Low-fat dairy consumption improves intestinal immune function more than high-fat dairy in a diet-induced swine model of insulin resistance.

PURPOSE: To understand the effects of consuming high-fat and low-fat dairy products on postprandial cardiometabolic risk factors and intestinal immune function, we used an established low birthweight (LBW) swine model of diet-induced insulin resistance. METHODS: LBW piglets were randomized to consume one of the 3 experimental high fat diets and were fed for a total of 7 weeks: (1) Control high fat (LBW-CHF), (2) CHF diet supplemented with 3 servings of high-fat dairy (LBW-HFDairy) and (3) CHF diet supplemented with 3 servings of low-fat dairy (LBW-LFDairy). As comparison groups, normal birthweight (NBW) piglets were fed a CHF (NBW-CHF) or standard pig grower diet (NBW-Chow). At 11 weeks of age, all piglets underwent an established modified oral glucose and fat tolerance test. At 12 weeks of age, piglets were euthanized and ex vivo cytokine production by cells isolated from mesenteric lymph node (MLN) stimulated with mitogens was assessed. RESULTS: Dairy consumption did not modulate postprandial plasma lipid, inflammatory markers and glucose concentrations. A lower production of IL-2 and TNF-α after pokeweed mitogen (PWM) stimulation was observed in LBW-CHF vs NBW-Chow (P < 0.05), suggesting impaired MLN T cell function. While feeding high-fat dairy had minimal effects, feeding low-fat dairy significantly improved the production of IL-2 and TNF-α after PWM stimulation (P < 0.05). CONCLUSIONS: Irrespective of fat content, dairy had a neutral effect on postprandial cardiometabolic risk factors. Low-fat dairy products improved intestinal T cell function to a greater extent than high-fat dairy in this swine model of obesity and insulin resistance.

Methionine restriction alleviates diabetes-associated cognitive impairment via activation of FGF21.

Glucose metabolism disturbances may result in diabetes-associated cognitive decline (DACI). Methionine restriction (MR) diet has emerged as a potential dietary strategy for managing glucose homeostasis. However, the effects and underlying mechanisms of MR on DACI have not been fully elucidated. Here, we found that a 13-week MR (0.17 % methionine, w/w) intervention starting at 8 weeks of age improved peripheral insulin sensitivity in male db/db mice, a model for type 2 diabetes. Notably, MR significantly improved working as well as long-term memory in db/db mice, accompanied by increased PSD-95 level and reduced neuroinflammatory factors, malondialdehyde (MDA), and 8-hydroxy-2'-deoxyguanosine (8-OHdG). We speculate that this effect may be mediated by MR activating hepatic fibroblast growth factor 21 (FGF21) and the brain FGFR1/AMPK/GLUT4 signaling pathway to enhance brain glucose metabolism. To further delineate the mechanism, we used intracerebroventricular injection of adeno-associated virus to specifically knock down FGFR1 in the brain to verify the role of FGFR1 in MR-mediated DACI. It was found that the positive effects of MR on DACI were offset, reflected in decreased cognitive function, impaired synaptic plasticity, upregulated neuroinflammation, and balanced enzymes regulating reactive oxygen species (Sod1, Sod2, Nox4). Of note, the FGFR1/AMPK/GLUT4 signaling pathway and brain glucose metabolism were inhibited. In summary, our study demonstrated that MR increased peripheral insulin sensitivity, activated brain FGFR1/AMPK/GLUT4 signaling through FGF21, maintained normal glucose metabolism and redox balance in the brain, and thereby alleviated DACI. These results provide new insights into the effects of MR diet on cognitive dysfunction caused by impaired brain energy metabolism.

Muscle Fiber, Connective Tissue and Meat Quality Characteristics of Pork from Low Birth Weight Pigs as Affected by Diet-Induced Increased Fat Absorption and Preferential Muscle Marbling.

This study investigated how birth weight differences in piglets affected carcass and muscle fiber properties as well as meat quality at slaughter. Within litters, piglets were grouped according to their birth weight as either normal (NBW; 1.62-1.73 kg) or low (LBW; 1.18-1.29 kg). At 5 weeks of age, NBW piglets were randomly transitioned to control (C) or isocaloric high fat diets derived from non-dairy (HF), while LBW piglets were randomly transitioned to high fat diets derived from non-dairy (HF) or dairy sources (HFHD). Piglets were reared in individual pens under standardized housing and feeding conditions. Live weight was recorded weekly, and pigs were slaughtered at 12 weeks of age. Hot carcass weights, dressing percentages, lean meat yield, and primal cut proportions were determined. The m. longissimus thoracis was collected from the right side of the carcass for measurement of physical and chemical properties of meat and muscle fiber characteristics. Results indicated that LBW pigs compensated for their live weight compared to NBW pigs at 6 weeks of age. The mean muscle fiber diameter of LBW-HFHD group is significantly higher than NBW-C and NBW-HF group, and the type I muscle fiber diameter is significantly higher than NBW-C group. Dairy fat inclusion in LBW pig diet reduced carcass back fat thickness. This increased the calculated lean meat yield to be comparable to that of NBW pigs fed a commercial diet. Incorporating dairy-sourced high-fat into LBW pigs' diets appears to be an effective strategy for producing carcasses equivalent to NBW pigs.

Corrigendum: The interplay of obesity, dyslipidemia and immune dysfunction: a brief overview on pathophysiology, animal models, and nutritional modulation.

[This corrects the article DOI: 10.3389/fnut.2022.840209.].

Preferential deposition of dairy derived fatty acids in muscle tissue is partially due to the upregulation of CD36 in a low-birth-weight swine model.

Metabolic syndrome is a worldwide health issue. Previous research has revealed that low-birth weight (LBW) swine fed a high-fat (HF) diet were susceptible to insulin resistance (IR) and developed a preferential intestinal lipid absorption, hypertriglyceridemia, and muscle steatosis. We hypothesized that fatty acid transporters such as CD36, FATP4, and FABP2 could potentially explain the development of these conditions. In addition, dairy-derived fatty acids have been shown to be valid biomarkers to assess dairy intake, which can be utilized to investigate muscle lipid deposition in LBW swine. The overall aim of this study was to delineate molecular transport candidates responsible for intestinal lipid absorption and muscle lipid deposition in LBW swine; and secondly to determine what dietary fatty acids might accumulate preferentially in pork muscle when consuming dairy products. At 5 weeks of age, normal birth weight (NBW) and LBW piglets were randomly assigned to three experimental diets: 1-chow diet, 2-HF diet, or 3-isocaloric HF diet supplemented with full fat dairy products. At 12 weeks of age, piglets were euthanized, and carcass, fasting plasma, biceps femoris and jejunum mucosal scrapings were collected. Results showed that HF-fed LBW swine exhibited early signs of IR (fasting glucose, P < 0.05; fasting insulin, P = 0.091; HOMA-IR, P = 0.086) compared with NBW-Chow, which were attenuated with increased dairy intake. Muscle samples from HF-fed LBW swine contained significantly more triglyceride compared to Chow-fed NBW swine (P < 0.05). Increased dairy intake significantly increased myristic acid (C14:0) and DPA (C22:5n3) relative to HF feeding alone (P < 0.05). All HF-fed LBW swine (regardless of dairy intake) exhibited an upregulation of CD36 expression (but not FABP2) compared with NBW littermates in both the small intestine and muscle (P < 0.05). Interestingly, increased dairy intake significantly increased the Canadian Lean Yield percentage in LBW swine fed an HF diet (P < 0.05). Findings from this study provide evidence on the mechanistic pathway of intestinal and muscle lipid metabolism in an innovative LBW swine model. We have also revealed that increasing dairy intake can enhance the incorporation of dietary long-chain polyunsaturated fatty acids into pork, as well as increasing the predicted lean yield of the carcass.

Metabolic syndrome affects millions of people worldwide, and large animal models represent a unique opportunity for research advancement. Intensive swine production can induce low-birth weight (LBW) litters. We have developed an innovative LBW swine model to investigate insulin resistance and dyslipidemia. We present evidence to explain how LBW swine can upregulate lipid intestinal absorption as well as preferentially increase pork marbling. We have also identified a potential added value approach to increase healthy fatty acids in pork and/or increase the carcass lean yield in LBW swine.

Corrigendum: 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.

[This corrects the article DOI: 10.3389/fnut.2022.923120.].

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.

A combination of single nucleotide polymorphisms is associated with the interindividual variability in the blood lipid response to dietary fatty acid consumption in a randomized clinical trial.

BACKGROUND: Blood lipid concentrations display high interindividual variability in response to dietary interventions, partly due to genetic factors. Existing studies have focused on single nucleotide polymorphisms (SNPs) analyzed individually, which only explain a limited fraction of the variability of these complex phenotypes. OBJECTIVE: We aimed to identify combinations of SNPs associated with the variability in LDL cholesterol and triglyceride (TG) concentration changes following 5 dietary interventions. DESIGN: In a multicenter randomized crossover trial, 92 participants with elevated waist circumference and low HDL cholesterol concentrations consumed 5 isoenergetic diets for 4 wk: a diet rich in saturated fatty acids (SFAs) from cheese, SFA from butter, monounsaturated fatty acids (MUFAs), n-6 polyunsaturated fatty acids (PUFAs), and a diet higher in carbohydrates (CHO). The association between 22 candidate SNPs in genes involved in lipid and bile acid metabolism and transport and changes in LDL cholesterol and TG concentrations was assessed with univariate statistics followed by partial least squares regression. RESULTS: Endpoint LDL cholesterol concentrations were significantly different (cheese: 3.18 ± 0.04, butter: 3.31 ± 0.04, MUFA: 3.00 ± 0.04, PUFA: 2.81 ± 0.04, CHO: 3.11 ± 0.04 mmol/L; P < 0.001) while endpoint TG concentrations were not (P = 0.117). Both displayed consistently elevated interindividual variability following the dietary interventions (CVs of 34.5 ± 2.2% and 55.8 ± 1.8%, respectively). Among the 22 candidate SNPs, only ABCA1-rs2066714 and apolipoprotein E (APOE) isoforms exhibited consistent significant effects, namely on LDL cholesterol concentrations. However, several SNPs were significantly associated with changes in LDL cholesterol and TG concentrations in a diet-specific fashion. Generated multivariate models explained from 16.0 to 33.6% of the interindividual variability in LDL cholesterol concentration changes and from 17.5 to 32.0% of that in TG concentration changes. CONCLUSIONS: We report combinations of SNPs associated with a significant part of the variability in LDL cholesterol and TG concentrations following dietary interventions differing in their fatty acid profiles.

Use of starch-based fat replacers in foods as a strategy to reduce dietary intake of fat and risk of metabolic diseases.

Cardiovascular disease (CVD) has emerged as one of the leading causes of death worldwide. Elevated blood cholesterol and low-density lipoprotein levels are crucial risk factors that contribute to the development of CVD and other metabolic diseases. Dietary fat is believed to be the key factor in modulating circulating cholesterol levels. Thus, reducing dietary intake of fat appears to be an effective strategy to reduce the risk of heart disease. Also, excessive intake of fat and high-calorie foods is also related to the development of obesity, which contributes to the development of CVD. Therefore, the consumption of low-fat low-calorie foods is part of a healthier dietary pattern. However, simply removing fat from foods may lead to compromised overall quality and reduced acceptance of the food products. Thus, fat replacers have emerged as ideal alternatives to dietary fat, which can not only reduce the overall fat and calorie content of the foods but also mimic the physiochemical properties of dietary fat. Starch-based fat replacers are one kind of fat mimetic that can be produced either chemically as modified starch or enzymatically as maltodextrins. Both modified starch and maltodextrins have been demonstrated to have a promising ability to improve the overall quality of reduced-fat foods. Modified starch granules act directly as fat globules in modulating the structure and sensory characteristics of the foods, whereas maltodextrins can form thermoreversible gels. Both modified starch granules and maltodextrins can create a fat-like mouthfeel and therefore are potential fat replacers. This review article aims to discuss the following topics: (a) the effect of carbohydrates and fat on human cardiovascular health and other disease risks, (b) the functionality of starch-based fat replacers in foods, (c) the applications of starch-based fat replacers in various foods, and (d) the current and future market value of starch-based fat replacers.

Is Plant Sterols a Good Strategy to Lower Cholesterol?

Cardiovascular disease (CVD) has emerged as the leading cause of dealth worldwide today. Lowering circulating total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) is one of the most effective approaches of CVD prevention. Dietary guidelines and health organizations approved using plant sterols (PS) as the alternative to conventional method in attenuating circulating TC and LDL-C levels and risk of CVD. However, current findings apprear to be controversial on the efficacy of PS. Giving the rise of the field "Nutrigenetics", single nucleotide polymorphisms (SNPs) such as CYP7A1-rs3808607 have been identified that strongly associate with cholesterol metabolism in response to PS intake, towards causing inter-individual variations. This review article aims to discuss the efficacy of dietary PS in managing cholesterol levels based on findings from recent studies. The scope includes reviewing evidence on supporting the efficacy, the metabolic claims, inter-individual variations as well as sitosterolemia associated with PS intake.

Comparison of the impact of SFAs from cheese and butter on cardiometabolic risk factors: a randomized controlled trial.

Background: Controversies persist concerning the association between intake of dietary saturated fatty acids (SFAs) and cardiovascular disease risk.Objective: We compared the impact of consuming equal amounts of SFAs from cheese and butter on cardiometabolic risk factors.Design: In a multicenter, crossover, randomized controlled trial, 92 men and women with abdominal obesity and relatively low HDL-cholesterol concentrations were assigned to sequences of 5 predetermined isoenergetic diets of 4 wk each separated by 4-wk washouts: 2 diets rich in SFAs (12.4-12.6% of calories) from either cheese or butter; a monounsaturated fatty acid (MUFA)-rich diet (SFAs: 5.8%, MUFAs: 19.6%); a polyunsaturated fatty acid (PUFA)-rich diet (SFAs: 5.8%, PUFAs: 11.5%); and a low-fat, high-carbohydrate diet (fat: 25%, SFAs: 5.8%).Results: Serum HDL-cholesterol concentrations were similar after the cheese and butter diets but were significantly higher than after the carbohydrate diet (+3.8% and +4.7%, respectively; P < 0.05 for both). LDL-cholesterol concentrations after the cheese diet were lower than after the butter diet (-3.3%, P < 0.05) but were higher than after the carbohydrate (+2.6%), MUFA (+5.3%), and PUFA (+12.3%) diets (P < 0.05 for all). LDL-cholesterol concentrations after the butter diet also increased significantly (from +6.1% to +16.2%, P < 0.05) compared with the carbohydrate, MUFA, and PUFA diets. The LDL-cholesterol response to treatment was significantly modified by baseline values (P-interaction = 0.02), with the increase in LDL cholesterol being significantly greater with butter than with cheese only among individuals with high baseline LDL-cholesterol concentrations. There was no significant difference between all diets on inflammation markers, blood pressure, and insulin-glucose homeostasis.Conclusions: The results of our study suggest that the consumption of SFAs from cheese and butter has similar effects on HDL cholesterol but differentially modifies LDL-cholesterol concentrations compared with the effects of carbohydrates, MUFAs, and PUFAs, particularly in individuals with high LDL cholesterol. In contrast, SFAs from either cheese or butter have no significant effects on several other nonlipid cardiometabolic risk factors. This trial was registered at clinicaltrials.gov as NCT02106208.