Reduced in vivo phosphodiesterase-4 response to acute noradrenaline challenge in diet-induced obese rats

Altered sympathetic nervous activity has been linked to the development and persistence of obesity, partly relating to overfeeding. Binding of the selective, positron-emitting phosphodiesterase-4 (PDE4) inhibitor (R)-[[sup.11]C]rolipram provides a direct index of the CAMP-hydrolyzing enzyme PDE4. This study examines progressive alterations in PDE4 in a high-fat-fed obese animal model. (R)-[[sup.11]C]Rolipram was injected into diet-induced obese (DIO) and diet-resistant (DR) rats; the animals were killed after 45 min, tissues were extracted, and radioactivity was quantified. Responsiveness of PDE4 to acute noradrenaline (NA) stimulation was determined by 3 h pretreatment with the NA reuptake inhibitor desipramine. There was minimal variance in caloric intake, weight gain, fasting glucose, insulin, and energy expenditure (indirect calorimetry) measures. Basal (R)-[[sup.11]C]rolipram binding was comparable between DIO and DR rats at 2 or 8 weeks of feeding. The normal increase of PDE4 levels in response to elevated NA by desipramine pretreatment was ablated in PDE4-rich tissues, including brain, heart, and skeletal muscle, of DIO animals after 8 weeks of high-fat diet. Lean DR rats maintained PDE4 responsiveness indicative of a normal NA signal transduction. Key words: diet-induced thermogenesis, sympathetic nervous system, noradrenergic signaling, (R)-[[sup.11]C]rolipram, positron emission tomography, high-fat diet, obesity. Une modification de l'activite nerveuse sympathique a ete liee au developpement et au maintien de l'obesite, decoulant en partie d'une suralimentation. La fixation de l'inhibiteur selectif de la phosphodiesterase-4 (PDE4) emetteur de positons, (R)-[[sup.11]C]rolipram, fournit un indice direct de l'enzyme PDE4 hydrolysant l'AMPc. La presente etude examine les modifications progressives de la PDE4 dans un modele animal obese soumis a une diete hyperlipidique. On a injecte le (R)-[[sup.11]C]rolipram a des rats rendus obeses par la diete (OD) et a des rats resistants a la diete (RD), sacrifie les animaux apres 45 min, extrait les tissus et quantifie la radioactivite. On a determine la reactivite de la PDE4 a une stimulation aigue induite par la noradrenaline (NA), 3 h apres un pretraitement avec l'inhibiteur de recapture de NA, desipramine. On a observe une variance minimale dans les mesures de l'apport calorique, de gain corporel, de glucose a jeun, d'insuline et de depense energetique (calorimetrie indirecte). La retention basale de (R)-[[sup.11]C]rolipram a ete comparable chez les rats OD et RD apres 2 ou 8 semaines de diete. L'augmentation normale des taux de PDE4 en reponse a l'augmentation de NA par le pretraitement a la desipramine a ete supprimee dans les tissus riches en PDE4, dont le cerveau, le coeur et le muscle squelettique, des animaux OD apres 8 semaines de diete hyperlipidique. Les rats RD maigres ont maintenu une reactivite de la PDE4 indiquant une transduction de signal normale par la NA. Mots-cles : thermogenese induite par la diete, systeme nerveux sympathique, signalisation noradrenergique, (R)-[[sup.11]C]rolipram, tomographie d'emission de positons, diete hyperlipidique, obesite. [Traduit par la Redaction]
Introduction Obesity confers elevated risk for several comorbidities, including type 2 diabetes mellitus, hypertension, and cardiovascular disease (Kannel et al. 1967; Poirier et al. 2006). The sympathetic nervous system (SNS) [...]