Potential of Nutraceutical Supplementation in the Modulation of White and Brown Fat Tissues in Obesity-Associated Disorders: Role of Inflammatory Signalling

Abstract

The high incidence of obesity is associated with an increasing risk of several chronic diseases such as cardiovascular disease, type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). Sustained obesity is characterized by a chronic and unsolved inflammation of adipose tissue, which leads to a greater expression of proinflammatory adipokines, excessive lipid storage and adipogenesis. The purpose of this review is to clarify how inflammatory mediators act during adipose tissue dysfunction in the development of insulin resistance and all obesity-associated diseases. In particular, we focused our attention on the role of inflammatory signaling in brown adipose tissue (BAT) thermogenic activity and the browning of white adipose tissue (WAT), which represent a relevant component of adipose alterations during obesity. Furthermore, we reported the most recent evidence in the literature on nutraceutical supplementation in the management of the adipose inflammatory state, and in particular on their potential effect on common inflammatory mediators and pathways, responsible for WAT and BAT dysfunction. Although further research is needed to demonstrate that targeting pro-inflammatory mediators improves adipose tissue dysfunction and activates thermogenesis in BAT and WAT browning during obesity, polyphenols supplementation could represent an innovative therapeutic strategy to prevent progression of obesity and obesity-related metabolic diseases.

Keywords: BAT; WAT; browning; inflammation; metabolic diseases; nutraceutical supplementation; obesity; polyphenols.

Figure 1

Role of gut in inducing adipose tissue inflammation. Inflammation alters the gut barrier function through a reduction in the thickness of the intestinal mucus layer and a subsequent increase in gut permeability [18]. Lipopolysaccharide (LPS), trigger inflammation in adipocytes and, along with macrophage colony-stimulating factor (M-CSF), infiltrated from the intestine, promotes ATM recruitment within the mesenteric fat depot [19]. Once in the circulation, LPS could reach adipose tissue and acts as a Toll-like receptor agonist (TLR)-4, increasing the expression of proinflammatory markers [20]. TLR4 binds to LPS through the formation of a complex with LPS-binding proteins (LBP), MD-2 (myeloid differentiation factor 2) and CD14 (cluster of differentiation 14). This complex activates the myeloid differentiation primary-response protein 88 (MyD88)-dependent pathway leading to Nuclear factor- κB (NF-κB) activation and to transcription of proinflammatory genes both in adipocytes and ATM [21,22].

Figure 2

Macrophages polarization and pro-inflammatory cytokines expression. FAAs released by hypertrophic adipose tissue stimulate polarization of M2 macrophages through activation of the TLR4 pathway resulting in pro-inflammatory cytokines secretion.

Figure 3

Intracellular Pathways that Control Inflammatory Signaling. In adipose tissue of obese patients, FFAs and proinflammatory cytokines mediate the activation of JNK and NF-kB pathways, which in turn promote insulin resistance and the transcription of target genes encoding for inflammatory mediators.

Figure 4

Involvement of ER stress in adipose tissue inflammation. In obese adipose tissue, accumulation of unfolded proteins, excess of FFAs, insulin resistance, and decreased vascularization determine ER stress, responsible of an inflammatory response via activation of JNK and NF-κB pathways, as well as production of ROS.

Figure 5

Inflammatory signaling impairs insulin sensitivity of BAT through a TNFα-mediated mechanism.