Obesity Activates a Program of Lysosomal-Dependent Lipid Metabolism in Adipose Tissue Macrophages Independently of Classic Activation

Abstract

SUMMARY Obesity activates a complex systemic immune response that includes the recruitment of macrophages and other immune cells to key metabolic tissues. Current models postulate that obesity and excess lipids classically activate macrophages, polarizing them toward an M1 (inflammatory) state. Little is known about noninflammatory functions of adipose tissue macrophages (ATMs). Here, we show that the expansion of adipose tissue (AT) across models of obesity induces a program of lysosome biogenesis in ATMs and is associated with lipid catabolism but not a classic inflammatory phenotype. This program is induced by factors produced by AT and is tightly coupled to lipid accumulation by ATMs. Inhibition of ATM lysosome function impairs lipid metabolism and increases lipid content in ATMs and reduces whole AT lipolysis. These data argue that ATMs contribute quantitatively to the development of obesity-induced inflammation but also serve an important role in lipid trafficking independent of their inflammatory phenotype.

MECHANISMS IN ENDOCRINOLOGY: White, brown and pink adipocytes: the extraordinary plasticity of the adipose organ

“…Altogether, we think that the death and degeneration of hypertrophic adipocytes, with the consequent exposure to the extracellular milieu of nuclear and cytoplasmic (mainly, lipid droplets) determinants that are normally segregated into the cell, represent the primary events triggering the inflammatory and immune reactions in the obese adipose tissue. This view has been recently reinforced by data from Xu et al (77), showing the importance of lipid catabolism in the macrophages infiltrating the obese adipose tissue. Interestingly, this…”

Fatty acids from fat cell lipolysis do not activate an inflammatory response but are stored as triacylglycerols in adipose tissue macrophages

“…The uptake and metabolism of FAs in macrophages may modify their phenotype as shown in several recent studies [43,44]. Along with this hypothesis, in vivo impairment of FA catabolism in ATMs that have accumulated lipids has systemic and local consequences [45]. However, long term lipid accumulation in ATMs promotes M1 polarisation and AT inflammation [46].…”

Exploring the activated adipogenic niche: Interactions of macrophages and adipocyte progenitors

“…19,40,41 It is presently unclear whether this heterogeneity represents differences in anatomical distribution, for example cells in CLS vs. those scattered throughout the tissue. 22,42 This is an important issue, since obesity involves adipocyte turnover and recruitment, yet is also associated with generalized proinflammatory signaling that contributes to insulin resistance.…”

“…For example, recent work identified populations of macrophages from obese animals that have a mixed M1/M2 profile and display elevated lysosomal lipid metabolism. 41 These cells appear to suppress adipocyte lipolysis while promoting lysosome-mediated fat clearance. It is presently unclear whether activation of lysosome biogenesis is specific to hypertrophied adipose tissue, or if it is a general mechanism of lipid catabolism in adipose tissue macrophages.…”