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)-[11C]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)-[11C]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)-[11C]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.