RESUMO
An emerging number of rare genetic disorders termed ciliopathies are associated with pediatric obesity. It is becoming clear that the mechanisms associated with cilia dysfunction and obesity in these syndromes are complex. In addition to ciliopathic syndromic forms of obesity, several cilia-associated signaling gene mutations also lead to morbid obesity. While cilia have critical and diverse functions in energy homeostasis including their roles in centrally mediated food intake as well as in peripheral tissues, many questions remain. Here, we briefly discuss the syndromic ciliopathies and monoallelic cilia signaling gene mutations associated with obesity. We also describe potential ways cilia may be involved in common obesity. We discuss how neuronal cilia impact food intake potentially through leptin signaling and changes in ciliary G protein-coupled receptor (GPCR) signaling. We highlight several recent studies that have implicated the potential for cilia in peripheral tissues such as adipose and the pancreas to contribute to metabolic dysfunction. Then we discuss the potential for cilia to impact energy homeostasis through their roles in both development and adult tissue homeostasis. The studies discussed in this review highlight how a comprehensive understanding of the requirement of cilia for the regulation of diverse biological functions will contribute to our understanding of common forms of obesity.
Assuntos
Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Cílios/metabolismo , Ciliopatias/genética , Leptina/genética , Obesidade Mórbida/genética , Obesidade Infantil/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Adulto , Dioxigenase FTO Dependente de alfa-Cetoglutarato/metabolismo , Animais , Criança , Cílios/patologia , Ciliopatias/metabolismo , Ciliopatias/patologia , Ingestão de Alimentos/genética , Regulação da Expressão Gênica , Humanos , Hipotálamo/metabolismo , Hipotálamo/patologia , Leptina/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Obesidade Mórbida/metabolismo , Obesidade Mórbida/patologia , Pâncreas/metabolismo , Pâncreas/patologia , Obesidade Infantil/metabolismo , Obesidade Infantil/patologia , Transdução de SinaisRESUMO
Nephronophthisis is an autosomal recessive kidney disease with high genetic heterogeneity. Understanding the functions of the individual genes contributing to this disease is critical for delineating the pathomechanisms of this disorder. Here, we investigated kidney function of a novel gene associated with nephronophthisis, CEP164, coding a centriolar distal appendage protein, using a Cep164 knockout mouse model. Collecting duct-specific deletion of Cep164 abolished primary cilia from the collecting duct epithelium and led to rapid postnatal cyst growth in the kidneys. Cell cycle and biochemical studies revealed that tubular hyperproliferation is the primary mechanism that drives cystogenesis in the kidneys of these mice. Administration of roscovitine, a cell cycle inhibitor, blocked cyst growth in the cortical collecting ducts and preserved kidney parenchyma in Cep164 knockout mice. Thus, our findings provide evidence that therapeutic modulation of cell cycle activity can be an effective approach to prevent cyst progression in the kidney.