Cancer-induced Anorexia and Malaise Are Mediated by CGRP Neurons in the Parabrachial Nucleus

Nat Neurosci. 2017 Jul;20(7):934-942. doi: 10.1038/nn.4574. Epub 2017 Jun 5.

Abstract

Anorexia is a common manifestation of chronic diseases, including cancer. Here we investigate the contribution to cancer anorexia made by calcitonin gene-related peptide (CGRP) neurons in the parabrachial nucleus (PBN) that transmit anorexic signals. We show that CGRPPBN neurons are activated in mice implanted with Lewis lung carcinoma cells. Inactivation of CGRPPBN neurons before tumor implantation prevents anorexia and loss of lean mass, and their inhibition after symptom onset reverses anorexia. CGRPPBN neurons are also activated in Apcmin/+ mice, which develop intestinal cancer and lose weight despite the absence of reduced food intake. Inactivation of CGRPPBN neurons in Apcmin/+ mice permits hyperphagia that counteracts weight loss, revealing a role for these neurons in a 'nonanorexic' cancer model. We also demonstrate that inactivation of CGRPPBN neurons prevents lethargy, anxiety and malaise associated with cancer. These findings establish CGRPPBN neurons as key mediators of cancer-induced appetite suppression and associated behavioral changes.

MeSH terms

  • Adenomatous Polyposis Coli Protein / genetics
  • Animals
  • Anorexia / physiopathology*
  • Behavior, Animal / physiology
  • Body Weight
  • Cachexia / physiopathology
  • Calcitonin Gene-Related Peptide / antagonists & inhibitors
  • Calcitonin Gene-Related Peptide / genetics
  • Calcitonin Gene-Related Peptide / physiology*
  • Carcinoma, Lewis Lung / physiopathology*
  • Clozapine / analogs & derivatives
  • Clozapine / pharmacology
  • Energy Metabolism / physiology
  • Female
  • Illness Behavior / physiology*
  • Male
  • Metalloendopeptidases / pharmacology
  • Mice
  • Mice, Transgenic
  • Neoplasms / physiopathology*
  • Parabrachial Nucleus / drug effects
  • Parabrachial Nucleus / physiology*
  • Tetanus Toxin / pharmacology
  • Tumor Cells, Cultured / transplantation

Substances

  • Adenomatous Polyposis Coli Protein
  • Calca protein, mouse
  • Tetanus Toxin
  • adenomatous polyposis coli protein, mouse
  • Metalloendopeptidases
  • zinc-endopeptidase, tetanus neurotoxin
  • Clozapine
  • Calcitonin Gene-Related Peptide
  • clozapine N-oxide