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.
Greene
Michael
M
National Cardiac PET Centre, Division of Cardiology, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, ON K1Y4W7, Canada; and Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada.
Thackeray
James T
JT
Kenk
Miran
M
Thorn
Stephanie L
SL
Bevilacqua
Lisa
L
Harper
Mary-Ellen
ME
Beanlands
Rob S
RS
Dasilva
Jean N
JN
D000818:Animals; D002153:Calorimetry, Indirect; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000502:physiology*; D003891:Desipramine / Q000494:pharmacology; D004041:Dietary Fats / Q000008:administration & dosage; D008297:Male; D009638:Norepinephrine / Q000494:pharmacology*; D009765:Obesity / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020889:Rolipram / Q000378:metabolism; D015398:Signal Transduction; D013564:Sympathetic Nervous System / Q000502:physiology
D004041:Dietary Fats; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram; D003891:Desipramine; D009638:Norepinephrine