Cachexia in MAC16 adenocarcinoma: suppression of hunger despite normal regulation of leptin, insulin and hypothalamic neuropeptide Y.
Weight loss normally stimulates hunger, through mechanisms that include falls in circulating leptin and insulin, leading to stimulation of hypothalamic neuropeptide Y (NPY). Here, we investigated the leptin, insulin and NPY to clarify why hunger is suppressed in mice with severe cachexia due to the MAC16 adenocarcinoma. MAC16-bearing mice progressively lost weight (19% below controls) and fat (- 61%) over 16 days after tumour transplantation, while total food intake fell by 10%. Pair-fed mice showed less wasting, with final weight being 9% and fat mass 25% below controls. Plasma leptin fell by 85% in MAC16 and 51% in pair-fed mice, in proportion to loss of fat. Plasma insulin was also reduced by 49% in MAC16 and 53% in pair-fed groups. Hypothalamic leptin receptor (OB-Rb) mRNA was significantly increased in both MAC16 (+ 223%) and pair-fed (+192%) mice. Hypothalamic NPY mRNA was also significantly raised in MAC16 (+152%) and pair-fed (+ 99%) groups, showing negative correlations with plasma leptin and insulin, and a positive association with OB-Rb mRNA. In MAC16-induced cachexia, leptin production and hypothalamic OB-Rb and NPY expression are regulated appropriately in response to fat depletion. Therefore, suppression of hunger is probably due to tumour products that inhibit NPY transport or release, or that interfere with neuronal targets downstream of NPY.
Bing
C
C
Diabetes and Endocrinology Research Group, Department of Medicine, University of Liverpool, Liverpool, UK. bing@liverpool.ac.uk
Taylor
S
S
Tisdale
M J
MJ
Williams
G
G
D000230:Adenocarcinoma / Q000473:pathology* / Q000523:psychology*; D000273:Adipose Tissue / Q000473:pathology; D000818:Animals; D015152:Blotting, Northern; D002100:Cachexia / Q000473:pathology* / Q000523:psychology*; D002352:Carrier Proteins / Q000378:metabolism; D004435:Eating / Q000523:psychology; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D006815:Hunger / Q000502:physiology*; D007031:Hypothalamus / Q000502:physiology*; D007328:Insulin / Q000097:blood / Q000502:physiology*; D020738:Leptin / Q000097:blood / Q000235:genetics / Q000502:physiology*; D051379:Mice; D009368:Neoplasm Transplantation; D009478:Neuropeptide Y / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
D002352:Carrier Proteins; D007328:Insulin; D020738:Leptin; D009478:Neuropeptide Y; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; C515447:leptin receptor, mouse