Leucine‐rich diet minimises liver glycogen mobilisation and modulates liver gluconeogenesis enzyme expression in tumour‐bearing cachectic rats

Abstract

Aims Cachexia is defined as a complex metabolic syndrome that is associated with tissue damage. Some studies have shown that the liver metabolic alterations contribute to overall host tissue wasting. Knowing that leucine acts as cell signalling, we evaluated hepatic metabolism in Walker 256 tumour‐bearing rats and investigated the modulatory effects of a leucine‐rich diet. Methods and Results Wistar rats were distributed into 4 groups: control (C) and tumour‐bearing (W) groups, fed a control diet, and leucine (L) and leucine tumour‐bearing (LW) groups, which fed a leucine‐rich diet. After tumour evolution (21 days), liver samples were collected, and assessed the glycogen content via histological periodic acid‐Schiff (PAS) staining and performed the molecular and biochemical analysis. A higher liver‐to‐body weight rate was observed in W and LW groups, whereas a lower muscle‐to‐body weight ratio was observed only in W group. Hepatic glycogen content was lower only in W group, which had a greater number of hepatocyte nuclei; these parameters were unchanged in LW rats. Moreover, phosphoenolpyruvate carboxykinase (PEPCK), glycogen synthase, and lactate dehydrogenase (LDHA) gene expressions were higher in liver tissue from W group than in LW group. However, liver alkaline phosphatase and γGT activities, and also liver AMP‐activated protein kinase (AMPK) expression were higher in both tumour‐bearing groups. Conclusions Our results suggest that a leucine‐rich diet has a protective effect on the loss of skeletal muscle and also minimises the liver failure induced by Walker 256 tumours. Despite the lack of protection against liver damage, the leucine‐rich diet modulated liver energy stores, likely decreasing the futile Cori cycle and reducing energy expenditures.

Walker-256 Tumour-Induced Cachexia Altered Liver Metabolomic Profile and Function in Weanling and Adult Rats

“…The role of the liver during cancer-cachexia has aroused increasing interest, with evidence suggesting that it is closely involved in cachexia-induced body weight loss and muscle atrophy [24,25]. Following literature data, here, we found a diminished carcass weight added to a reduction in serum albumin and total protein levels, features related to the cachexia process.…”

“…In muscle wasting during cachexia, amino acids are mobilised and released from skeletal muscle, providing higher availability of precursors for gluconeogenesis [29,30]. Moreover, liver gluconeogenesis could also be supported by substrates provided from lipolysis (glycerol) and other sources, such as lactate derived from muscle and tumour tissue [25]. In the present study, we found an increase in amino acid content in the liver tissue of tumour-bearing animals.…”

Tumor Cytokine-Induced Hepatic Gluconeogenesis Contributes to Cancer Cachexia: Insights from Full Body Single Nuclei Sequencing

“…In other organs that do not undergo gluconeogenesis, PDK reduces the levels of acetyl-CoA, leading to the repression of fatty acid synthesis from glucose (Huang et al, 2002;Zhang et al, 2014). Notably, tumor-bearing mice and rats with cachexia display increased hepatic expression of PEPCK (Tisdale, 2009;Narsale et al, 2015;Viana et al, 2018), suggesting increased hepatic gluconeogenesis in these animals. Indeed, the association between increased hepatic gluconeogenesis activity and cancer cachexia has been observed for decades (Holroyde et al, 1975(Holroyde et al, , 1984.…”