Selective stimulatory actions of corticotropin-releasing factor ligands on correlates of energy balance.
Acute administration of corticotropin-releasing factor (CRF) results in anorexic and sympathomimetic effects that suggest efficacy in chronic models of energy balance. The present studies employed a broad spectrum energy balance indices in lean and genetically obese Zucker rats in order to fully characterize the pharmacological efficacy of CRF and a CRF binding protein (CRF-BP) ligand inhibitor, CRF(6-33), which is thought to liberate CRF from CRF-BP. Acute administration of CRF(6-33) significantly increased CRF(2) receptor density by 10% within the ventromedial hypothalamic (VMH) nucleus of Zucker lean rats and decreased density by 10% in Zucker obese rats. A single infusion of CRF(6-33) increased nonshivering thermogenesis by 25-30% as measured by proton conductance in brown adipose tissue of both lean and obese rats. Chronic CRF(6-33) infusion suppressed body weight gain and elevated core temperature irrespective of genotype while increasing motor activity in obese rats without altering heart rate or blood pressure. Taken together, these results document strain-dependent, long-term effects of a CRF-BP ligand inhibitor on a select subset of physiological and behavioral measures of increased energy expenditure.
Heinrichs
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SC
Neurocrine Biosciences, Inc., 10555 Science Center Drive, San Diego, CA 92121, USA. stephen.heinrichs@bc.edu
Joppa
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Lapsansky
J
J
Jeske
K
K
Nelson
R
R
De Souza
E
E
D002001:Adipose Tissue, Brown / Q000187:drug effects; D000324:Adrenocorticotropic Hormone / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001345:Autoradiography; D001831:Body Temperature / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects / Q000502:physiology; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D002940:Circadian Rhythm / Q000187:drug effects; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism / Q000502:physiology*; D004734:Energy Metabolism / Q000187:drug effects*; D006153:Guanosine Diphosphate / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects; D007276:Injections, Intraventricular; D008024:Ligands; D008297:Male; D051381:Rats; D011924:Rats, Zucker; D013686:Telemetry; D022722:Thermogenesis / Q000187:drug effects; D015430:Weight Gain / Q000187:drug effects
D002352:Carrier Proteins; D008024:Ligands; C067133:corticotropin releasing factor-binding protein; D006153:Guanosine Diphosphate; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone