ABSTRACT
SCOPE: Activation of the nod-like receptor protein 3 (NLRP3) inflammasome is required for IL-1ß release and is a key component of obesity-induced inflammation and insulin resistance. This study hypothesized that supplementation with a casein hydrolysate (CH) would attenuate NLRP3 inflammasome mediated IL-1ß secretion in adipose tissue (AT) and improve obesity-induced insulin resistance. METHODS AND RESULTS: J774.2 macrophages were LPS primed (10 ng/mL) and stimulated with adenosine triphosphate (5 mM) to assess NLRP3 inflammasome activity. Pretreatment with CH (1 mg/mL; 48 h) reduced caspase-1 activity and decreased IL-1ß secretion from J774.2 macrophages in vitro. 3T3-L1 adipocytes cultured with conditioned media from CH-pretreated J774.2 macrophages demonstrated increased phosphorylated (p)AKT expression and improved insulin sensitivity. C57BL/6JOLaHsd mice were fed chow or high fat diet (HFD) for 12 wk ± CH resuspended in water (0.5% w/v). CH supplementation improved glucose tolerance in HFD-fed mice as determined by glucose tolerance test. CH supplementation increased insulin-stimulated pAKT protein levels in AT, liver, and muscle after HFD. Cytokine secretion was measured from AT and isolated bone marrow macrophages cultured ex vivo. CH supplementation attenuated IL-1ß, tumor necrosis factor alpha (TNF-α) and IL-6 secretion from AT and IL-1ß, IL-18, and TNF-α from bone marrow macrophages following adenosine triphosphate stimulation ex vivo. CONCLUSION: This novel CH partially protects mice against obesity-induced hyperglycemia coincident with attenuated IL-1ß secretion and improved insulin signaling.
Subject(s)
Adipose Tissue/metabolism , Caseins/pharmacology , Inflammasomes/metabolism , Obesity/metabolism , 3T3-L1 Cells , Animals , Cytokines/metabolism , Diabetes Mellitus, Type 2/diet therapy , Diet, High-Fat/adverse effects , Hyperglycemia/metabolism , Inflammation/metabolism , Insulin/metabolism , Insulin Resistance/physiology , Interleukin-1beta/metabolism , Interleukin-6/metabolism , Mice , Mice, Inbred C57BL , NLR Family, Pyrin Domain-Containing 3 Protein , NLR Proteins , Tumor Necrosis Factor-alpha/drug effects , Tumor Necrosis Factor-alpha/metabolismABSTRACT
Saturated fatty acid (SFA) high-fat diets (HFDs) enhance interleukin (IL)-1ß-mediated adipose inflammation and insulin resistance. However, the mechanisms by which different fatty acids regulate IL-1ß 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-1ß 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-1ß priming, attenuated adipose IL-1ß 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-1ß 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-1ß-mediated insulin resistance and adipose dysfunction despite obesity via the preservation of AMPK activity.
Subject(s)
Adipose Tissue/drug effects , Adipose Tissue/metabolism , Carrier Proteins/metabolism , Diet, High-Fat/adverse effects , Fatty Acids, Monounsaturated/pharmacology , Insulin Resistance/physiology , Interleukin-1beta/metabolism , Obesity/metabolism , AMP-Activated Protein Kinases/genetics , AMP-Activated Protein Kinases/metabolism , Animals , Cells, Cultured , Humans , Male , Mice , Mice, Inbred C57BL , NLR Family, Pyrin Domain-Containing 3 ProteinABSTRACT
The metabolic syndrome (MetS) is a complex multifactorial disorder and its incidence is on the increase worldwide. Due to the definitive link between obesity and the MetS weight loss strategies are of prime importance in halting the spread of MetS. Numerous epidemiological studies provide evidence linking dietary patterns to incidence of MetS symptoms. As a consequence of the epidemiology studies, dietary intervention studies which analyse the effects of supplementing diets with particular nutrients of interest on the symptoms of the MetS have been conducted. Evidence has shown that lifestyle intervention comprising changes in dietary intake and physical activity leads to an improved metabolic profile both in the presence or absence of weight loss thus highlighting the importance of a multi-faceted approach in combating MetS. Nutritional therapy research is not focused solely on reducing energy intake and manipulating macronutrient intake but is investigating the role of functional foods or bioactive components of food. Such bioactives which target weight maintenance and /or insulin sensitivity may have a potentially positive effect on the symptoms of the MetS. However the efficacy of different functional nutrients needs to be further defined and clearly demonstrated.
