Repetitive spikes of glucose and lipid induce senescence-like phenotypes of bone marrow stem cells through H3K27me3 demethylase-mediated epigenetic regulation

Bone marrow-derived endothelial progenitor cells (EPCs) contribute to endothelial repair and angiogenesis. Reduced number of circulating EPCs is associated with future cardiovascular events. We tested whether dysregulated glucose and/or triglyceride (TG) metabolism has an impact on EPC homeostasis. The analysis of metabolic factors associated with circulating EPC number in humans revealed that postprandial hyperglycemia is negatively correlated with circulating EPC number and this correlation appears to be further enhanced in the presence of postprandial hypertriglyceridemia (hTG). We therefore examined the effect of glucose/TG spikes on bone marrow lineage-sca-1+c-kit+ (LSK) cells in mice, because primitive EPCs reside in bone marrow LSK fraction.Repetitive glucose+lipid (GL) spikes, but not glucose (G) or lipid (L) spikes alone, induced senescence-like phenotypes of LSK cells, and this phenomenon was reversible after cessation of GL spikes. G spikes and GL spikes differentially affected transcriptional program of LSK cell metabolism and differentiation. GL spikes upregulated a histone H3K27 demethylase JMJD3, and inhibition of JMJD3 eliminated GL spikes-induced LSK cell senescence-like phenotypes. These observations suggest that postprandial glucose/TG dysmetabolism modulate transcriptional regulation in LSK cells through H3K27 demethylase-mediated epigenetic regulation, leading to senescence-like phenotypes of LSK cells, reduced number of circulating EPCs, and development of atherosclerotic cardiovascular disease.

Postprandial Lipid Metabolism in Normolipidemic Subjects and Patients with Mild to Moderate Hypertriglyceridemia: Effects of Test Meals Containing Saturated Fatty Acids, Mono-Unsaturated Fatty Acids, or Medium-Chain Fatty Acids

Fasting and postprandial hypertriglyceridemia are causal risk factors for atherosclerosis. The prevalence of hypertriglyceridemia is approximately 25–30% and most hypertriglyceridemic patients suffer from mild to moderate hypertriglyceridemia. Data regarding dietary interventions on postprandial triglyceride metabolism of mildly to moderately hypertriglyceridemic patients is, however, sparse. In a randomized controlled trial, eight mildly hypertriglyceridemic patients and five healthy, normolipidemic controls received three separate standardized fat-meals containing either saturated fatty acids (SFA), mono-unsaturated fatty acids (MUFA), or medium-chain fatty acids (MCFA) in a randomized order. Fasting and postprandial lipid parameters were determined over a 10 h period and the (incremental) area under the curve (AUC/iAUC) for plasma triglycerides and other parameters were determined. MCFA do not lead to a significant elevation of postprandial total plasma triglycerides and other triglyceride parameters, while both SFA (patients: p = 0.003, controls: p = 0.03 compared to MCFA) and MUFA (patients: p = 0.001; controls: p = 0.14 compared to MCFA) do lead to such an increase. Patients experienced a significantly more pronounced increase of plasma triglycerides than controls (SFA: patients iAUC = 1006 mg*h/dL, controls iAUC = 247 mg*h/dL, p = 0.02; MUFA: patients iAUC = 962 mg*h/dL, controls iAUC = 248 mg*h/dL, p = 0.05). Replacing SFA with MCFA may be a treatment option for mildly to moderately hypertriglyceridemic patients as it prevents postprandial hypertriglyceridemia.

Elevated Levels of Apolipoprotein CIII Increase the Risk of Postprandial Hypertriglyceridemia

BackgroundTo investigate possible mechanisms of postprandial hypertriglyceridemia (PPT), we analyzed serum lipid and apolipoprotein (Apo) AI, B, CII and CIII levels before and after a high-fat meal.MethodsThe study has been registered with the China Clinical Trial Registry (registration number:ChiCTR1800019514; URL: http://www.chictr.org.cn/index.aspx). We recruited 143 volunteers with normal fasting triglyceride (TG) levels. All subjects consumed a high-fat test meal. Venous blood samples were obtained during fasting and at 2, 4, and 6 hours after the high-fat meal. PPT was defined as TG ≥2.5 mmol/L any time after the meal. Subjects were divided into two groups according to the high-fat meal test results: postprandial normal triglyceride (PNT) and PPT. We compared the fasting and postprandial lipid and ApoAI, ApoB, ApoCII and ApoCIII levels between the two groups.ResultsSignificant differences were found between the groups in fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR), TG, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), TG-rich lipoprotein remnants (TRLRs), ApoB, ApoCIII, ApoAI/ApoB and ApoCII/ApoCIII. The insulin, HOMA-IR, TG, TC, LDL-C, non-HDL-C, TRLRs, ApoB, ApoCIII and ApoCII/ApoCIII values were higher in the PPT group, while the ApoAI/ApoB ratio was higher in the PNT group. The postprandial TG level peaked in the PNT group 2 hours after the meal but was significantly higher in the PPT group and peaked at 4 hours. TRLRs gradually increased within 6 hours after the high-fat meal in both groups. The area under the curve (AUC) of TG and TRLRs and the AUC increment were higher in the PPT group (P < 0.001). ApoCIII peaked in the PNT group 2 hours after the meal and gradually decreased. ApoCIII gradually increased in the PPT group within 6 hours after the meal, exhibiting a greater AUC increment (P < 0.001). Fasting ApoCIII was positively correlated with age, systolic and diastolic blood pressure, body mass index (BMI), waist circumference, TC, TG, LDL-C, non-HDL-C, TRLRs, and ApoB (P<0.05). ApoCIII was an independent risk factor of PPT after adjustment for BMI, waist circumference, TC, LDL-C, and ApoB (P < 0.001, OR=1.188).ConclusionsElevated ApoCIII levels may cause PPT.

Effect of food intake on complete blood count of healthy dogs

The present determined the hematological alterations of healthy dogs at the peak of postprandial hypertriglyceridemia. Twenty-four clinically healthy dogs had blood samples collected to perform complete blood count on three consecutive days at the same time every day: first day after a 12-hour fast; second day three hours after feeding with commercial feed, during the peak of postprandial lipemia; and third day after a 12-hour fast. Feeding led to an increase in MCHC, hemoglobin and white blood cell count due to the increase in segmented neutrophil, monocyte and eosinophil concentrations. A significant increase in total plasma protein content was also observed. Postprandial condition at the peak of hypertriglyceridemia influences hematological parameters of healthy dogs, which is an important finding, however transient, when interpreting laboratory blood tests.

Understanding the potential contribution of a third “T” to FITT exercise prescription: the case of timing in exercise for obesity and cardiometabolic management in children

Currently, exercise prescription relies heavily on parameters included in the FITT principle: frequency, intensity, time (duration), and type of exercise. In this paper, the benefits of including timing (FITT+T), referring to when exercise is performed in relation to meal-time, is discussed. Current research indicates that timing is outcome-specific. Total energy and lipid intakes, and postprandial hypertriglyceridemia can be reduced when exercise is performed pre-meal, while glycemic control is improved with post-meal exercise. Although findings indicate that timing can aid in obesity management and cardiometabolic-risk reduction, most research involves adult subjects and acute investigations. Some research with children, concerning the effect of timing on appetite, indicates that pre-meal exercise helps regulate energy balance, but also identifies key differences in response compared with adults. Overall, current findings support the benefits of timing, but research is required to establish guidelines that are specific to the pediatric population and their health-related goals, while incorporating other FITT components.