Chronic inflammation in obesity and the metabolic syndrome

Abstract

The increasing incidence of obesity and the metabolic syndrome is disturbing. The activation of inflammatory pathways, used normally as host defence, reminds the seriousness of this condition. There is probably more than one cause for activation of inflammation. Apparently, metabolic overload evokes stress reactions, such as oxidative, inflammatory, organelle and cell hypertrophy, generating vicious cycles. Adipocyte hypertrophy, through physical reasons, facilitates cell rupture, what will evoke an inflammatory reaction. Inability of adipose tissue development to engulf incoming fat leads to deposition in other organs, mainly in the liver, with consequences on insulin resistance. The oxidative stress which accompanies feeding, particularly when there is excessive ingestion of fat and/or other macronutrients without concomitant ingestion of antioxidant-rich foods/beverages, may contribute to inflammation attributed to obesity. Moreover, data on the interaction of microbiota with food and obesity brought new hypothesis for the obesity/fat diet relationship with inflammation. Beyond these, other phenomena, for instance psychological and/or circadian rhythm disturbances, may likewise contribute to oxidative/inflammatory status. The difficulty in the management of obesity/metabolic syndrome is linked to their multifactorial nature where environmental, genetic and psychosocial factors interact through complex networks.

Figure 1

Overview of the complex interplay between obesity-inflammation-metabolic syndrome: metabolic overload impacts on adipose tissue, leading to organelle stress with production of ROS and adipokines, as well as activation of kinases that potentiate the transcription of inflammatory genes and interfere with insulin signaling. Hyperthrophy facilitates rupture of adipocytes which attract and activate macrophages that markedly reinforce the inflammatory process through further production of ROS and inflammatory cytokines. Production of adiponectin, an anti-inflammatory cytokine, is reduced. Increase of FFA concentration, namely, SFA, coming both from feeding and adipose tissue overflow, accumulates in the liver, among other organs. Fat accumulation in the liver leads to overproduction of LDLs and, together with IL-6, of CRP. NAFLD is a frequent consequence of these metabolic dysregulations, and all this impacts on insulin sensitivity. SFA activates TOLL-like receptors in adipocytes, contributing to the activation of the inflammatory response. Fat has also effects on intestinal permeability and on the microbiota, with systemic inflammatory consequences. Most excess metabolites and cytokines produced throughout these processes converge on insulin resistance, a central characteristic of the metabolic syndrome. AP-1: activator protein-1; CRP: C-reactive protein; FFA: free (nonesterified) fatty acids; IL-n: interleukins; IKK: inhibitor of NF-κB kinase; IL-6: interleukin-6; Int: intestine; IR: insulin resistance; JNK: c-Jun N-terminal kinase; LDL: low density lipoprotein; M: microbiota; NAFLD: nonalcoholic fatty liver disease; NF-κB: nuclear factor κB; OxS: oxidative stress; ROS: reactive oxygen species; PKC: protein kinase C; SFA: saturated fatty acids; TAG: triacylglycerols; TLR: TOLL-like receptors; TNFalpha: tumour necrosis factor alpha.