Peritumoral adipose tissue promotes lipolysis and white adipocytes browning by paracrine action

Abstract

BackgroundStromal adipocytes and tumor breast epithelial cells undergo a mutual metabolic adaptation within tumor microenvironment. Therefore, browning and lipolysis occur in cancer associated adipocytes (CAA). However, the paracrine effects of CAA on lipid metabolism and microenvironment remodeling remain poorly understood.MethodsTo analyze these changes, we evaluated the effects of factors in conditioned media (CM) derived from explants of human breast adipose tissue from tumor (hATT) or normal (hATN) on morphology, degree of browning, the levels of adiposity, maturity, and lipolytic-related markers in 3T3-L1 white adipocytes by Western blot, indirect immunofluorescence and lipolytic assay. We analyzed subcellular localization of UCP1, perilipin 1 (Plin1), HSL and ATGL in adipocytes incubated with different CM by indirect immunofluorescence. Additionally, we evaluated changes in adipocyte intracellular signal pathways.ResultsWe found that adipocytes incubated with hATT-CM displayed characteristics that morphologically resembled beige/brown adipocytes with smaller cell size and higher number of small and micro lipid droplets (LDs), with less triglyceride content. Both, hATT-CM and hATN-CM, increased Pref-1, C/EBPβ LIP/LAP ratio, PPARγ, and caveolin 1 expression in white adipocytes. UCP1, PGC1α and TOMM20 increased only in adipocytes that were treated with hATT-CM. Also, hATT-CM increased the levels of Plin1 and HSL, while decreased ATGL. hATT-CM modified the subcellular localization of the lipolytic markers, favoring their relative content around micro-LDs and induced Plin1 segregation. Furthermore, the levels of p-HSL, p-ERK and p-AKT increased in white adipocytes after incubation with hATT-CM.ConclusionsIn summary, these findings allow us to conclude that adipocytes attached to the tumor could induce white adipocyte browning and increase lipolysis as a means for endocrine/paracrine signaling. Thus, adipocytes from the tumor microenvironment exhibit an activated phenotype that could have been induced not only by secreted soluble factors from tumor cells but also by paracrine action from other adipocytes present in this microenvironment, suggesting a “domino effect”.

Dietary Apigenin Relieves Body Weight and Glycolipid Metabolic Disturbance via Pro‐Browning of White Adipose Mediated by Autophagy Inhibition

“…Immunofluorescence assay was conducted as previously reported. [29] 3T3-L1 preadipocytes were seeded onto a confocal dish at a density of 1 × 10 4 mL −1 and were induced for 6 days in a differentiation cocktail. After the induction of the first 6 days, the adipocytes were treated with or without AP (50 μM) for additional 48 h. Next, the cells were washed twice with PBS, and were stained for 30 min with a mitochondrial fluorescence probe dye (mito-tracker green).…”

The Role of Cancer Stem Cell Markers in Ovarian Cancer

“…Multiple cancer types utilise fatty acids from surrounding adipose tissue by inducing adipocyte lipolysis, promoting energy metabolism (β-oxidation) and the biosynthesis of lipid-derived cell signalling molecules [ 104 ]. The adipocytes in adipose tissue contribute to sustaining CSC properties through paracrine secretion into the TME [ 105 ]. Cancer-associated adipocytes were found to exhibit distinct phenotypes and effects compared to normal adipocytes.…”