RESUMO
Reduced expression of the plasma membrane citrate transporter INDY (acronym I'm Not Dead, Yet) extends life span in lower organisms. Deletion of the mammalian Indy (mIndy) gene in rodents improves metabolism via mechanisms akin to caloric restriction, known to lower blood pressure (BP) by sympathoadrenal inhibition. We hypothesized that mIndy deletion attenuates sympathoadrenal support of BP. Continuous arterial BP and heart rate (HR) were reduced in mINDY-KO mice. Concomitantly, urinary catecholamine content was lower, and the decreases in BP and HR by mIndy deletion were attenuated after autonomic ganglionic blockade. Catecholamine biosynthesis pathways were reduced in mINDY-KO adrenals using unbiased microarray analysis. Citrate, the main mINDY substrate, increased catecholamine content in pheochromocytoma cells, while pharmacological inhibition of citrate uptake blunted the effect. Our data suggest that deletion of mIndy reduces sympathoadrenal support of BP and HR by attenuating catecholamine biosynthesis. Deletion of mIndy recapitulates beneficial cardiovascular and metabolic responses to caloric restriction, making it an attractive therapeutic target.
Assuntos
Pressão Sanguínea/genética , Pressão Sanguínea/fisiologia , Transportadores de Ácidos Dicarboxílicos/genética , Transportadores de Ácidos Dicarboxílicos/fisiologia , Sistema Simpático-Suprarrenal/fisiologia , Simportadores/genética , Simportadores/fisiologia , Glândulas Suprarrenais/anatomia & histologia , Glândulas Suprarrenais/fisiologia , Animais , Restrição Calórica , Catecolaminas/biossíntese , Linhagem Celular , Células Cromafins/fisiologia , Transportadores de Ácidos Dicarboxílicos/deficiência , Expressão Gênica , Frequência Cardíaca/genética , Frequência Cardíaca/fisiologia , Longevidade/genética , Longevidade/fisiologia , Malatos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Cardiovasculares , Atividade Motora/genética , Atividade Motora/fisiologia , Piridinas/farmacologia , Simportadores/deficiênciaRESUMO
OBJECTIVE: Adiponectin encoded by the ADIPOQ gene modulates insulin sensitivity and glucose homeostasis. The aim of the current study was to investigate whether ADIPOQ gene variants in the promoter region predict adiponectin levels and type 2 diabetes progression. RESEARCH DESIGN AND METHODS: A total of 550 subjects with increased risk of type 2 diabetes were investigated; they underwent a 75-g oral glucose tolerance test, repeated after 3 years. Adiponectin levels were analyzed, and two ADIPOQ promoter variant single nucleotide polymorphisms, -11391G>A and -11377C>G, were genotyped. RESULTS: Tertiles of the adjusted adiponectin levels were associated with single nucleotide polymorphism -11391G>A and -11377C>G haplotypes (P < 0.0001). Carriers of the intermediate/high-level haplotype combination showed a bisected diabetes risk at the 3-year follow-up and were characterized by a "regression" of glucose tolerance. Evolution of disease status correlates with preexisting low adiponectin levels at inclusion rather than with variation in adiponectin levels. CONCLUSIONS: We present data that gene variants in the ADIPOQ promoter region are associated with variations in adiponectin levels and thus with future type 2 diabetes and disease progression.