Peripheral administration of nesfatin-1 reduces food intake in mice: the leptin-independent mechanism

Endocrinology. 2009 Feb;150(2):662-71. doi: 10.1210/en.2008-0598. Epub 2008 Oct 16.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anorexia / chemically induced
  • Arcuate Nucleus of Hypothalamus / drug effects
  • Arcuate Nucleus of Hypothalamus / metabolism
  • Calcium-Binding Proteins
  • Conditioning, Psychological / drug effects
  • DNA-Binding Proteins
  • Diabetes Mellitus, Experimental / pathology
  • Diabetes Mellitus, Experimental / physiopathology
  • Down-Regulation / drug effects
  • Eating / drug effects*
  • Eating / physiology
  • Injections, Intraperitoneal
  • Leptin / physiology*
  • Male
  • Mice
  • Mice, Inbred ICR
  • Nerve Tissue Proteins / administration & dosage*
  • Nerve Tissue Proteins / chemistry
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Nucleobindins
  • Pro-Opiomelanocortin / genetics
  • Pro-Opiomelanocortin / metabolism
  • Protein Structure, Tertiary / physiology
  • Proto-Oncogene Proteins c-fos / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Signal Transduction / physiology
  • Solitary Nucleus / drug effects
  • Solitary Nucleus / metabolism
  • Taste / drug effects

Substances

  • Calcium-Binding Proteins
  • DNA-Binding Proteins
  • Leptin
  • Nerve Tissue Proteins
  • Nucb1 protein, mouse
  • Nucleobindins
  • Proto-Oncogene Proteins c-fos
  • cocaine- and amphetamine-regulated transcript protein
  • Pro-Opiomelanocortin