Molecular Characterization Of Adipose Tissue In Cachexia

Abstract

Cancer cachexia as a systemic disease that affects multiple tissues and organs via a variety of different metabolic pathways. Depletion of adipose tissue together with the Systemic inflammation, progressive weight loss, and loss of the skeletal muscle, that are not thoroughly reversible, are characteristic features of cachexia. Despite various studies on clinical features of cancer induced cachexia, the complexity of the syndrome and time of the diagnosis are big burdens and therefore no single standard treatment has been declared so far, consequently, exploring the molecular characterizations of the underlying events in cachexia will open the doors to more specific diagnostic and treatment options. Previous studies show that the gene transcription of the fundamental adipogenic factors, C/EBPα (CCAAT-enhancer-binding proteins) and PPARɣ (Peroxisome proliferator- activated receptor gamma), decrease considerably in the WAT (white adipose tissue) of cancer cachectic mice. Among these changes, mRNA levels of C/EBPα and concomitantly its protein expression is repressed the most. C/EBPα- deficiency in mice has shown to cause a decrease in body fat and also less lipid accumulation in C/EBPα- deficient adipocytes were observed. Furthermore, PPARɣ expression were disrupted along with a complete absence of insulin-stimulated glucose transport. Furthermore, Hormone-sensitive lipase (HSL / Lipe), encoded by the LIPE gene, is also involved in lipolysis. This enzyme mediates triglyceride hydrolysis to provide free fatty acids and glycerol in adipocytes in a hormonally controlled lipolysis process. Adipose triglyceride lipase (ATGL), encoded by Pnpla2, is the key-enzyme for the release of fatty acids (FAs) from triacylglycerol (TG) stores during intracellular lipolysis producing FAs used for energy production. Studies show that the lipolytic breakdown during the FA mobilization process has basic regulatory functions that affect the cell signalling, gene expression, metabolism, cell growth, cell death, and lipotoxicity. Regulation of ATGL is therefore vital for maintaining a defined balance between lipid storage and mobilization. Other studies showed that the loss of UCP1 dramatically alters lipid homeostasis in WAT at the level of gene transcription and substrate flux, inducing fatty acid synthesis and promoting inguinal (i.e., subcutaneous) adipocyte hyperplasia and depot expansion. Moreover, brown adipose tissue (BAT) which is part of the thermoregulation is associated with regulation of UCP1. K14-HPV16 transgenic mice are described as models for cachexia, since muscle wasting has been observed in these mice by our group (published results). Adipose tissue wasting is still not described in this model, but when necropsy is performed in these mice, it has been observed by our researchers that adipose tissue is reduced in transgenic mice when compared to wild type. The main goal of this dissertation is to validate at molecular level K14-HPV16 transgenic mice as a model for adipose tissue wasting in cachexia. The expected result is to observe at molecular level the decrease in expression of C/EBPα, PPARɣ, and UCP1 and an increase in expression of Lipe and Pnpla2 in comparison to wild type mice.