A role for arcuate cocaine and amphetamine-regulated transcript in hyperphagia, thermogenesis, and cold adaptation.
We have recently shown that injection of the hypothalamic peptide cocaine and amphetamine regulated transcript (CART) into discrete hypothalamic nuclei stimulates food intake. This stimulation was particularly marked in the arcuate nucleus. Here we show that twice daily intra-arcuate injection of 0.2 nmole CART peptide for 7 days was associated with a 60% higher daytime food intake, an 85% higher thermogenic response to the beta3 agonist BRL 35135, and a 60% increase in brown adipose tissue UCP-1 mRNA. In a separate study, using stereotactically targeted gene transfer, a CART transgene was delivered by using polyethylenimine to the arcuate nucleus of adult rats. Food intake was increased significantly during ad libitum feeding and following periods of food withdrawal and food restriction in CART over-expressing animals. CART over-expressing animals lost 12% more weight than controls following a 24-h fast. Brown adipose tissue uncoupling protein-1 (UCP-1) mRNA levels (collected Day 25) were 80% higher in CART over-expressing animals. Finally, by using quantitative in situ hybridization, we found that chronic cold exposure (20 days at 4oC) increased arcuate nucleus CART mRNA by 124%. Together with the orexigenic and thermogenic effects of CART, this finding suggests a role for arcuate nucleus CART in cold adaptation.
Kong
Wing  May
W
Department of Metabolic Medicine, Division of Investigative Sciences, Hammersmith Campus, Faculty of Medicine, Imperial College School of Science, Technology and Medicine, London, UK. w.kong@imperial.ac.uk
Stanley
Sarah
S
Gardiner
James
J
Abbott
Caroline
C
Murphy
Kevin
K
Seth
Asha
A
Connoley
Ian
I
Ghatei
Mohammed
M
Stephens
David
D
Bloom
Stephen
S
D000222:Adaptation, Physiological; D002001:Adipose Tissue, Brown / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000187:drug effects / Q000502:physiology*; D002352:Carrier Proteins / Q000378:metabolism; D003080:Cold Temperature; D004435:Eating / Q000187:drug effects; D006963:Hyperphagia / Q000139:chemically induced / Q000209:etiology*; D007031:Hypothalamus / Q000378:metabolism; D007267:Injections; D007473:Ion Channels; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D024101:Mitochondrial Proteins; D008959:Models, Neurological; D009419:Nerve Tissue Proteins / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D022722:Thermogenesis; D013972:Thyrotropin / Q000097:blood; D000071256:Uncoupling Protein 1; D000098882:Cocaine- and Amphetamine-Regulated Transcript Protein
D002352:Carrier Proteins; D007473:Ion Channels; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; C000604373:Ucp1 protein, rat; D000071256:Uncoupling Protein 1; D000098882:Cocaine- and Amphetamine-Regulated Transcript Protein; D013972:Thyrotropin