Relationship between the lipidome, inflammatory markers and insulin resistance.

The objectives of the present study were to (1) examine the effects of the phenotypic factors age, gender and BMI on the lipidomic profile and (2) investigate the relationship between the lipidome, inflammatory markers and insulin resistance. Specific ceramide, phosphatidylcholine and phosphatidylethanolamine lipids were increased in females relative to males and specific lysophosphatidylcholine, lysophosphatidylethanolamine, phosphatidylcholine and phosphatidylethanolamine lipids decreased as BMI increased. However, age had a minimal effect on the lipid profile with significant differences found in only two lipid species. Network analysis revealed strong negative correlations between the inflammatory markers CRP, TNF-α, resistin and MCP-1 and lipids in the LPC, PC and PE classes, whereas IL-8 formed positive correlations with lipids from the CER and SM classes. Further analysis revealed that LPC a C18:1 and PE ae C40:6 were highly associated with insulin resistance as indicated by HOMA-IR score. The present study identified lipids that are affected by BMI and gender and identified a series of lipids which had significant relationships with inflammatory markers. LPC a C18:1 and PE ae C40:6 were found to be highly associated with insulin resistance pointing to the possibility that the alterations in these specific lipids may play a role in the development of insulin resistance.

Long-term exposure to a high-fat diet results in the development of glucose intolerance and insulin resistance in interleukin-1 receptor I-deficient mice.

Emerging evidence has demonstrated that saturated fatty acids prime pro-IL-1ß production and inflammasome-mediated IL-1ß 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.

Remission of chronic fungal asthma in the absence of CCR8.

BACKGROUND: Experimental studies have generated conflicting data regarding the role of CCR8 in antigen-driven allergic airway disease models, thereby dampening enthusiasm for further exploration of the targeting of CCR8 in asthma. OBJECTIVE: Recent data show that the absence of CCR8 leads to a marked amplification of the innate immune response, and these data provided impetus for the current study, which addressed the role of this chemokine receptor in a model of fungal asthma. METHODS: Wild-type (CCR8(+/+)) and CCR8-deficient (CCR8(-/-)) mice were sensitized to Aspergillus fumigatus antigens and challenged via intra-tracheal injection with live fungal conidia, and parameters of airway hyperresponsiveness, inflammation, and remodeling were examined. RESULTS: At day 7 after conidia challenge in wild-type (CCR8(+/+)) and CCR8-deficient (CCR8(-/-)) mice sensitized to A. fumigatus antigens, markedly less fungal material was present in the lungs of the CCR8(-/-) group compared with the CCR8(+/+) group. At day 14 after conidia challenge, all characteristic airway physiology, inflammatory, and remodeling parameters of fungal asthma were significantly decreased or abolished in the CCR8(-/-) group relative to the CCR8(+/+) group. CONCLUSION: Together these data show that an enhanced innate immune response in the absence of CCR8 promotes the rapid clearance of fungal material from the lung, thereby facilitating the remission of fungal asthma. CLINICAL IMPLICATIONS: This study shows that the clearance of fungal material from the lung was enhanced in the absence of CCR8, which suggests that this receptor may be an attractive target in fungal-allergic asthma and other fungal-associated pulmonary diseases.