Evaluation of Browning Markers in Subcutaneous Adipose Tissue of Newly Diagnosed Gastrointestinal Cancer Patients with and without Cachexia

Abstract

We assessed the molecular phenotype of the browning of white adipose tissue in newly diagnosed cancer patients and controls undergoing surgery for gastrointestinal tumors and for non-malignant diseases, respectively. We collected subcutaneous adipose tissue (SAT) samples and using RT-PCR, we analyzed the expression of markers of browning and using Western blot the protein levels of UCP1 and PGC1α. The Ucp1 mRNA levels were lower in cancer patients vs. controls (p = 0.01), whereas Cidea and Tmem26 mRNA levels were higher in cancer patients. We found higher PGC1α protein levels in patients vs. controls, while no differences were seen for UCP1. The Ucp1 expression was lower in cachectic and non-cachectic patients vs. controls, whereas Cidea expression was higher in cachectic and non-cachectic patients vs. controls. Pgc1α mRNA levels were higher in cachectic vs. non-cachectic patients (p = 0.03) vs. controls (p = 0.016). According to type of tumors, we did not observe differences in Cidea expression, whereas Pgc1α was higher in pancreatic cancer vs. colorectal and vs. controls. We observed the lower expression of Ucp1 in pancreatic and colorectal cancer vs. controls. We documented higher UCP1 protein levels in pancreatic cancer patients vs. colorectal (p = 0.002) and vs. controls (p = 0.031). PGC1α protein levels were higher in pancreatic cancer patients vs. controls. Different markers of the browning of SAT are modulated, and pancreatic cancer showed changes in UCP1 and PGC1α; PGC1α was highly expressed in cachectic patients, with clinical implications that should be further clarified.

Metabolic and histomorphological changes of adipose tissue in cachexia

“…Recently, we have investigated the modifications of browning process in patients with gastrointestinal cancer with and without cachexia, observing that several markers of the browning of subcutaneous adipose tissue (SAT) were modulated, but only in pancreatic cancer we observed an increased in protein levels of UCP1 as compared to controls and colorectal cancer [14 ▪ ]. In this study, no differences were present in UCP1 protein levels between cachectic and noncachectic cancer patients [14 ▪ ].…”

“…Recently, we have investigated the modifications of browning process in patients with gastrointestinal cancer with and without cachexia, observing that several markers of the browning of subcutaneous adipose tissue (SAT) were modulated, but only in pancreatic cancer we observed an increased in protein levels of UCP1 as compared to controls and colorectal cancer [14 ▪ ]. In this study, no differences were present in UCP1 protein levels between cachectic and noncachectic cancer patients [14 ▪ ]. These data were also confirmed in a cohort of gastrointestinal and genitourinary cancer with and without weight loss [15 ▪▪ ], indicating that mechanisms beyond thermogenesis induced by UCP1 may possibly contribute to the progression of cancer cachexia.…”

Identification of Potential Biomarkers for Cancer Cachexia and Anti-Fn14 Therapy

“…The reduced expression of browning and thermogenesis proteins UCP1 and DIO2 may contribute to increased WAT mass in 002 mAb treated mice. Cell death-inducing DNA fragmentation factor-alpha-like effector A (CIDEA) and Peroxisome proliferator-activated receptor gamma coactivator-1-α (PGC-1α) have been shown to be involved in regulating wasting and browning of adipose tissues in cancer cachexia [ 15 , 16 ]. Increased CIDEA expression was observed in BAT from PC3* model, but no significant change was observed with 002 mAb treatment ( Figure 1 E).…”

Adipose tissue browning and thermogenesis under physiologically energetic challenges: a remodelled thermogenic system

“…Exosomes secreted by cells from Lewis lung carcinoma transported extracellular PTHrP through fusion with adipocytes, thus activating the intracellular protein kinase A (PKA) pathway to induce WAT browning and lipolysis (Hu et al, 2021). Similarly, in the patients with pancreatic cancer, a dramatic increase in biomarkers of browning, especially PGC1α expression, were observed in subcutaneous WAT (Molfino et al, 2022). Blocking the p38 mitogen-activated protein kinase pathway alleviated the browning phenotype and increased the volume and mass of WAT (Zhao et al, 2022).…”