the metabolic disorders associated with BBS, we assessed the development of obesity in these mouse models and found that BBS-null mice were hyperphagic, had low locomotor activity, and had elevated circulating levels of the hormone leptin. The effect of exogenous leptin on body weight and food intake was attenuated in BBS mice, which suggests that leptin resistance may contribute to hyperleptinemia. In other mouse models of obesity, leptin resistance may be selective rather than systemic; although mice became resistant to leptin's anorectic effects, the ability to increase renal sympathetic nerve activity (SNA) was preserved. Although all 3 of the BBS mouse models were similarly resistant to leptin, the sensitivity of renal SNA to leptin was maintained in Bbs4 -/- and Bbs6 -/- mice, but not in Bbs2 -/- mice. Consequently, Bbs4 -/- and Bbs6 -/- mice had higher baseline renal SNA and arterial pressure and a greater reduction in arterial pressure in response to ganglionic blockade. Furthermore, we found that BBS mice had a decreased hypothalamic expression of proopiomelanocortin, which suggests that BBS genes play an important role in maintaining leptin sensitivity in proopiomelanocortin neurons.

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    • "The hyperphagic childhood obesity associated with loss of BDNF expression or loss of TrkB is highly reminiscent of that seen in BBS and other obesity ciliopathies [19], [31]. Given that evidence implicating a direct causal role for other anorexigenic signals, such as leptin, is conflicting [32], [33], it is possible that perturbation of satiety signals or of neurogenesis induced by BDNF in the hypothalamus may offer an alternate or additional explanation for the increased food intake and weight gain in BBS. Much attention has focused on the putative role of CART/POMC neurons in the arcuate nucleus of the hypothalamus, for example, but there is little evidence to suggest a role for BDNF in the activity of these neurons [14], [34]. "
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    ABSTRACT: Primary cilia regulate an expanding list of signaling pathways in many different cell types. It is likely that identification of the full catalog of pathways associated with cilia will be necessary to fully understand their role in regulation of signaling and the implications for diseases associated with their dysfunction, ciliopathies. Bardet-Biedl Syndrome (BBS) is one such ciliopathy which is characterized by a spectrum of phenotypes. These include neural defects such as impaired cognitive development, centrally mediated hyperphagia and peripheral sensory defects. Here we investigate potential defects in a signaling pathway associated with neuronal function, brain derived neurotrophic factor (BDNF) signaling. Upon loss of BBS4 expression in cultured cells, we observed decreased phosphorylation and activation by BDNF of its target receptor, TrkB. Assessment of ciliary localization revealed that, TrkB localized to the axonemes or basal bodies of cilia only in the presence of BDNF. Axonemal localization, specifically, was abrogated with loss of BBS4. Finally, we present evidence that loss of the ciliary axoneme through depletion of KIF3A impedes activation of TrkB. Taken together, these data suggest the possibility of a previously uninvestigated pathway associated with perturbation of ciliary proteins.
    Full-text · Article · May 2014 · PLoS ONE
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    • "signaling leading to leptin resistance (Rahmouni et al., 2008), because obesity occurs despite elevations in leptin, a satiety signal, and because loss of cilia specifically in leptin-responsive proopiomelanocortin (POMC) neurons results in obesity (Davenport et al., 2007). Bbs1 interacts with the leptin receptor and mediates its trafficking, and mice lacking Bbs2, Bbs4, and Bbs6 also present leptin resistance, failing to reduce food intake in response to leptin (Seo et al., 2009) (Figure 3). "
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    ABSTRACT: Primary cilia were the largely neglected nonmotile counterparts of their better-known cousin, the motile cilia. For years these nonmotile cilia were considered evolutionary remnants of little consequence to cellular function. Fast forward 10 years and we now recognize primary cilia as key integrators of extracellular ligand-based signaling and cellular polarity, which regulate neuronal cell fate, migration, differentiation, as well as a host of adult behaviors. Important future questions will focus on structure-function relationships, their roles in signaling and disease and as areas of target for treatments.
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    • "A considerable body of literature supports the conclusion that deletions or mutations of BBS genes in the mouse genome produce animals with symptoms similar to the human disease phenotype. Early studies demonstrated that knock-out mice lacking either the Bbs2 or Bbs4 genes express many of the major symptoms of BBS [15]–[19]. Although there are variations in the expression of secondary symptoms of the human disorder in these Bbs-/- animals (e.g., hypertension; [19]), the core symptoms of the disease largely mimic those observed in the human disease. "
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    ABSTRACT: Bardet-Biedl syndrome (BBS) is a genetically heterogeneous inherited human disorder displaying a pleotropic phenotype. Many of the symptoms characterized in the human disease have been reproduced in animal models carrying deletions or knock-in mutations of genes causal for the disorder. Thinning of the cerebral cortex, enlargement of the lateral and third ventricles, and structural changes in cilia are among the pathologies documented in these animal models. Ciliopathy is of particular interest in light of recent studies that have implicated primary neuronal cilia (PNC) in neuronal signal transduction. In the present investigation, we tested the hypothesis that areas of the brain responsible for learning and memory formation would differentially exhibit PNC abnormalities in animals carrying a deletion of the Bbs4 gene (Bbs4-/-). Immunohistochemical localization of adenylyl cyclase-III (ACIII), a marker restricted to PNC, revealed dramatic alterations in PNC morphology and a statistically significant reduction in number of immunopositive cilia in the hippocampus and amygdala of Bbs4-/- mice compared to wild type (WT) littermates. Western blot analysis confirmed the decrease of ACIII levels in the hippocampus and amygdala of Bbs4-/- mice, and electron microscopy demonstrated pathological alterations of PNC in the hippocampus and amygdala. Importantly, no neuronal loss was found within the subregions of amygdala and hippocampus sampled in Bbs4-/- mice and there were no statistically significant alterations of ACIII immunopositive cilia in other areas of the brain not known to contribute to the BBS phenotype. Considered with data documenting a role of cilia in signal transduction these findings support the conclusion that alterations in cilia structure or neurochemical phenotypes may contribute to the cognitive deficits observed in the Bbs4-/- mouse mode.
    Full-text · Article · Apr 2014 · PLoS ONE
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