A central role for neuronal adenosine 5'-monophosphate-activated protein kinase in cancer-induced anorexia.
The pathogenesis of cancer anorexia is multifactorial and associated with disturbances of the central physiological mechanisms controlling food intake. However, the neurochemical mechanisms responsible for cancer-induced anorexia are unclear. Here we show that chronic infusion of 5-amino-4imidazolecarboxamide-riboside into the third cerebral ventricle and a chronic peripheral injection of 2 deoxy-d-glucose promotes hypothalamic AMP-activated protein kinase (AMPK) activation, increases food intake, and prolongs the survival of anorexic tumor-bearing (TB) rats. In parallel, the pharmacological activation of hypothalamic AMPK in TB animals markedly reduced the hypothalamic production of inducible nitric oxide synthase, IL-1beta, and TNF-alpha and modulated the expression of proopiomelanocortin, a hypothalamic neuropeptide that is involved in the control of energy homeostasis. Furthermore, the daily oral and intracerebroventricular treatment with biguanide antidiabetic drug metformin also induced AMPK phosphorylation in the central nervous system and increased food intake and life span in anorexic TB rats. Collectively, the findings of this study suggest that hypothalamic AMPK activation reverses cancer anorexia by inhibiting the production of proinflammatory molecules and controlling the neuropeptide expression in the hypothalamus, reflecting in a prolonged life span in TB rats. Thus, our data indicate that hypothalamic AMPK activation presents an attractive opportunity for the treatment of cancer-induced anorexia.
Ropelle
Eduardo R
ER
Department of Internal Medicine, FCM, State University of Campinas-UNICAMP, 13083-970 Campinas, São Paulo, Brazil.
Pauli
José R
JR
Zecchin
Karina G
KG
Ueno
Mirian
M
de Souza
Cláudio T
CT
Morari
Joseane
J
Faria
Marcel C
MC
Velloso
Lício A
LA
Saad
Mario J A
MJ
Carvalheira
José B C
JB
D055372:AMP-Activated Protein Kinases; D000620:Aminoimidazole Carboxamide / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000855:Anorexia / Q000201:enzymology / Q000209:etiology*; D003847:Deoxyglucose / Q000008:administration & dosage / Q000494:pharmacology; D004333:Drug Administration Routes; D007031:Hypothalamus / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008687:Metformin / Q000008:administration & dosage / Q000494:pharmacology; D009097:Multienzyme Complexes / Q000378:metabolism / Q000502:physiology*; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000150:complications* / Q000201:enzymology / Q000401:mortality / Q000473:pathology; D009474:Neurons / Q000201:enzymology / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D012265:Ribonucleotides / Q000008:administration & dosage / Q000494:pharmacology; D016019:Survival Analysis; D014407:Tumor Cells, Cultured
D009097:Multienzyme Complexes; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D008687:Metformin; D003847:Deoxyglucose; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide