High-fat diet-induced obesity is associated with a chronic state of low-grade inflammation, which pre-disposes to insulin resistance (IR), which can subsequently lead to type 2 diabetes mellitus. Macrophages represent a heterogeneous population of cells that are instrumental in initiating the innate immune response. Recent studies have shown that macrophages are key mediators of obesity-induced IR, with a progressive infiltration of macrophages into obese adipose tissue. These adipose tissue macrophages are referred to as classically activated (M1) macrophages. They release cytokines such as IL-1β, IL-6 and TNFα creating a pro-inflammatory environment that blocks adipocyte insulin action, contributing to the development of IR and type 2 diabetes mellitus. In lean individuals macrophages are in an alternatively activated (M2) state. M2 macrophages are involved in wound healing and immunoregulation. Wound-healing macrophages play a major role in tissue repair and homoeostasis, while immunoregulatory macrophages produce IL-10, an anti-inflammatory cytokine, which may protect against inflammation. The functional role of T-cell accumulation has recently been characterised in adipose tissue. Cytotoxic T-cells are effector T-cells and have been implicated in macrophage differentiation, activation and migration. Infiltration of cytotoxic T-cells into obese adipose tissue is thought to precede macrophage accumulation. T-cell-derived cytokines such as interferon γ promote the recruitment and activation of M1 macrophages augmenting adipose tissue inflammation and IR. Manipulating adipose tissue macrophages/T-cell activity and accumulation in vivo through dietary fat modification may attenuate adipose tissue inflammation, representing a therapeutic target for ameliorating obesity-induced IR.

OBJECTIVEHigh-fat diet (HFD)-induced adipose tissue inflammation is a critical feature of diet-induced insulin resistance (IR); however, the contribution of interleukin-1 receptor I (IL-1RI)-mediated signals to this phenotype has not been defined. We hypothesized that lack of IL-1RI may ameliorate HFD-induced IR by attenuating adipose tissue inflammation.RESEARCH DESIGN AND METHODSGlucose homeostasis was monitored in chow- and HFD-fed wild-type (WT) and IL-1RI−/− mice by glucose tolerance and insulin tolerance tests. Macrophage recruitment and cytokine signature of adipose tissue macrophages was evaluated. Insulin sensitivity and cytokine secretion from adipose explants was quantified. Cytokine secretion and adipocyte insulin sensitivity was measured in cocultures of WT or IL-1RI−/− macrophages with 3T3L1 adipocytes. Synergistic effects of IL-1β with tumor necrosis factor (TNF)-α on inflammation was monitored in WT and IL-1RI−/− bone-marrow macrophages and adipose explants.RESULTSLean and obese IL-1RI−/− animals exhibited enhanced glucose homeostasis by glucose tolerance test and insulin tolerance test. M1/M2 macrophage number in adipose tissue was comparable between genotypes; however, TNF-α and IL-6 secretion was lower from IL-1RI−/− adipose tissue macrophages. IL-1RI−/− adipose exhibited enhanced insulin sensitivity, elevated pAKT, lower cytokine secretion, and attenuated induction of phosphorylated signal transducer and activator of transcription 3 and suppressor of cytokine signaling molecule 3 after HFD. Coculture of WT, but not IL-1RI−/− macrophages, with 3T3L1 adipocytes enhanced IL-6 and TNF-α secretion, reduced adiponectin secretion, and impaired adipocyte insulin sensitivity. TNF-α and IL-1β potently synergized to enhance inflammation in WT macrophages and adipose, an effect lost in the absence of IL-1RI.CONCLUSIONSLack of IL-1RI protects against HFD-induced IR coincident with reduced local adipose tissue inflammation, despite equivalent immune cell recruitment.

SFA represent metabolic triggers priming the inflammasome, promoting adipocyte inflammation/IR, suggesting direct effects of SFA on inflammasome activation via TLR4.

Aging and adiposity are associated with chronic low-grade inflammation, which underlies the development of obesity-associated complications, including type 2 diabetes mellitus (T2DM). The mechanisms underlying adipose inflammation may include macrophage infiltration and activation, which, in turn, affect insulin sensitivity of adipocytes. There is a growing appreciation that specific lipid mediators (including lipoxins, resolvins, and protectins) can promote the resolution of inflammation. Here, we investigated the effect of lipoxin A4 (LXA4), the predominant endogenously generated lipoxin, on adipose tissue inflammation. Using adipose tissue explants from perigonadal depots of aging female C57BL/6J mice (Animalia, Chordata, Mus musculus) as a model of age-associated adipose inflammation, we report that LXA4 (1 nM) attenuates adipose inflammation, decreasing IL-6 and increasing IL-10 expression (P<0.05). The altered cytokine milieu correlated with increased GLUT-4 and IRS-1 expression, suggesting improved insulin sensitivity. Further investigations revealed the ability of LXA4 to rescue macrophage-induced desensitization to insulin-stimulated signaling and glucose uptake in cultured adipocytes, using vehicle-stimulated cells as controls. This was associated with preservation of Akt activation and reduced secretion of proinflammatory cytokines, including TNF-α. We therefore propose that LXA4 may represent a potentially useful and novel therapeutic strategy to subvert adipose inflammation and insulin resistance, key components of T2DM.

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Macrophage infiltration is a critical determinant of high-fat diet induced adipose tissue inflammation and insulin resistance. The precise mechanisms underpinning the initiation of macrophage recruitment and activation are unclear. Macrophage migration inhibitory factor (MIF), a pro-inflammatory cytokine, displays chemokine-like properties. Circulating MIF levels are elevated during obesity however its role in high-fat diet induced adipose inflammation and insulin resistance remains elusive. Wildtype and MIF−/− C57Bl\6J mice were fed chow or high-fat diet. Body weight and food intake was assessed. Glucose homeostasis was monitored by glucose and insulin tolerance tests. Adipose tissue macrophage recruitment and adipose tissue insulin sensitivity was evaluated. Cytokine secretion from stromal vascular fraction, adipose explants and bone marrow macrophages was measured. Inflammatory signature and insulin sensitivity of 3T3-L1-adipocytes co-cultured with wildtype and MIF−/− macrophage was quantified. Hepatic triacylglyceride levels were assessed. MIF−/− exhibited reduced weight gain. Age and weight-matched obese MIF−/− mice exhibited improved glucose homeostasis coincident with reduced adipose tissue M1 macrophage infiltration. Obese MIF−/− stromal vascular fraction secreted less TNFα and greater IL-10 compared to wildtype. Activation of JNK was impaired in obese MIF−/−adipose, concomitant with pAKT expression. 3T3-L1-adipocytes cultured with MIF−/− macrophages had reduced pro-inflammatory cytokine secretion and improved insulin sensitivity, effects which were also attained with MIF inhibitor ISO-1. MIF−/− liver exhibited reduced hepatic triacyglyceride accumulation, enhanced pAKT expression and reduced NFκB activation. MIF deficiency partially protects from high-fat diet induced insulin resistance by attenuating macrophage infiltration, ameliorating adipose inflammation, which improved adipocyte insulin resistance ex vivo. MIF represents a potential therapeutic target for treatment of high-fat diet induced insulin resistance.

Emerging evidence has demonstrated that saturated fatty acids prime pro-IL-1β production and inflammasome-mediated IL-1β activation is critical in obesity-associated insulin resistance (IR). Nonetheless, IL-1 receptor I-deficient (IL-1RI−/−) mice develop mature-onset obesity despite consuming a low-fat diet (LFD). With this apparent contradiction, the present study evaluated whether IL-1RI−/− mice were protected against long-term (6 mo) high-fat diet (HFD)-induced IR. Male wild-type and IL-1RI−/− mice were fed LFD or HFD for 3 or 6 mo, and glucose and insulin tolerance tests were performed. Adipose insulin sensitivity, cytokine profiles, and adipocyte morphology were assessed. The adipogenic potential of stromal vascular fraction was determined. Hepatic lipid accumulation and insulin sensitivity were characterized. IL-1RI−/− mice developed glucose intolerance and IR after 6 mo HFD compared with 3 mo HFD, coincident with enhanced weight gain, hyperinsulinemia, and hyperleptinemia. The aggravated IR phenotype was associated with loss of adipose functionality, switch from adipocyte hyperplasia to hypertrophy and hepatosteatosis. Induction of adipogenic genes was reduced in IL-1RI−/− preadipocytes after 6 mo HFD compared with 3 mo HFD. Obese LFD-IL-1RI−/− mice exhibited preserved metabolic health. IL-1RI−/− mice develop glucose intolerance and IR after 6 mo HFD intervention. While mature-onset obesity is evident in LFD-IL-1RI−/− mice, the additional metabolic insult of HFD was required to drive adipose inflammation and systemic IR. These findings indicate an important interaction between dietary fat and IL-1, relevant to optimal metabolic health.

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