AUTHOR=Pagnotta Priscila , Gantov Mariana , Fletcher Sabrina , Lombardi Antonella , Crosbie María Lujan , Santiso Natalia , Ursino Anabela , Frascarolli Celeste , Amato Alicia , Dreszman Rubén , Calvo Juan Carlos , Toneatto Judith 

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

JOURNAL=Frontiers in Endocrinology

VOLUME=Volume 14 - 2023

YEAR=2023

URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2023.1144016

DOI=10.3389/fendo.2023.1144016

ISSN=1664-2392

ABSTRACT=Background: There is emerging evidence that demonstrates a reciprocal metabolic adaptation between stromal adipocytes and breast cancer cells. As a consequence, browning and lipolysis occur in cancer associated adipocytes (CAA). However, the paracrine effects of CAA on lipid metabolism and microenvironment remodeling remain poorly understood. 
Methods: To analyze these changes, we evaluated the effects of factors derived from conditioned media (CM) from human breast cancer adipose tissue explants (hATT) or normal breast adipose tissue explants (hATN) on morphology, degree of browning, the levels of adipogenic, 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 as an effect of CM treatment.
Results: We 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 TG content. hATT-CM and hATN-CM increased Pref-1, C/EBPβ LIP/LAP ratio, PPARγ, and CAV-1 expression levels in white adipocytes. UCP1, PGC1α and TOMM20 increased only in adipocytes 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 inducing Plin1 segregation. Furthermore, the levels of p-HSL, p-ERK and p-AKT increased in white adipocytes after incubation with hATT-CM.
Conclusions: In summary, these findings allow us to conclude that hATT secrete soluble factors, which induce browning of white adipocytes and changes in lipolytic activity, favoring the turnover of LDs. This experimental approach suggests that adipocytes attached to the tumor could induce white adipocyte browning and increase lipolysis in its microenvironment, as a means for endocrine/paracrine signaling. This would indicate a loss of normal functions (such as energy storage) in mature adipocytes attached to the tumor, in support of others that might favor tumor growth.