The objective of this comprehensive review is to summarize and discuss the available evidence of how adipose tissue inflammation affects insulin sensitivity and glucose tolerance. Low-grade, chronic adipose tissue inflammation is characterized by infiltration of macrophages and other immune cell populations into adipose tissue, and a shift towards more pro-inflammatory subtypes of leukocytes. The infiltration of pro-inflammatory cells in adipose tissue is associated with an increased production of key chemokines such as C-C motif chemokine ligand 2, pro-inflammatory cytokines including tumor necrosis factor α and interleukins 1β and 6, as well as reduced expression of the key insulin sensitizing adipokine, adiponectin. In both rodent models and humans, adipose tissue inflammation is consistently associated with excess fat mass and insulin resistance. In humans, associations with insulin resistance are stronger and more consistent for inflammation in visceral as opposed to subcutaneous fat. Further, genetic alterations in mouse models of obesity that reduce adipose tissue inflammation are – almost without exception - associated with improved insulin sensitivity. However, a dissociation between adipose tissue inflammation and insulin resistance can be observed in very few rodent models of obesity as well as in humans following bariatric surgery- or low-calorie diet-induced weight loss, illustrating that the etiology of insulin resistance is multifactorial. Taken together, adipose tissue inflammation is a key factor in the development of insulin resistance and type 2 diabetes in obesity, along with other factors that likely include inflammation and fat accumulation in other metabolically active tissues.

Background Dairy foods, particularly yogurt, and plasma biomarkers of dairy fat intake are consistently inversely associated with incident type 2 diabetes. Yet, few trials assessing the impact of dairy on glucose homeostasis include fermented or full-fat dairy foods. Objectives We aimed to compare the effects of diets rich in low-fat or full-fat milk, yogurt, and cheese on glucose tolerance and its determinants, with those of a limited dairy diet. Methods In this parallel-design randomized controlled trial, 72 participants with metabolic syndrome completed a 4-wk wash-in period, limiting dairy intake to ≤3 servings/wk of nonfat milk. Participants were then randomly assigned to either continue the limited dairy diet, or switch to a diet containing 3.3 servings/d of either low-fat or full-fat dairy for 12 wk. Outcome measures included glucose tolerance (area under the curve glucose during an oral-glucose-tolerance test), insulin sensitivity, pancreatic β-cell function, systemic inflammation, liver-fat content, and body weight and composition. Results In the per-protocol analysis (n = 67), we observed no intervention effect on glucose tolerance (P = 0.340). Both the low-fat and full-fat dairy diets decreased the Matsuda insulin sensitivity index (ISI) (means ± SDs −0.47 ± 1.07 and −0.25 ± 0.91, respectively) and as compared with the limited dairy group (0.00 ± 0.92) (P = 0.012 overall). Body weight also changed differentially (P = 0.006 overall), increasing on full-fat dairy (+1.0 kg; −0.2, 1.8 kg) compared with the limited dairy diet (−0.4 kg; −2.5, 0.7 kg), whereas the low-fat dairy diet (+0.3 kg; −1.1, 1.9 kg) was not significantly different from the other interventions. Intervention effects on the Matsuda ISI remained after adjusting for changes in adiposity. No intervention effects were detected for liver fat content or systemic inflammation. Findings in intent-to-treat analyses (n = 72) were consistent. Conclusions Contrary to our hypothesis, neither dairy diet improved glucose tolerance in individuals with metabolic syndrome. Both dairy diets decreased insulin sensitivity through mechanisms largely unrelated to changes in key determinants of insulin sensitivity. This trial was registered at clinicaltrials.gov as NCT02663544.

Dietary guidelines commonly recommend that children aged >2 y consume reduced-fat dairy products rather than regular- or whole-fat dairy. In adults, most studies have not found the consumption of whole-fat dairy products to be associated with increased cardiometabolic or adiposity risk. Associations in children could differ due to growth and development. We systematically reviewed the literature in indexed, peer-reviewed journals to summarize pediatric studies (children aged from 2 to 18 y) assessing associations between whole- and reduced-fat dairy intake and measures of adiposity as well as biomarkers of cardiometabolic disease risk, including the serum lipid profile, blood pressure, low-grade chronic inflammation, oxidative stress, and measures of glucose homeostasis. For the purposes of this review, a “whole-fat” dairy product was defined as a product with the natural fat content, whereas a “reduced-fat” dairy product was defined as a product with some or all of the fat removed (including “low-fat” and “skim” versions). A total of 29 journal articles met our criteria for inclusion. The majority were conducted in the United States and were prospective or cross-sectional observational studies, with only 1 randomized controlled trial. Studies were consistent in reporting that whole-fat dairy products were not associated with increased measures of weight gain or adiposity. Most evidence indicated that consumption of whole-fat dairy was not associated with increased cardiometabolic risk, although a change from whole-fat to reduced-fat dairy improved outcomes for some risk factors in 1 study. Taken as a whole, the limited literature in this field is not consistent with dietary guidelines recommending that children consume preferably reduced-fat dairy products. High-quality randomized controlled trials in children that directly compare the effects of whole-fat compared with reduced-fat dairy intake on measures of adiposity or biomarkers of cardiometabolic disease risk are needed to provide better quality evidence in this area.

Background Non-alcoholic fatty liver disease (NAFLD) among Latinos is partially attributed to a prevalent C > G polymorphism in the patatin-like phospholipase 3 (PNPLA3) gene. Cross-sectional analyses in Latino children showed the association between dietary sugar and liver fat was exacerbated by GG genotype. Pediatric feeding studies show extreme sugar restriction improves liver fat, but no prior trial has examined the impact of a clinical intervention or whether effects differ by PNPLA3 genotype. Objectives To test effects of a clinical intervention to reduce dietary sugar versus standard dietary advice on change in liver fat, and secondary-endpoints changes in liver fibrosis, liver enzymes and anthropometrics; and whether effects differ by PNPLA3 genotype (assessed retrospectively) in Latino youth with obesity (BMI ≥ 95th percentile). Design This parallel-design trial randomized participants [n = 105; 12.7% baseline liver fat, 14.8 yrs] to control or sugar reduction (goal of ≤ 10% of calories from free sugar) for 12-weeks. Intervention participants met with a dietitian monthly and received delivery of bottled water. Changes in liver fat, by magnetic resonance imaging, were assessed by intervention group through general linear models. Results Free sugar intake decreased in intervention compared to control [11.5 to 7.3% vs. 13.9 to 10.7% (% Energy) respectively, P = 0.02], but there were no significant effects on liver outcomes or anthropometrics (pall > 0.10), and no PNPLA3 interactions (pall > 0.10). In exploratory analyses, participants with whole-body fat mass reduction (−1.9 ± 2.42.4 kg), irrespective of randomization, had significant reductions in liver fat compared to participants without fat mass reduction [−2.1% (−6.5, −0.8) vs. 0.3% (−1.0, 2.2), P < 0.001]. Conclusions In Latino youth with obesity, a dietitian-led sugar reduction intervention did not improve liver outcomes compared to control, regardless of PNPLA3 genotype. Results suggest fat mass reduction is important for liver fat reduction, confirming clinical recommendations of weight loss and a healthy diet for pediatric NAFLD.

Background Dietary guidelines traditionally recommend low-fat dairy because dairy's high saturated fat content is thought to promote cardiovascular disease (CVD). However, emerging evidence indicates that dairy fat may not negatively impact CVD risk factors when consumed in foods with a complex matrix. Objective The aim was to compare the effects of diets limited in dairy or rich in either low-fat or full-fat dairy on CVD risk factors. Methods In this randomized controlled trial, 72 participants with metabolic syndrome completed a 4-wk run-in period, limiting their dairy intake to ≤3 servings/wk of nonfat milk. Participants were then randomly assigned to 1 of 3 diets, either continuing the limited-dairy diet or switching to a diet containing 3.3 servings/d of either low-fat or full-fat milk, yogurt, and cheese for 12 wk. Exploratory outcome measures included changes in the fasting lipid profile and blood pressure. Results In the per-protocol analysis (n = 66), there was no intervention effect on fasting serum total, LDL, and HDL cholesterol; triglycerides; free fatty acids; or cholesterol content in 38 isolated plasma lipoprotein fractions (P > 0.1 for all variables in repeated-measures ANOVA). There was also no intervention effect on diastolic blood pressure, but a significant intervention effect for systolic blood pressure (P = 0.048), with a trend for a decrease in the low-fat dairy diet (−1.6 ± 8.6 mm Hg) compared with the limited-dairy diet (+2.5 ± 8.2 mm Hg) in post hoc testing. Intent-to-treat results were consistent for all endpoints, with the exception that systolic blood pressure became nonsignificant (P = 0.08). Conclusions In men and women with metabolic syndrome, a diet rich in full-fat dairy had no effects on fasting lipid profile or blood pressure compared with diets limited in dairy or rich in low-fat dairy. Therefore, dairy fat, when consumed as part of complex whole foods, does not adversely impact these classic CVD risk factors. This trial was registered at clinicaltrials.gov as NCT02663544.

Purpose of review To discuss recent evidence from observational and intervention studies on the relationship between fruit and vegetable consumption and metabolic disease. Recent findings Observational studies have consistently demonstrated a modest inverse association between the intake of fruit and leafy green vegetables, but not total vegetables, and biomarkers of metabolic disease as well as incident type 2 diabetes mellitus. This is in contrast to limited evidence from recently published randomized controlled dietary intervention trials, which – in sum - suggest little to no impact of increased fruit and vegetable consumption on biomarkers of metabolic disease. Summary Evidence from observational studies that fruit and leafy green vegetable intake is associated with lower type 2 diabetes risk and better metabolic health could not be confirmed by dietary intervention trials. It is unclear whether this discrepancy is due to limitations inherent in observational studies (e.g., subjective dietary assessment methods, residual confounding), or due to limitations in the few available intervention studies (e.g., short duration of follow-up, interventions combining whole fruit and fruit juice, or lack of compliance). Future studies that attempt to address these limitations are needed to provide more conclusive insight into the impact of fruit and vegetable consumption on metabolic health.

Angiogenesis is a hallmark of fibrocalcific aortic valve disease (CAVD). An imbalance of pro- and anti-angiogenic factors is thought to play a role in driving this disease process, and valvular interstitial cells (VICs) may act as a significant source of these factors. CAVD is also known to exhibit sexual dimorphism in its presentation, and previous work suggested that VICs may exhibit cellular-scale sex differences in the context of angiogenesis. The current study sought to investigate the production of angiogenesis-related factors by male and female VICs possessing quiescent (qVIC) or activated (aVIC) phenotypes. Production of several pro-angiogenic growth factors was elevated in porcine aVICs relative to qVICs, with sex differences found in both the total amounts secreted and their distribution across media vs. lysate. Porcine valvular endothelial cells (VECs) were also sex-separated in culture and found to behave similarly with respect to metabolic activity, viability, and tubulogenesis, but male VECs exhibited higher proliferation rates than female VECs. VECs responded to sex-matched media conditioned by VICs with increased tubulogenesis, but decreased proliferation, particularly upon treatment with aVIC-derived media. It is likely that this attenuation of proliferation resulted from a combination of decreased basic fibroblast growth factor and increased thrombospondin-2 (TSP2) secreted by aVICs. Overall, this study indicates that VICs regulate angiogenic VEC behavior via an array of paracrine molecules, whose secretion and sequestration are affected by both VIC phenotype and sex. Moreover, strong sex differences in TSP2 secretion by VICs may have implications for understanding sexual dimorphism in valve fibrosis, as TSP2 is also a powerful regulator of fibrosis.

Breast milk contains thousands of bioactive compounds including extracellular vesicle microRNAs (EV-miRNAs), which may regulate pathways such as infant immune system development and metabolism. We examined the associations between the expression of EV-miRNAs and laboratory variables (i.e., batch effects, sample characteristics), sequencing quality indicators, and maternal-infant characteristics. The study included 109 Latino mother-infant dyads from the Southern California Mother’s Milk Study. Mothers were age 28.0 ± 5.6 and 23-46 days postpartum. We used principal components analysis to evaluate whether EV-miRNA expression was associated with factors of interest. Then, we used linear models to estimate relationships between these factors and specific EV-miRNA counts and analyzed functional pathways associated with those EV-miRNAs. Finally, we explored which maternal-infant characteristics predicted sequencing quality indicators. Sequencing quality indicators, predominant breastfeeding, and breastfeedings/day were associated with EV-miRNA principal components. Maternal body mass index and breast milk collection timing predicted proportion of unmapped reads. Expression of 2 EV-miRNAs were associated with days postpartum, 23 EV-miRNAs were associated with breast milk collection time, 23 EV-miRNAs were associated with predominant breastfeeding, and 38 EV-miRNAs were associated with breastfeedings/day. These EV-miRNAs were associated with pathways including Hippo signaling pathway and ECM-receptor interaction, among others. This study identifies several important factors that may contribute to breast milk EV-miRNA expression. Future studies should consider these findings in the design and analysis of breast milk miRNA research.