Saturated fatty acid (SFA) high-fat diets (HFDs) enhance interleukin (IL)-1β–mediated adipose inflammation and insulin resistance. However, the mechanisms by which different fatty acids regulate IL-1β and the subsequent effects on adipose tissue biology and insulin sensitivity in vivo remain elusive. We hypothesized that the replacement of SFA for monounsaturated fatty acid (MUFA) in HFDs would reduce pro-IL-1β priming in adipose tissue and attenuate insulin resistance via MUFA-driven AMPK activation. MUFA-HFD–fed mice displayed improved insulin sensitivity coincident with reduced pro-IL-1β priming, attenuated adipose IL-1β secretion, and sustained adipose AMPK activation compared with SFA-HFD–fed mice. Furthermore, MUFA-HFD–fed mice displayed hyperplastic adipose tissue, with enhanced adipogenic potential of the stromal vascular fraction and improved insulin sensitivity. In vitro, we demonstrated that the MUFA oleic acid can impede ATP-induced IL-1β secretion from lipopolysaccharide- and SFA-primed cells in an AMPK-dependent manner. Conversely, in a regression study, switching from SFA- to MUFA-HFD failed to reverse insulin resistance but improved fasting plasma insulin levels. In humans, high-SFA consumers, but not high-MUFA consumers, displayed reduced insulin sensitivity with elevated pycard-1 and caspase-1 expression in adipose tissue. These novel findings suggest that dietary MUFA can attenuate IL-1β–mediated insulin resistance and adipose dysfunction despite obesity via the preservation of AMPK activity.

Obstructive sleep apnoea (OSA) is increasingly associated with insulin resistance. The underlying pathophysiology remains unclear but intermittent hypoxia (IH)-mediated inflammation and subsequent dysfunction of the adipose tissue has been hypothesised to play a key role.We tested this hypothesis employing a comprehensive translational approach using a murine IH model of lean and diet-induced obese mice, an innovative IH system for cell cultures and a tightly controlled patient cohort.IH led to the development of insulin resistance in mice, corrected for the degree of obesity, and reduced insulin-mediated glucose uptake in 3T3-L1 adipocytes, associated with inhibition of the insulin-signalling pathway and downregulation of insulin-receptor substrate-1 mRNA. Providing mechanistic insight, IH induced a pro-inflammatory phenotype of visceral adipose tissue in mice with pro-inflammatory M1 macrophage polarisation correlating with the severity of insulin resistance. Complimentary analysis demonstrated that IH led to M1 polarisation of THP1-derived macrophages. In subjects without comorbidities (n=186), OSA was independently associated with insulin resistance. Furthermore, we found an independent correlation of OSA severity with the M1 macrophage inflammatory marker sCD163.This study provides evidence that IH induces a pro-inflammatory phenotype of the adipose tissue, which may be a crucial link between OSA and the development of insulin resistance.

H igh-density lipoprotein (HDL) particles play a pivotal role in reverse cholesterol transport (RCT) by facilitating cholesterol efflux from peripheral cells and delivering acquired lipid to the liver for elimination in the feces. 1 Obesity increases the risk of developing cardiovascular disease (CVD) 2 ; however, little is known about the impact of obesity on HDL function and RCT. Chronic inflammation is a classic hallmark of obesity 3 and CVD, 4 and it is plausible there is a common inflammatory-driven mechanism Background-Acute inflammation impairs reverse cholesterol transport (RCT) and reduces high-density lipoprotein (HDL) function in vivo. This study hypothesized that obesity-induced inflammation impedes RCT and alters HDL composition, and investigated if dietary replacement of saturated (SFA) for monounsaturated (MUFA) fatty acids modulates RCT. Methods and Results-Macrophage-to-feces RCT, HDL efflux capacity, and HDL proteomic profiling was determined in C57BL/6j mice following 24 weeks on SFA-or MUFA-enriched high-fat diets (HFDs) or low-fat diet. The impact of dietary SFA consumption and insulin resistance on HDL efflux function was also assessed in humans. Both HFDs increased plasma 3 H-cholesterol counts during RCT in vivo and ATP-binding cassette, subfamily A, member 1-independent efflux to plasma ex vivo, effects that were attributable to elevated HDL cholesterol. By contrast, ATP-binding cassette, subfamily A, member 1-dependent efflux was reduced after both HFDs, an effect that was also observed with insulin resistance and high SFA consumption in humans. SFA-HFD impaired liver-to-feces RCT, increased hepatic inflammation, and reduced ABC subfamily G member 5/8 and ABC subfamily B member 11 transporter expression in comparison with low-fat diet, whereas liver-to-feces RCT was preserved after MUFA-HFD. HDL particles were enriched with acute-phase proteins (serum amyloid A, haptoglobin, and hemopexin) and depleted of paraoxonase-1 after SFA-HFD in comparison with MUFA-HFD. Conclusions-Ex vivo efflux assays validated increased macrophage-to-plasma RCT in vivo after both HFDs but failed to capture differential modulation of hepatic cholesterol trafficking. By contrast, proteomics revealed the association of hepatic-derived inflammatory proteins on HDL after SFA-HFD in comparison with MUFA-HFD, which reflected differential hepatic cholesterol trafficking between groups. Acute-phase protein levels on HDL may serve as novel biomarkers of impaired liver-to-feces RCT in vivo. Correspondence to Fiona C. McGillicuddy, UCD Conway Institute, School of Medicine, University College Dublin, Dublin 4, Ireland. E-mail fiona.mcgillicuddy@ucd.ie © 2016 The Authors. Circulation is published on behalf of the American Heart Association, Inc., by Wolters Kluwer. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited and is not used for commercial pur...

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Scope: Insulin resistance (IR) and chronic inflammation are hallmarks of Type 2 Diabetes (T2D). The ‘nod like receptor pyrin domain containing-3’ (NLRP3) inflammasome is a metabolic sensor activated by saturated fatty acids (SFA) to initiate IL-β inflammation and IR. This study investigated whether interactions between SFA intake and genetic variants related to NLRP3, altered T2D risk factors. Methods: Fixed-effect meta-analyses of six Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium (n=19,005), tested interactions between SFA and NLRP3 related SNPs and modulation of fasting insulin, fasting glucose, and Homeostasis Model Assessment of Insulin Resistance. Results: rs12143966 interacted with SFA, each 1% increase in SFA energy intake, increased fasting insulin by 0.0063 IU/mL (SE± 0.002, p=0.001) per each copy of the major (G) allele. rs4925663 (OR2B11 upstream of NLRP3), interacted with SFA (β ± SE = −0.0058 ± 0.002, p=0.004), to increase fasting insulin by 0.0058 IU/mL, per additional copy of the major (C) allele. Both associations are close to significance threshold (P<0.0001). rs4925663 causes a missense mutation affecting NLRP3 expression. Conclusion: Two NLRP3-related SNPs showed a novel interaction with dietary SFA to modulate fasting insulin. Greater SFA intake may heighten T2D risk, depending on inflammasome related genetic variants.