Obese Adipose Tissue Secretion Induces Inflammation in Preadipocytes: Role of Toll-Like Receptor-4

Abstract

In obesity, the dysfunctional adipose tissue (AT) releases increased levels of proinflammatory adipokines such as TNFα, IL-6, and IL-1β and free fatty acids (FFAs), characterizing a chronic, low-grade inflammation. Whilst FFAs and proinflammatory adipokines are known to elicit an inflammatory response within AT, their relative influence upon preadipocytes, the precursors of mature adipocytes, is yet to be determined. Our results demonstrated that the conditioned medium (CM) derived from obese AT was rich in FFAs, which guided us to evaluate the role of TLR4 in the induction of inflammation in preadipocytes. We observed that CM derived from obese AT increased reactive oxygen species (ROS) levels and NF-ĸB nuclear translocation together with IL-6, TNFα, and IL-1β in 3T3-L1 cells in a TLR4-dependent manner. Furthermore, TLR4 signaling was involved in the increased expression of C/EBPα together with the release of leptin, adiponectin, and proinflammatory mediators, in response to the CM derived from obese AT. Our results suggest that obese AT milieu secretes lipokines, which act in a combined paracrine/autocrine manner, inducing inflammation in preadipocytes via TLR4 and ROS, thus creating a paracrine loop that facilitates the differentiation of adipocytes with a proinflammatory profile.

Physiological Changes and Pathological Pain Associated with Sedentary Lifestyle-Induced Body Systems Fat Accumulation and Their Modulation by Physical Exercise

“…Finally, in obese subjects, the adipocytes from VAT and SAT also express several molecules, such as lipocalin-2 [321,322], tenascin C, toll-like receptor 4 [323], and protein pentraxin 3 (PTX3) [324], which are related to adipose tissue inflammation and secretion of pro-inflammatory cytokines [321][322][323][325][326][327][328][329][330], insulin resistance [325,331], hyperglycemia and glucose intolerance [325,[332][333][334], endothelial dysfunction with hypertension [335], cardiovascular dysfunctions [336,337], and atherosclerosis [338,339].…”

Maternal obesity and programming of metabolic syndrome in the offspring: searching for mechanisms in the adipocyte progenitor pool

“…While the signals emanating from adipose tissue to recruit the ASC pool for differentiation remain unresolved, current evidence demonstrates that adipose expansion is associated with a shift in the adipose secretome towards higher release of pro-inflammatory mediators [ 46 – 48 ]. Interestingly, a recent study showed an increase in differentiation of ASC exposed to the secretome of adipose explants from high fat-fed mice [ 46 ]. Adipocyte-specific dominant-negative mutation of the pro-inflammatory cytokine, TNFα, prevented diet-induced WAT expansion, demonstrating that adipocyte inflammation is required for adaptive WAT remodeling [ 49 ].…”

Microbiome Dysbiosis: A Pathological Mechanism at the Intersection of Obesity and Glaucoma

“…Moreover, animals lacking TLR4 were protected against insulin resistance generated by a high-fat diet [ 204 ]. In an ex vivo study, Renovato-Martins et al [ 205 ] demonstrated that the conditioned medium derived from obese adipose tissue induces inflammation in preadipocytes via increased TLR4 signaling and ROS production, thereby creating a paracrine loop that promotes the differentiation of preadipocytes into adipocytes with a proinflammatory profile. High levels of circulating free fatty acids (FFAs) are associated with obesity and have been demonstrated to induce insulin resistance via many proinflammatory pathways [ 174 , 206 , 207 , 208 ].…”