Adipocytes and macrophages secretomes coregulate catecholamine-synthesizing enzymes

Abstract

Obesity associates with macrophage accumulation in adipose tissue where these infiltrating cells interact with adipocytes and contribute to the systemic chronic metabolic inflammation present in immunometabolic diseases. Tyrosine hydroxylase (TH) and phenylethanolamine N-methyltransferase (PNMT) are two of the main enzymes of catecholamines (CA) synthesis. Adipocytes and macrophages produce, secrete and respond to CA, but the regulation of their synthesis in the interplay between immune and metabolic systems remains unknown. A model of indirect cell coculture with conditioned medium (CM) from RAW 264.7 macrophages with or without LPS-activation and 3T3-L1 adipocytes and preadipocytes was established to study the effect of cellular secretomes on the expression of the above enzymes. During the adipocyte differentiation process, we found a decrease of TH and PNMT expression. The secretome from LPS-activated macrophages downregulated TH and PNMT expression in preadipocytes, but not in mature adipocytes. Mature adipocytes CM induced a decrease of PNMT levels in RAW 264.7 macrophages. Pre and mature adipocytes showed a similar pattern of TH, PNMT and peroxisome proliferator-activated receptor gamma expression after exposure to pro and anti-inflammatory cytokines. We evidenced macrophages and adipocytes coregulate the expression of CA synthesis enzymes through secretome, with non-inflammatory signaling networks possibly being involved. Mediators released by macrophages seem to equally affect CA production by adipocytes, while adipocytes secretome preferentially affect AD production by macrophages. CA synthesis seems to be more determinant in early stages of adipogenic differentiation. Our results suggest that CA are key signaling molecules in the regulation of immune-metabolic crosstalk within the adipose tissue.