Agrp neurons mediate Sirt1's action on the melanocortin system and energy balance: roles for Sirt1 in neuronal firing and synaptic plasticity.
Sirt1 has been associated with various effects of calorie restriction, including an increase in lifespan. Here we show in mice that a central regulatory component in energy metabolism, the hypothalamic melanocortin system, is affected by Sirt1, which promotes the activity and connectivity of this system resulting in negative energy balance. In adult mice, the pharmacological inhibition of brain Sirt1 activity decreased Agrp neuronal activity and the inhibitory tone on the anorexigenic POMC neurons, as measured by the number of synaptic inputs to these neurons. When a Sirt1 inhibitor (EX-527) was injected either peripherally (i.p., 10 mg/kg) or directly into the brain (i.c.v., 1.5 nmol/mouse), it decreased both food intake during the dark cycle and ghrelin-induced food intake. This effect on feeding is mediated by upstream melanocortin receptors, because the MC4R antagonist, SHU9119, reversed Sirt1's effect on food intake. This action of Sirt1 required an appropriate shift in the mitochondrial redox state: in the absence of such an adaptation enabled by the mitochondrial protein, UCP2, Sirt1-induced cellular and behavioral responses were impaired. In accordance with the pharmacological results, the selective knock-out of Sirt1 in hypothalamic Agrp neurons through the use of Cre-Lox technology decreased electric responses of Agrp neurons to ghrelin and decreased food intake, leading to decreased lean mass, fat mass, and body weight. The present data indicate that Sirt1 has a central mode of action by acting on the NPY/Agrp neurons to affect body metabolism.
Dietrich
Marcelo O
MO
Program on Cell and Neurobiology of Energy Metabolism, Section of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Antunes
Catiele
C
Geliang
Gan
G
Liu
Zhong-Wu
ZW
Borok
Erzsebet
E
Nie
Yongzhan
Y
Xu
Allison W
AW
Souza
Diogo O
DO
Gao
Qian
Q
Diano
Sabrina
S
Gao
Xiao-Bing
XB
Horvath
Tamas L
TL
D054369:Agouti-Related Protein / Q000096:biosynthesis / Q000502:physiology*; D000818:Animals; D002227:Carbazoles / Q000008:administration & dosage; D004338:Drug Combinations; D004435:Eating / Q000187:drug effects / Q000502:physiology; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology*; D005260:Female; D008297:Male; D053486:Melanocortins / Q000378:metabolism / Q000502:physiology*; D009074:Melanocyte-Stimulating Hormones / Q000008:administration & dosage; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D010084:Oxidation-Reduction / Q000187:drug effects; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000502:physiology*; D013569:Synapses / Q000187:drug effects / Q000502:physiology*; D055366:Synaptic Potentials / Q000187:drug effects / Q000502:physiology*
C550547:6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide; D054369:Agouti-Related Protein; C515199:Agrp protein, mouse; D002227:Carbazoles; D004338:Drug Combinations; D053486:Melanocortins; C103272:SHU 9119; D009074:Melanocyte-Stimulating Hormones; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
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