Adipose Tissue Remodeling during Cancer-Associated Cachexia: Translational Features from Adipose Tissue Dysfunction

Abstract

Cancer-associated cachexia is defined by systemic inflammation, bodyweight loss, adipose tissue remodeling, and muscle wasting. Interestingly, until nowadays, the etiology for this syndrome still unclear. It is well known that multiple factors can contribute to adipose tissue remodeling, and longitudinal studies show that adipose tissue is affected early in the course of this syndrome. During cancer cachexia, adipose tissue remodeling is associated with adipocyte atrophy, impairment of fatty acid turnover, inflammation, reorganization of the extracellular matrix, and increased thermogenic gene programming of adipose tissue. Another attractive pathway is the adipose tissue lipolysis, which is the catabolic process that is leading to the breakdown of triglycerides stored in adipocytes and the release of fatty acids and glycerol. This pathway is highly involved in the adipose tissue wasting during cancer cachexia. Whole-body deletion of the genes that encode the lipolytic enzymes attenuates the effects of the syndrome on the reduction of body fat and muscle mass. These sets of changes, in addition to metabolites derived from this process, may be the initial trigger of the sequence of events that result in the remodeling and consequent dysfunction of adipose tissue during cancer cachexia. Therefore, this review aimed to investigate the main morpho-functional events that are resulting in adipose tissue remodeling in the context of cancer-associated cachexia.

Pathological beige remodeling induced by cancer cachexia depends on the disease severity and involves mainly the trans-differentiation of mature white adipocytes

“…Hence, we used the S-CC group for phenotypic and comparative analyses. The morphofunctional changes leading to WAT remodeling are well described in CAC [1, 6, 12, 28, 29]; however, beige cells (browning) appear to depend on the animal model and experimental conditions. Considering this, we compared the presence of UCP1-expressing cells in different experimental groups after scAT remodeling.…”

“…Cancer associated cachexia (CAC) is characterized by body weight loss, systemic inflammation, remodeling of adipose tissue (AT), and skeletal muscle wasting [1]. This affects the quality of life, the survival rate, and the complications associated with cancer treatment.…”

“…The observation of increased UCP1+ multilocular cells from CAC indicates that adipocyte atrophy may be associated with increased beige remodeling in human cancer cachexia. Additionally, considering the relevance of beige remodeling as a relevant event in the different stages of cachexia, pharmacological treatment with β-adrenergic antagonists, nonsteroidal antiinflammatory drugs (Sunlidac), and TLR4 antagonists (Simvastatin) has been shown to effectively reduce beige remodeling in CAC in tumor-bearing animals while preserving body mass [1]. Only the latter showed significant effects and increased survival.…”

“…Aside from this phenotypic picture, an increase in WAT thermogenesis has been identified in the literature as an important contributor to accelerated energy expenditure and weight loss in CAC mouse models [8, 9]. The “beige remodeling” occurs in preclinical models of CAC when WAT cells gradually differentiate into Brown Adipose Tissue (BAT)-like cells, also referred to as “beige” cells [1, 8, 9]. CAC has been shown to switch white adipocytes in WAT from mice and humans [3, 9] to beige adipocytes.…”

IGFBP-3 promotes cachexia-associated lipid loss by suppressing insulin-like growth factor/insulin signaling

“…Recently, accumulating evidence has demonstrated its unveiled roles in the development of cachexia through remodeling of adipose tissue which is associated with adipocyte atrophy, impairment of lipid turnover, modification of extracellular matrix, enhanced inflammatory signaling, and dysfunction of energy metabolism. [11] Adipogenesis represents the deposition of triglycerides (TGs) in cytoplasmic lipid droplets, while adipose triglyceride lipase (ATGL) as well as the hormone-sensitive lipase (HSL) mediate intracellular lipolysis. [12] Noticeably, unbalanced lipid turnover including increased lipolysis and impaired adipogenesis plays an important role in cachexia.…”