Bardet-Biedl syndrome (BBS) is an autosomal, recessive, heterogeneous human disorder characterized by a pleiotropic phenotype including eariy onset obesity, hypertension and cardiovascular disease. Although BBS is a rare Mendelian disorder, identifying the underiying mechanisms of the phenotypes associated with this syndrome has garnered great interest because the pathophysiology of the phenotypes such as obesity and hypertension in BBS may yield clues to understanding common human obesity and hypertension. Our preliminary data obtained using a series of novel mouse models that phenocopy human BBS point to the importance of the neurogenic mechanisms for the metabolic and cardiovascular dysregulations associated with BBS. Indeed, we identified an intrinsic hypothalamic leptin resistance as a major cause of energy imbalance and obesity in BBS. Our data also indicate that neural mechanisms play a major pathophysiological role in the hypertension associated with deletion of Bbs genes in mice. More recently, we found that CNS deletion of Bbsl gene (using a novel conditional Bbsl flox/flox mouse model) recapitulates the obesity phenotype associated with BBS highlighting the importance of Bbs genes in the central nervous for energy homeostasis. Moreover, Bbs-deficiency causes defects in ER stress and activation of the renin-angiotensin system in the brain. Based on these findings, we hypothesize that Bbs genes in the central nervous system are critical for energy homeostasis and the autonomic regulation of arterial pressure. We plan to test our central hypothesis by pursuing the following 3 hypotheses: 1) Neuronal BBS proteins are important for metabolic and cardiovascular regulation, and disruption of the Bbsl gene in specific neuronal populations alters energy homeostasis, autonomic function and arterial pressure;2) Defects in the brain BBSome, receptor trafficking, ER stress, and the brain renin-angiotensin system are critically involved in the metabolic, autonomic and arterial pressure alterations associated with BBS;and 3) Haploinsufficiency of Bbs genes increases susceptibility to obesity, autonomic dysfunction and hypertension.
These studies are significant because they will provide important insight into the role of neuronal Bbs genes and identify new fundamental mechanisms underiying the regulation of metabolic and cardiovascular functions by Bbs genes in the central nervous system. The novel information gained from these studies will have potential implications for the management of obesity and associated cardiovascular disorders in BBS as well as in common human obesity.
|Contreras, Cristina; González-García, Ismael; Martínez-Sánchez, Noelia et al. (2014) Central ceramide-induced hypothalamic lipotoxicity and ER stress regulate energy balance. Cell Rep 9:366-77|
|Borges, Giulianna R; Morgan, Donald A; Ketsawatsomkron, Pimonrat et al. (2014) Interference with peroxisome proliferator-activated receptor-? in vascular smooth muscle causes baroreflex impairment and autonomic dysfunction. Hypertension 64:590-6|
|Li, Wencheng; Peng, Hua; Mehaffey, Eamonn P et al. (2014) Neuron-specific (pro)renin receptor knockout prevents the development of salt-sensitive hypertension. Hypertension 63:316-23|
|Rahmouni, Kamal (2014) Obesity-associated hypertension: recent progress in deciphering the pathogenesis. Hypertension 64:215-21|
|Sones, Jenny L; Lob, Heinrich E; Isroff, Catherine E et al. (2014) Role of decidual natural killer cells, interleukin-15, and interferon-? in placental development and preeclampsia. Am J Physiol Regul Integr Comp Physiol 307:R490-2|
|Coble, Jeffrey P; Johnson, Ralph F; Cassell, Martin D et al. (2014) Activity of protein kinase C-? within the subfornical organ is necessary for fluid intake in response to brain angiotensin. Hypertension 64:141-8|
|Ramkumar, Nirupama; Stuart, Deborah; Rees, Sara et al. (2014) Collecting duct-specific knockout of renin attenuates angiotensin II-induced hypertension. Am J Physiol Renal Physiol 307:F931-8|
|Owen, Bryn M; Ding, Xunshan; Morgan, Donald A et al. (2014) FGF21 acts centrally to induce sympathetic nerve activity, energy expenditure, and weight loss. Cell Metab 20:670-7|
|Grobe, Justin L; Sigmund, Curt D (2014) Another reason to eat your greens: cardiopulmonary protection by dietary delivery of angiotensin-converting enzyme-2 and angiotensin-(1-7) made in plants. Hypertension 64:1182-3|
|Shi, Peng; Grobe, Justin L; Desland, Fiona A et al. (2014) Direct pro-inflammatory effects of prorenin on microglia. PLoS One 9:e92937|
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