Obesity: An Immunometabolic Perspective

Abstract

Obesity, characterized by chronic activation of inflammatory pathways, is a critical factor contributing to insulin resistance (IR) and type 2 diabetes (T2D). Free fatty acids (FFAs) are increased in obesity and are implicated as proximate causes of IR and induction of inflammatory signaling in adipose, liver, muscle, and pancreas. Cells of the innate immune system produce cytokines, and other factors that affect insulin signaling and result in the development of IR. In the lean state, adipose tissue is populated by adipose tissue macrophage of the anti-inflammatory M2 type (ATM2) and natural killer (NK) cells; this maintains the insulin-sensitive phenotype because ATM2 cells secrete IL10. In contrast, obesity induces lipolysis and release of pro-inflammatory FFAs and factors, such as chemokine (C–C motif) ligand 2 (CCL2) and tumor necrosis factor alpha (TNF-α), which recruit blood monocytes in adipose tissue, where they are converted to macrophages of the highly pro-inflammatory M1-type (ATM1). Activated ATM1 produce large amounts of pro-inflammatory mediators such as TNF-α, interleukin-1β, IL-6, leukotriene B4, nitric oxide (NO), and resistin that work in a paracrine fashion and cause IR in adipose tissue. In the liver, both pro-inflammatory Kupffer cells (M1-KCs) and recruited hepatic macrophages (Ly6Chigh) contribute to decreased hepatic insulin sensitivity. The present mini-review will update the bidirectional interaction between the immune system and obesity-induced changes in metabolism in adipose tissue and liver and the metabolic consequences thereof.

Lysophosphatidic Acid Inhibits Insulin Signaling in Primary Rat Hepatocytes via the LPA3 Receptor Subtype and is Increased in Obesity

“…Adipocyte hypertrophy and obesity are associated with hepatic insulin resistance which are main risk factors for the progression of T2DM [17]. However the molecular mechanisms responsible for the interaction between adipose tissue and the suppression of insulin action in hepatocytes are not fully understood.…”

“…However the molecular mechanisms responsible for the interaction between adipose tissue and the suppression of insulin action in hepatocytes are not fully understood. On the one hand, ectopic lipid accumulation in peripheral tissue in response to increased circulating free fatty acids due to an elevated lipolysis rate in adipose tissue is considered as an initiator for this pathological condition [17]. On the other hand, the generation and secretion of adipokines from adipose tissue are discussed as another conceivable mechanism involved in the interaction of obesity and insulin resistance.…”

The Fat of the Matter: Obesity and Visceral Adiposity in Treated HIV Infection

“…Although the exact mechanisms are not well understood, there may be several contributing factors not common among HIV-uninfected persons. First, HIV infection is characterized by persistent inflammation and immune activation[77], which 1) could help explain higher rates of NASH and liver disease severity in HIV infection (63% vs 37% in HIV-uninfected)[78] and 2) contributes to greater insulin resistance, furthering metabolic dysregulation in both adipose tissue and the liver[79, 80]. In addition to traditional risk factors (older age, sedentary lifestyle), HIV-/ART-specific factors (dyslipidemia, microbial translocation, mitochondrial dysfunction) likely contribute.…”

Diabetic Cardiomyopathy: An Immunometabolic Perspective

“…Inflammation is a key pathogenic feature of lipid excess and diabetes. The innate immune system comprising of neutrophils, dendritic cells, macrophages, mast cells, and eosinophils also induces chronic metabolic inflammation (126, 127). Myocardial inflammation is implicated in the development of DCM (128–131).…”