Activation of thermogenesis in brown adipose tissue and dysregulated lipid metabolism associated with cancer cachexia in mice.
Cancer cachexia/anorexia is a complex syndrome that involves profound metabolic imbalances and is directly implicated as a cause of death in at least 20% to 30% of all cancers. Brown adipose tissue (BAT) plays a key role in thermogenesis and energy balance and potentially contributes to the physiologic perturbations associated with cachexia. In this study, we investigated the impact of cachexia-inducing colorectal tumor on BAT in mice. We found that brown adipocytes were smaller and exhibited profound delipidation in cachectic tumor-bearing mice. Diurnal expression profiling of key regulators of lipid accumulation and fatty acid β-oxidation and their corresponding target genes revealed dramatic molecular changes indicative of active BAT. Increased Ucp1, Pbe, and Cpt1α expression at specific points coincided with higher BAT temperatures during the dark cycle, suggestive of a temporal stimulation of thermogenesis in cachexia. These changes persisted when cachectic mice were acclimatized to 28°C confirming inappropriate stimulation of BAT despite thermoneutrality. Evidence of inflammatory signaling also was observed in the BAT as an energetically wasteful and maladaptive response to anorexia during the development of cachexia.
Cancer Pharmacology Unit, Centre for Education and Research on Ageing, ANZAC Research Institute, Concord, Australia.
Maria
M
Tsoli
Melissa
M
Moore
Dominic
D
Burg
Arran
A
Painter
Ryland
R
Taylor
Sarah H
SH
Lockie
Nigel
N
Turner
Alessandra
A
Warren
Greg
G
Cooney
Brian
B
Oldfield
Stephen
S
Clarke
Graham
G
Robertson
D000230:Adenocarcinoma / Q000378:metabolism; D002001:Adipose Tissue, Brown / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001835:Body Weight; D002100:Cachexia / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism; D004435:Eating; D004734:Energy Metabolism; D020869:Gene Expression Profiling; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics; D008297:Male; D051379:Mice; D009369:Neoplasms / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D009929:Organ Size; D015398:Signal Transduction; D013696:Temperature; D022722:Thermogenesis / Q000235:genetics
D016207:Cytokines