Immune Cell Toll-like Receptor 4 Mediates the Development of Obesity- and Endotoxemia-Associated Adipose Tissue Fibrosis

Abstract

Adipose tissue fibrosis development blocks adipocyte hypertrophy and favors ectopic lipid accumulation. Here, we show that adipose tissue fibrosis is associated with obesity and insulin resistance in humans and mice. Kinetic studies in C3H mice fed a high-fat diet show activation of macrophages and progression of fibrosis along with adipocyte metabolic dysfunction and death. Adipose tissue fibrosis is attenuated by macrophage depletion. Impairment of Toll-like receptor 4 signaling protects mice from obesity-induced fibrosis. The presence of a functional Toll-like receptor 4 on adipose tissue hematopoietic cells is necessary for the initiation of adipose tissue fibrosis. Continuous low-dose infusion of the Toll-like receptor 4 ligand, lipopolysaccharide, promotes adipose tissue fibrosis. Ex vivo, lipopolysaccharide-mediated induction of fibrosis is prevented by antibodies against the profibrotic factor TGFβ1. Together, these results indicate that obesity and endotoxemia favor the development of adipose tissue fibrosis, a condition associated with insulin resistance, through immune cell Toll-like receptor 4.

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

“…In vivo, stimulation of lipolysis promoted accumulation of neutral lipids in ATMs without change in number and phenotypes. Lipid droplet accumulation into ATMs occurred without a change in the number of crown-like structures that result from the recruitment of macrophages around dead adipocytes, which is a TLR4-dependent mechanism [24,40,41]. These data point to the presence of lipids from dead adipocytes rather than to FAs released from lipolysis in eliciting the proinflammatory response through TLR4-dependent signalling.…”

“…To investigate the in vivo relationship between AT lipolysis and inflammation, we treated two strains of high-fat diet-fed mice in the morning with the antilipolytic drug HSLi for 15 days. C3H/HeOuJ mice have intact TLR4 signalling (WT), whereas C3H/HeJ mice show defective TLR4 signalling (TLR4 mut ) [24]. The chronic inhibition of lipolysis was shown by a robust decrease in plasma glycerol levels in the two strains (ESM Fig.…”

Adipose tissue adaptive response totrans‐10,cis‐12‐conjugated linoleic acid engages alternatively activated M2 macrophages

“…Although opposite in terms of excess vs. deficiency of fat mass, obesity and lipodystrophy share common WAT alterations, including inflammation and macrophage infiltration, as shown in several lipodystrophic mouse models (1-3) and in patients with HIV-associated lipodystrophy (4-6). Enhanced extracellular matrix (ECM) deposition and fibrosis are additional signatures of WAT pathology in both conditions (4,7,8). These local alterations are accompanied by systemic inflammation and insulin resistance, the most prevalent outcomes of WAT dysfunction common to obesity and lipodystrophy (9).…”

PDGFRα signaling drives adipose tissue fibrosis by targeting progenitor cell plasticity

“…White adipose tissue (WAT) fibrosis is significant because of its intimate relationship with WAT dysfunction, chronic inflammation, and insulin resistance in humans and mice (Khan et al 2009;Pasarica et al 2009;Divoux et al 2010;Sun et al 2013;Vila et al 2014 …”