Abstract
Obesity is one of the major health burdens of the 21st century as it contributes to the growing prevalence of its related comorbidities, including insulin resistance and type 2 diabetes. Growing evidence suggests a critical role for overnutrition in the development of low-grade inflammation. Specifically, chronic inflammation in adipose tissue is considered a crucial risk factor for the development of insulin resistance and type 2 diabetes in obese individuals. The triggers for adipose tissue inflammation are still poorly defined. However, obesity-induced adipose tissue expansion provides a plethora of intrinsic signals (e.g., adipocyte death, hypoxia, and mechanical stress) capable of initiating the inflammatory response. Immune dysregulation in adipose tissue of obese subjects results in a chronic low-grade inflammation characterized by increased infiltration and activation of innate and adaptive immune cells. Macrophages are the most abundant innate immune cells infiltrating and accumulating into adipose tissue of obese individuals; they constitute up to 40% of all adipose tissue cells in obesity. In obesity, adipose tissue macrophages are polarized into pro-inflammatory M1 macrophages and secrete many pro-inflammatory cytokines capable of impairing insulin signaling, therefore promoting the progression of insulin resistance. Besides macrophages, many other immune cells (e.g., dendritic cells, mast cells, neutrophils, B cells, and T cells) reside in adipose tissue during obesity, playing a key role in the development of adipose tissue inflammation and insulin resistance. The association of obesity, adipose tissue inflammation, and metabolic diseases makes inflammatory pathways an appealing target for the treatment of obesity-related metabolic complications. In this review, we summarize the molecular mechanisms responsible for the obesity-induced adipose tissue inflammation and progression toward obesity-associated comorbidities and highlight the current therapeutic strategies.
Highlights
Overweight and obesity are the consequence of a chronic imbalance between energy intake and energy expenditure, culminating in the excess of fat accumulation in adipose tissue (AT)
The activation of two branches is mediated by protein kinase RNA (PKR)-like endoplasmic reticulum (ER) kinase (PERK) and activating transcription factor 6 (ATF6)
In 2016, we have reported that unfolded protein response (UPR) hyper-activation by glucose insult leads to a pro-inflammatory phenotype in preadipocytes
Summary
Overweight and obesity are the consequence of a chronic imbalance between energy intake and energy expenditure, culminating in the excess of fat accumulation in AT. Accumulation of lipids that occurs in AT during obesity triggers an inflammatory response that results in an increased secretion of several inflammatory cytokines (Haase et al, 2014; Raciti et al, 2017) Such molecules can activate JNK and NF-κB signaling pathways in the liver and skeletal muscle, inhibiting systemic insulin signaling (Hotamisligil et al, 1993; Ciccarelli et al, 2016). Obesity contributes to the development of chronic muscle inflammation, characterized by increased pro-inflammatory M1 macrophage infiltration (Fink et al, 2013, 2014) These macrophages secrete many cytokines, which have been shown to trigger inflammatory pathways within myocyte, culminating in decreased insulin signaling (Varma et al, 2009; Pillon et al, 2012; Patsouris et al, 2014). These inflammatory mediators contribute to liver steatosis by promoting lipogenesis and toxic ceramide biosynthesis (Schubert et al, 2000; Obstfeld et al, 2010)
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