Peripheral administration of nesfatin-1 reduces food intake in mice: the leptin-independent mechanism.
Nesfatin-1 is a novel satiety molecule in the hypothalamus and is also present in peripheral tissues. Here we sought to identify the active segment of nesfatin-1 and to determine the mechanisms of its action after peripheral administration in mice. Intraperitoneal injection of nesfatin-1 suppressed food intake in a dose-dependent manner. Nesfatin-1 has three distinct segments; we tested the effect of each segment on food intake. Injection of the midsegment decreased food intake under leptin-resistant conditions such as db/db mice and mice fed a high-fat diet. After injection of the midsegment, expression of c-Fos was significantly activated in the brainstem nucleus tractus solitarius (NTS) but not in the hypothalamic arcuate nucleus; the nicotinic cholinergic pathway to the NTS contributed to midsegment-induced anorexia. Midsegment injection significantly increased expression of proopiomelanocortin and cocaine- and amphetamine-regulated transcript genes in the NTS but not in the arcuate nucleus. Investigation of mutant midsegments demonstrated that a region with amino acid sequence similarity to the active site of agouti-related peptide was indispensable for anorexigenic induction. Our findings indicate that the midsegment of nesfatin-1 causes anorexia, possibly by activating POMC and CART neurons in the NTS via a leptin-independent mechanism after peripheral stimulation.
Shimizu
H
H
Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Japan. hshimizu@showa.gunma-u.ac.jp
Oh-I
S
S
Hashimoto
K
K
Nakata
M
M
Yamamoto
S
S
Yoshida
N
N
Eguchi
H
H
Kato
I
I
Inoue
K
K
Satoh
T
T
Okada
S
S
Yamada
M
M
Yada
T
T
Mori
M
M
D000818:Animals; D000855:Anorexia / Q000139:chemically induced; D001111:Arcuate Nucleus of Hypothalamus / Q000187:drug effects / Q000378:metabolism; D002135:Calcium-Binding Proteins; D003213:Conditioning, Psychological / Q000187:drug effects; D004268:DNA-Binding Proteins; D003921:Diabetes Mellitus, Experimental / Q000473:pathology / Q000503:physiopathology; D015536:Down-Regulation / Q000187:drug effects; D004435:Eating / Q000187:drug effects* / Q000502:physiology; D007274:Injections, Intraperitoneal; D020738:Leptin / Q000502:physiology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009419:Nerve Tissue Proteins / Q000008:administration & dosage* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000080866:Nucleobindins; D011333:Pro-Opiomelanocortin / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000502:physiology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D017552:Solitary Nucleus / Q000187:drug effects / Q000378:metabolism; D013649:Taste / Q000187:drug effects; D000098882:Cocaine- and Amphetamine-Regulated Transcript Protein
D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; D020738:Leptin; D009419:Nerve Tissue Proteins; C000630651:Nucb1 protein, mouse; D000080866:Nucleobindins; D016760:Proto-Oncogene Proteins c-fos; D000098882:Cocaine- and Amphetamine-Regulated Transcript Protein; D011333:Pro-Opiomelanocortin