Reducing hypothalamic AGRP by RNA interference increases metabolic rate and decreases body weight without influencing food intake.
BACKGROUND
Several lines of evidence strongly suggest that agouti-related peptide (AGRP) plays a key role in the regulation of metabolic function but ablation of the AGRP gene has no apparent effect on metabolic function. Since specific pharmacological antagonists of AGRP do not presently exist, we assessed if reduction of hypothalamic AGRP mRNA by RNA interference (RNAI) would influence metabolic function, an outcome suggesting that pharmacological antagonists might constitute useful reagents to treat obesity.


RESULTS
The RNAI protocol specifically reduced hypothalamic expression of AGRP mRNA by 50% and resulted in reduction of AGRP peptide immunoreactivity. Physiologically, the reduction in AGRP levels was associated with increased metabolic rate and reduced body weight without changes in food intake.


CONCLUSIONS
AGRP can function to increase body weight and reduce metabolic rate without influencing food intake. The present study demonstrates that RNAI protocols can be used to assess physiological function of neuronal genes in vivo.
Makimura
Hideo
H
Fishberg Center for Neurobiology, Neurobiology of Aging Laboratories, Mount Sinai School of Medicine, One Gustave L, Levy Place, Box 1639, New York, New York 10029, USA. Hideo.Makimura@mssm.edu
Mizuno
Tooru M
TM
Mastaitis
Jason W
JW
Agami
Reuven
R
Mobbs
Charles V
CV
D054369:Agouti-Related Protein; D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000187:drug effects / Q000378:metabolism; D001481:Basal Metabolism / Q000187:drug effects / Q000502:physiology*; D001835:Body Weight / Q000187:drug effects / Q000502:physiology*; D002153:Calorimetry, Indirect; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D004435:Eating / Q000187:drug effects; D049452:Green Fluorescent Proteins; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins; D008164:Luminescent Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D010101:Oxygen Consumption / Q000187:drug effects / Q000502:physiology; D011506:Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology*
D054369:Agouti-Related Protein; D036341:Intercellular Signaling Peptides and Proteins; D008164:Luminescent Proteins; D011506:Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D049452:Green Fluorescent Proteins