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

Mariana Renovato-Martins,Catharina Moreira-Nunes,Georgia C Atella,João Alfredo De Moraes,Christina Barja-Fidalgo

doi:10.3390/nu12092828

Mariana Renovato-Martins, Catharina Moreira-Nunes + Show 3 more

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https://doi.org/10.3390/nu12092828

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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.

Highlights

The obese state is described as the expansion of fat depots causing adipose tissue (AT)dysfunctionality, which is often characterized by low-grade inflammation in situ
The expansion in adiposity was accompanied by dramatic changes in the quality of free fatty acids (FFAs) released by the AT of obese mice
Once we had established that FFAs can activate TLR4, we examined the NF-kB activation in 3T3-L1 preadipocytes after treatment with the Conditioned Medium (CM) derived from obese AT

Summary

Introduction

Dysfunctionality, which is often characterized by low-grade inflammation in situ. This condition is highly correlated with the onset of obesity-related comorbidities including type 2 diabetes, insulin resistance, and several types of cancers [1]. It is consensual that AT-resident immune cells play a role in the regulation of this obesity-induced inflammation. Once in a proinflammatory state, mature adipocytes secrete adipokines, such as TNFα, IL-6, and IL-1β [4] with visceral AT releasing high amounts of FFAs. Low-grade inflammation and the high rate of lipolysis are responsible for the negative metabolic consequences of fat accumulation in the body, such as insulin resistance, dyslipidemia, and lipotoxicity [5,6]. AT-derived cytokines, i.e., TNFα and IL-6, are known to stimulate lipolysis and promote the release of FFAs [6]

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