Obese Adipocytes Have Altered Redox Homeostasis with Metabolic Consequences

Abstract

White and brown adipose tissues are organized to form a real organ, the adipose organ, in mice and humans. White adipocytes of obese animals and humans are hypertrophic. This condition is accompanied by a series of organelle alterations and stress of the endoplasmic reticulum. This stress is mainly due to reactive oxygen species activity and accumulation, lending to NLRP3 inflammasome activation. This last causes death of adipocytes by pyroptosis and the formation of large cellular debris that must be removed by macrophages. During their chronic scavenging activity, macrophages produce several secretory products that have collateral consequences, including interference with insulin receptor activity, causing insulin resistance. The latter is accompanied by an increased noradrenergic inhibitory innervation of Langerhans islets with de-differentiation of beta cells and type 2 diabetes. The whitening of brown adipocytes could explain the different critical death size of visceral adipocytes and offer an explanation for the worse clinical consequence of visceral fat accumulation. White to brown transdifferentiation has been proven in mice and humans. Considering the energy-dispersing activity of brown adipose tissue, transdifferentiation opens new therapeutic perspectives for obesity and related disorders.

Keywords: ROS; adipocyte; endoplasmic reticulum; obesity; stress; type 2 diabetes.

Figure 1

Mesenteric fat of obese db/db mice. Transmission (A) and high-resolution scanning electron microscopy (C) showing early stage of macrophages invasion (arrows). (B): MAC2 immunohistochemistry showing both early (asterisk) and late stages of macrophage invasion, ending in CLS formation (as indicated). In (C), the indicated macrophage is enlarged in the inset. CAP: capillary. Bar: 8 μm in (A), 80 μm in (B), and 20 μm in (C) (2 μm in inset).

Figure 2

Mesenteric fat of obese db/db mice. (A) Representative transmission electron microscopy of obese adipocytes. Endoplasmic reticulum is diffusely dilated (ER, some indicated). In (B), a fine microstructure network is visible in the ER lumen, possibly corresponding to accumulated ROS. Original figures by the author. CAP: capillary; MIT: mitochondrion. Bar: 0.4 μm in (A) and 0.6 μm in (B).