A Switch from White to Brown Fat Increases Energy Expenditure in Cancer-Associated Cachexia

Abstract

Cancer-associated cachexia (CAC) is a wasting syndrome characterized by systemic inflammation, body weight loss, atrophy of white adipose tissue (WAT) and skeletal muscle. Limited therapeutic options are available and the underlying mechanisms are poorly defined. Here we show that a phenotypic switch from WAT to brown fat, a phenomenon termed WAT browning, takes place in the initial stages of CAC, before skeletal muscle atrophy. WAT browning is associated with increased expression of uncoupling protein 1 (UCP1), which uncouples mitochondrial respiration toward thermogenesis instead of ATP synthesis, leading to increased lipid mobilization and energy expenditure in cachectic mice. Chronic inflammation and the cytokine interleukin-6 increase UCP1 expression in WAT, and treatments that reduce inflammation or β-adrenergic blockade reduce WAT browning and ameliorate the severity of cachexia. Importantly, UCP1 staining is observed in WAT from CAC patients. Thus, inhibition of WAT browning represents a promising approach to ameliorate cachexia in cancer patients.

Uncoupling protein 1 expression in adipocytes derived from skeletal muscle fibro/adipogenic progenitors is under genetic and hormonal control

“…Furthermore, increases in UCP1 protein levels in WAT after exercise training or cold exposure are much less pronounced in IL‐6 knockout mice,63 while cold‐induced UCP1 levels in intrascapular BAT seem to be unaffected 64. In mice, cancer cachexia‐induced UCP1 expression in WAT is largely reduced in IL‐6‐receptor knockout mice 65. In contrast, our results demonstrate that IL‐6 is not required for intramuscular Ucp1 expression after GLY‐induced fatty infiltration followed or not by beta 3‐adrenergic agonist treatment.…”

Establishment and characterization of a novel murine model of pancreatic cancer cachexia

“…52, 53 UCP1 acts as an uncoupler of mitochondrial electron transport, which shifts adipocyte metabolism to increase thermogenesis while decreasing ATP synthesis, thereby increasing energy expenditure and lipid mobilization. The energy loss is not accompanied by increased core body temperature, even in thermoneutral conditions 52. While we demonstrate a similar pattern to these prior experiments in regard to loss of body temperature in late‐stage cachexia, we found a loss in Ucp1 in all adipose tissue rather than an increase.…”

The role of adipose tissue in cancer-associated cachexia

“…84 The authors also performed functional analyses of the proposed beige adipose tissue to demonstrate increased energy expenditure using oxygen consumption rate assays as well as body weight, tissue weight, physical activity, oxygen uptake (VO 2 ), carbon dioxide production (VCO 2 ), respiratory exchange ratio (RER), and heat generation measurements. 83,84 Additionally, two drivers of white-to-beige trans-differentiation were identified: interleukin-6 (IL-6) 83 and parathyroid hormone-related peptide (PTH-rp). 84 These are the first studies to identify causative agents secreted by tumors that contribute to WAT browning and result in increased energy expenditure, which contributes to CAC.…”