Hindbrain cocaine- and amphetamine-regulated transcript induces hypothermia mediated by GLP-1 receptors.
Cocaine- and amphetamine-regulated transcript (CART) peptides are widely distributed throughout the neuraxis, including regions associated with energy balance. CART's classification as a catabolic neuropeptide is based on its inhibitory effects on feeding, coexpression with arcuate nucleus proopiomelanocortin neurons, and on limited analysis of its energy expenditure effects. Here, we investigate whether (1) caudal brainstem delivery of CART produces energetic, cardiovascular, and glycemic effects, (2) forebrain-caudal brainstem neural communication is required for those effects, and (3) glucagon-like peptide-1 receptors (GLP-1Rs) contribute to the mediation of CART-induced effects. Core temperature (Tc), heart rate (HR), activity, and blood glucose were measured in rats injected fourth intracerebroventricularly with CART (0.1, 1.0, and 2.0 microg). Food was withheld during physiologic recording and returned for overnight measurement of intake and body weight. CART induced a long-lasting (>6 h) hypothermia: a 1.5 degrees C and 1.6 degrees C drop in Tc for the 1.0 and 2.0 microg doses. Hindbrain CART application reduced food intake and body weight and increased blood glucose levels; no change in HR or activity was observed. Supracollicular decerebration eliminated the hypothermic response observed in intact rats to hindbrain ventricular CART, suggesting that forebrain processing is required for hypothermia. Pretreatment with the GLP-1R antagonist (exendin-9-39) in control rats attenuated CART hypothermia and hypophagia, indicating that GLP-1R activation contributes to hypothermic and hypophagic effects of hindbrain CART, whereas CART-induced hyperglycemia was not altered by GLP-1R blockade. Data reveal a novel function of CART in temperature regulation and open possibilities for future studies on the clinical potential of the hypothermic effect.
Skibicka
Karolina P
KP
Graduate Group of Psychology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. skibicka@mail.med.upenn.edu
Alhadeff
Amber L
AL
Grill
Harvey J
HJ
D000818:Animals; D019540:Area Under Curve; D001831:Body Temperature / Q000187:drug effects; D002552:Cerebral Ventricles / Q000187:drug effects; D003655:Decerebrate State; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects; D005106:Exploratory Behavior / Q000187:drug effects; D000067757:Glucagon-Like Peptide-1 Receptor; D006339:Heart Rate / Q000187:drug effects; D007035:Hypothermia / Q000139:chemically induced*; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism* / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors / Q000502:physiology*; D012249:Rhombencephalon / Q000187:drug effects / Q000378:metabolism*; D017552:Solitary Nucleus / Q000187:drug effects; D013686:Telemetry / Q000379:methods; D000098882:Cocaine- and Amphetamine-Regulated Transcript Protein
C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D018027:Receptors, Glucagon; D000098882:Cocaine- and Amphetamine-Regulated Transcript Protein; C428723:cocaine- and amphetamine-regulated transcript protein (55-102); C083773:exendin (9-39)