The Interplay of Obesity, Dyslipidemia and Immune Dysfunction: A Brief Overview on Pathophysiology, Animal Models, and Nutritional Modulation

Obesity has emerged as a leading global health concern. It is characterized by chronic low-grade inflammation, which impairs insulin signaling, lipid metabolism and immune function. Recent findings from animal and clinical studies have begun to elucidate the underlying mechanisms of immune dysfunction seen in the context of obesity. Here, we provide a brief review on the current understanding of the interplay between obesity, dyslipidemia and immunity. We also emphasize the advantages and shortcomings of numerous applicable research models including rodents and large animal swine that aim at unraveling the molecular basis of disease and clinical manifestations. Although there is no perfect model to answer all questions at once, they are often used to complement each other. Finally, we highlight some emerging nutritional strategies to improve immune function in the context of obesity with a particular focus on choline and foods that contains high amounts of choline

Effect of High-Fat and Low-Fat Dairy Products on Cardiometabolic Risk Factors and Immune Function in a Low Birthweight Swine Model of Diet-Induced Insulin Resistance

Although dairy intake has been shown to have a neutral or some beneficial effect on major cardiometabolic risk factors, the impact of dairy, and especially dairy fat, on immune function remains to be investigated. To understand the effect of consuming dairy fat on cardiometabolic risk factors and immune function, we used an established low birthweight (LBW) swine model of diet-induced insulin resistance to compare high-fat and low-fat dairy products to a control high-fat diet (CHF). LBW piglets were randomized to consume one of the 3 experimental HF diets: (1) CHF, (2) CHF diet supplemented with 3 servings/day of high-fat dairy (HFDairy) and (3) CHF diet supplemented with 3 servings/day of low-fat dairy (LFDairy). As comparison groups, normal birthweight (NBW) piglets were fed a CHF (NBW-CHF) or standard pig grower diet (NBW-Chow). A total of 35 pigs completed the study and were fed for a total of 7 weeks, including 1 week of CHF transition diet. At 12 weeks of age, piglets were euthanized. Fasting blood and tissue samples were collected. Ex vivo cytokine production by peripheral blood mononuclear cells (PBMCs) stimulated with pokeweed (PWM), phytohemagglutinin (PHA) and phorbol myristate acetate-ionomycin (PMA-I) were assessed. As expected, LBW-CHF piglets showed early signs of insulin resistance (HOMA-IR, P model = 0.08). Feeding high-fat dairy products improved fasting plasma glucose concentrations more than low-fat dairy compared to LBW-CHF (P < 0.05). Irrespective of fat content, dairy consumption had neutral effect on fasting lipid profile. We have also observed lower production of IL-2 after PWM and PHA stimulation as well as lower production of TNF-α and IFN-γ after PWM stimulation in LBW-CHF than in NBW-Chow (all, P < 0.05), suggesting impaired T cell and antigen presenting cell function. While feeding high-fat dairy had minimal effect on immune function, feeding low-fat dairy significantly improved the production of IL-2, TNF-α and IFN-γ after PWM stimulation, IL-2 and IFN-γ after PHA stimulation as well as TNF-α after PMA-I stimulation compared to LBW-CHF (all, P < 0.05). These data provide novel insights into the role of dairy consumption in counteracting some obesity-related cardiometabolic and immune perturbations

Vaccenic acid suppresses intestinal inflammation by increasing anandamide and related N-acylethanolamines in the JCR:LA-cp rat

Vaccenic acid (VA), the predominant ruminantderived trans fat in the food chain, ameliorates hyperlipidemia, yet mechanisms remain elusive. We investigated whether VA could influence tissue endocannabinoids (ECs) by altering the availability of their biosynthetic precursor, arachidonic acid (AA), in membrane phospholipids (PLs). JCR:LA-cp rats were assigned to a control diet with or without VA (1% w/w), cis-9, trans-11 conjugated linoleic acid (CLA) (1% w/w) or VA+CLA (1% + 0.5% w/w) for 8 weeks. VA reduced the EC, 2-arachidonoylglycerol (2-AG), in the liver and visceral adipose tissue (VAT) relative to control diet (P 0.05). Interestingly, VA increased jejunal concentrations of anandamide and those of the noncannabinoid signaling molecules, oleoylethanolamide and palmitoylethanolamide, relative to control diet (P < 0.05). This was consistent with a lower jejunal protein abundance (but not activity) of their degrading enzyme, fatty acid amide hydrolase, as well as the mRNA expression of TNFα and interleukin 1β (P < 0.05). The ability of VA to reduce 2-AG in the liver and VAT provides a potential mechanistic explanation to alleviate ectopic lipid accumulation. The opposing regulation of ECs and other noncannabinoid lipid signaling molecules by VA suggests an activation of benefit via the EC system in the intestine

Cardiomyocyte Antihypertrophic Effect of Adipose Tissue Conditioned Medium from Rats and Its Abrogation by Obesity is Mediated by the Leptin to Adiponectin Ratio.

White adipocytes are known to function as endocrine organs by secreting a plethora of bioactive adipokines which can regulate cardiac function including the development of hypertrophy. We determined whether adipose tissue conditioned medium (ATCM) generated from the epididymal regions of normal rats can affect the hypertrophic response of cultured rat ventricular myocytes to endothelin-1 (ET-1) administration. Myocytes were treated with ET-1 (10 nM) for 24 hours in the absence or presence of increasing ATCM concentrations. ATCM supressed the hypertrophic response to ET-1 in a concentration-dependent manner, an effect enhanced by the leptin receptor antagonist and attenuated by an antibody against the adiponectin AdipoR1 receptor. Antihypertrophic effects were also observed with ATCM generated from perirenal-derived adipose tissue. However, this effect was absent in ATCM from adipose tissue harvested from corpulent JCR:LA-cp rats. Detailed analyses of adipokine content in ATCM from normal and corpulent rats revealed no differences in the majority of products assayed, although a significant increase in leptin concentrations concomitant with decreased adiponectin levels was observed, resulting in a 11 fold increase in the leptin to adiponectin ratio in ATCM from JCR:LA-cp. The antihypertrophic effect of ATCM was associated with increased phosphorylation of AMP-activated protein kinase (AMPK), an effect abrogated by the AdipoR1 antibody. Moreover, the antihypertrophic effect of ATCM was mimicked by an AMPK activator. There was no effect of ET-1 on mitogen-activated protein kinase (MAPK) activities 24 hour after its addition either in the presence or absence of ATCM. Our study suggests that adipose tissue from healthy subjects exerts antihypertrophic effects via an adiponectin-dependent pathway which is impaired in obesity, most likely due to adipocyte remodelling resulting in enhanced leptin and reduced adiponectin levels

High Vaccenic Acid Content in Beef Fat Attenuates High Fat and High Carbohydrate Western Diet Induced Changes in Lipid Metabolism and Gut Microbiota in Pigs

High-fat diets (HFD) have been shown to induce substantial shifts in intestinal microbial community composition and activity which are associated with adverse metabolic outcomes. Furthermore, changes in microbial composition are affected by fatty acid composition; saturated, monounsaturated (MUFA), and industrial trans fats (iTFA) adversely affect microbial diversity while polyunsaturated fats (PUFA) have been shown to have neutral effects. The effects of naturally occurring trans fats on gut microbial composition are unknown. Vaccenic acid (VA) is the most abundant naturally occurring trans fat (abundant in meat and dairy), can be elevated by altering a cow’s diet, and has been shown to have hypolipidemic effects. The aim of this study was to determine how variations of VA content in beef fat affect gut microbial composition, insulin resistance, and lipid metabolism in pigs. Low birth weight (LBW) and control pigs were fed a control or high-fat, high-carbohydrate (HFHC) diet supplemented with beef fat containing either high or low VA levels for 7 weeks. An adapted modified oral glucose tolerance test and fat challenge test were performed at 9 weeks of age following implantation of jugular catheters. Impacts on microbial composition were assessed using 16S rRNA gene amplicon sequencing. The HFHC diet containing beef fat rich in VA had a mild insulin sensitizing effect (p p p < 0.05), and showed protection from HFHC-induced changes to gut microbial composition in LBW pigs as compared to HFHC diet containing standard beef fat. This is the first study to show effects of natural trans fats on gut dysbiosis; further studies are needed to elucidate mechanisms

Effect of fractionated ATCM using 30 kDa cut-off filters.

<p>Panel A shows surface area for myocytes treated with ET-1 with or without high molecular weight (>30 kDa) or low molecular weight (<30 kDa) ATCM for 24 hours after ET-1 addition whereas B and C show fetal gene α-Skeletal actin and ANP expression, respectively with identical treatments. Values indicate mean + SEM (n = 6). <i>*P <</i> .05 from untreated group; ^<i>#</i><i>P<</i>0.05 from ET-1 alone; ^<i>¥</i><i>P<</i>0.05 from ET-1 + >30kDa ATCM.</p