The Adipokines in Cancer Cachexia

Abstract

Cachexia is a devastating pathology induced by several kinds of diseases, including cancer. The hallmark of cancer cachexia is an extended weight loss mainly due to skeletal muscle wasting and fat storage depletion from adipose tissue. The latter exerts key functions for the health of the whole organism, also through the secretion of several adipokines. These hormones induce a plethora of effects in target tissues, ranging from metabolic to differentiating ones. Conversely, the decrease of the circulating level of several adipokines positively correlates with insulin resistance, metabolic syndrome, diabetes, and cardiovascular disease. A lot of findings suggest that cancer cachexia is associated with changed secretion of adipokines by adipose tissue. In agreement, cachectic patients show often altered circulating levels of adipokines. This review reported the findings of adipokines (leptin, adiponectin, resistin, apelin, and visfatin) in cancer cachexia, highlighting that to study in-depth the involvement of these hormones in this pathology could lead to the development of new therapeutic strategies.

Keywords: adipokines; adipose tissue; cancer cachexia.

Figure 1

The transcriptional network that guides adipogenesis. White adipogenesis (WAT) is controlled through PPARγ-dependent mechanisms. The pro-adipogenic factors—c/EBPα, c/EBPβ, c/EBPγ, and CHOP—activate adipogenesis, while GATA transcription factors act as anti-adipogenic factors. PPARγ up-regulates c/EBPα that, in turn, promotes PPARγ expression. Brown adipocyte differentiation (BAT) is induced by the transcriptional co-regulator PRDM16. In addition, PPARγ co-activators—PGC1α and PGC1β—promote brown adipocyte formation by inhibiting the c/EBP network. In inguinal fat, cold stress and β-adrenergic stimulation directly induce the differentiation of pre-adipocytes in beige/brite adipocytes, while in epididymal fat, the same stimuli promote the formation of the beige/brite adipocytes from bipotent pre-adipocytes able to differentiate also in WAT under excess caloric condition [16].

Figure 2

Modifications, occurring in adipose tissue in cancer cachexia. Cancer cachexia provokes both phenotypic and metabolic modifications in adipose tissue. (A) Healthy adipocytes undergo morphological rearrangements, ranging from a decrease of cell volume to fibrosis formation. (B) Cachectic adipocytes are characterized by enhanced lipolysis, leading to a considerable intracellular triglyceride breakdown. Lipolysis is activated by hormonal signals (as glucagon and catecholamine) that activate protein kinase A (PKA). PKA enhances adipocyte triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL) activity. These enzymes induce the cleavage of two fatty acids from glycerol, forming diglycerides and monoglycerides. Monoacylglycerol lipase (MAGL) induces the hydrolysis in monoglycerides of the third fatty acid, thus forming free glycerol. (C) “Browning” of adipose tissue is induced by the host or tumor-derived pro-inflammatory factors as interleukin-6 (IL-6), tumor-derived parathyroid hormone-related protein (PTH-rP), and tumor secretory factor zinc 2-glycoprotein (ZAG). Brown adipocyte is characterized by a high amount of mitochondria and an enhanced level of uncoupling protein 1 (UCP-1) that dissipates energy in heat, uncoupling oxidative phosphorylation from ATP synthesis.