'Browning' of White Fat Drives Cancer-Related Cachexia

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'Browning' of White Fat Drives Cancer-Related Cachexia
'Browning' of White Fat Drives Cancer-Related Cachexia

The transformation of white fat to brown fat is a key, early step in the development of cancer-associated cachexia and early treatment with anti-inflammatory agents may slow its progression, according to the results of recent animal studies.1

White adipose tissue (WAT) and brown adipose tissue (BAT) have opposing physiological functions, where WAT is responsible for energy storage and BAT is responsible for energy dissipation as heat. The conversion of white fat to brown fat has been extensively studied in obesity and diabetes because it has the effect of ameliorating those conditions. In cancer, however, it contributes to early death.

“It is the first time that this phenomenon we might call ‘burning fat' has been associated with a negative effect,” said Erwin Wagner, PhD, director of the BBVA Foundation-CNIO Cancer Cell Biology Programme in Spain, where the research took place. “What we observe[d] is that the transformation of white fat into brown fat has severe consequences in the context of cancer.”

Cachexia, a wasting syndrome, occurs in most cases of advanced cancer and contributes to the death of as many as 20% of patients with cancer. It is characterized by loss of body weight, atrophy of adipose tissue and loss of muscle mass. No effective treatment for cachexia is currently available.

Until recently, cachexia was viewed as a state of “autocannibalism”, in which the tumor's demand for energy depleted fat and muscle stores. It is now seen as an inflammatory and neuroendocrine response that affects not only patients with cancer but also those with chronic cardiac, pulmonary, neurological and infectious diseases.

Changes in Adipose Tissue Precede Cachexia

Using genetically engineered mouse cancer models, the researchers determined that cachexia was an almost universal consequence of cancer. Examination of adipose tissue from the cancerous mice demonstrated the formation of brown adipocytes within WAT, a process termed “WAT browning.” This transformation began long before the onset of clinical cachexia.

WAT browning continued to increase as cachexia developed and was associated with greater energy expenditure and thermogenic activity, both of which contribute to loss of body weight. Feeding a high-fat diet had no effect on WAT browning or on skeletal muscle wasting.

Underlying Causes of WAT Browning Suggest Treatment Pathways

Reasoning that systemic inflammation might underlie WAT browning, the investigators examined inflammation-induced signaling pathways in mouse models of pancreatic or colon cancer. In all models studied, markers of inflammation were enhanced. The pro-inflammatory cytokine interleukin-6 was found to play an especially important role in the pathogenesis of WAT browning.

Further study demonstrated that beta-adrenergic activation works together with inflammation to promote the transformation of white fat to brown fat.

Treatment of mouse cancer models with the nonsteroidal anti-inflammatory agent sulindac reduced WAT browning and ameliorated cachexia, but only if given early, before the onset of cachexia symptoms. Treatment with a beta-3-adrenergic receptor antagonist also reduced WAT browning, but was less effective than sulindac.

Examination of adipose tissue from human patients with cancer with cachexia identified similar changes, suggesting that inhibition of WAT browning with anti-inflammatory agents may be a promising approach to preventing or treating cachexia.

Reference

  1. Petruzzelli M, Schweiger M, Schreiber R, et al. A switch from white to brown fat increases energy expenditure in cancer-associated cachexia. Cell Metab. 2014 Jul 15. doi: 10.1016/j.cmet.2014.06.011. [Epub ahead of print.] 
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