Protection from Metabolic Dysregulation, Obesity, and Atherosclerosis by Citrus Flavonoids: Activation of Hepatic PGC1α-Mediated Fatty Acid Oxidation

Studies in a multitude of models including cell culture, animal and clinical studies demonstrate that citrus-derived flavonoids have therapeutic potential to attenuate dyslipidemia, correct hyperinsulinemia and hyperglycemia, and reduce atherosclerosis. Emerging evidence suggests the metabolic regulators, PPARα and PGC1α, are targets of the citrus flavonoids, and their activation may be at least partially responsible for mediating their metabolic effects. Molecular studies will add significantly to the concept of these flavonoids as viable and promising therapeutic agents to treat the dysregulation of lipid homeostasis, metabolic disease, and its cardiovascular complications

Antiatherogenic Properties of Flavonoids: Implications for Cardiovascular Health

Epidemiological studies suggest that higher flavonoid intake from fruits and vegetables is associated with decreased risk for the development of cardiovascular disease. The mechanisms explaining this observation remain unclear, but current evidence suggests that flavonoids may exert their effects through the improvement of cardiovascular risk factors. The present review summarizes data suggesting that flavonoids improve endothelial function. inhibit low-density lipoprotein oxidation, decrease blood pressure and improve dyslipidemia. A large number of studies have reported the impact of consuming flavonoid-rich foods on biomarkers of cardiovascular disease risk in healthy volunteers or at-risk individuals. Most studies have focused on cocoa, soy, and green and black tea. Recent evidence suggests that some polyphenols in their purified form, including resveratrol, berberine and naringenin, have beneficial effects on dyslipidemia in humans and/or animal models. In a mouse model of cardiovascular disease, naringenin treatment, through correction of dyslipidemia, hyperinsulinemia and obesity, attenuated atherosclerosis. Therefore, the beneficial effects of flavonoids on multiple risk factors may explain, in part, the observed beneficial effects of flavonoids on cardiovascular disease

Islet Health, Hormone Secretion, and Insulin Responsivity with Low-Carbohydrate Feeding in Diabetes

Exploring new avenues to control daily fluctuations in glycemia has been a central theme for diabetes research since the Diabetes Control and Complications Trial (DCCT). Carbohydrate restriction has re-emerged as a means to control type 2 diabetes mellitus (T2DM), becoming increasingly popular and supported by national diabetes associations in Canada, Australia, the USA, and Europe. This approval comes from many positive outcomes on HbA1c in human studies; yet mechanisms underlying their success have not been fully elucidated. In this review, we discuss the preclinical and clinical studies investigating the role of carbohydrate restriction and physiological elevations in ketone bodies directly on pancreatic islet health, islet hormone secretion, and insulin sensitivity. Included studies have clearly outlined diet compositions, including a diet with 30% or less of calories from carbohydrates

Exercise training reduces circulating cytokines in male patients with coronary artery disease and type 2 diabetes: A pilot study

Abstract Low‐grade inflammation is central to coronary artery disease (CAD) and type 2 diabetes (T2D) and is reduced by exercise training. The objective of this study was to compare the anti‐inflammatory potential of moderate‐to‐vigorous intensity continuous training (MICT) and high‐intensity interval training (HIIT) in patients with CAD with or without T2D. The design and setting of this study is based on a secondary analysis of registered randomized clinical trial NCT02765568. Male patients with CAD were randomly assigned to either MICT or HIIT, with subgroups divided according to T2D status (non‐T2D‐HIIT n = 14 and non‐T2D‐MICT n = 13; T2D‐HIIT n = 6 and T2D‐MICT n = 5). The intervention was a 12‐week cardiovascular rehabilitation program consisting of either MICT or HIIT (twice weekly sessions) and circulating cytokines measured pre‐ and post‐training as inflammatory markers. The co‐occurrence of CAD and T2D was associated with increased plasma IL‐8 (p = 0.0331). There was an interaction between T2D and the effect of the training interventions on plasma FGF21 (p = 0.0368) and IL‐6 (p = 0.0385), which were further reduced in the T2D groups. An interaction between T2D, training modalities, and the effect of time (p = 0.0415) was detected for SPARC, with HIIT increasing circulating concentrations in the control group, while lowering them in the T2D group, and the inverse occurring with MICT. The interventions also reduced plasma FGF21 (p = 0.0030), IL‐6 (p = 0.0101), IL‐8 (p = 0.0087), IL‐10 (p < 0.0001), and IL‐18 (p = 0.0009) irrespective of training modality or T2D status. HIIT and MICT resulted in similar reductions in circulating cytokines known to be increased in the context of low‐grade inflammation in CAD patients, an effect more pronounced in patients with T2D for FGF21 and IL‐6

Hematopoietic cell– versus enterocyte-derived dipeptidyl peptidase-4 differentially regulates triglyceride excursion in mice

Postprandial triglycerides (TGs) are elevated in people with type 2 diabetes (T2D). Glucose-lowering agents, such as glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors, also reduce postprandial TG excursion. Although the glucose-lowering mechanisms of DPP-4 have been extensively studied, how the reduction of DPP-4 activity improves lipid tolerance remains unclear. Here, we demonstrate that gut-selective and systemic inhibition of DPP-4 activity reduces postprandial TG excursion in young mice. Genetic inactivation of Dpp4 simultaneously within endothelial cells and hematopoietic cells using Tie2-Cre reduced intestinal lipoprotein secretion under regular chow diet conditions. Bone marrow transplantation revealed a key role for hematopoietic cells in modulation of lipid responses arising from genetic reduction of DPP-4 activity. Unexpectedly, deletion of Dpp4 in enterocytes increased TG excursion in high-fat diet–fed (HFD-fed) mice. Moreover, chemical reduction of DPP-4 activity and increased levels of GLP-1 were uncoupled from TG excursion in older or HFD-fed mice, yet lipid tolerance remained improved in older Dpp4–/– and Dpp4EC–/– mice. Taken together, this study defines roles for specific DPP-4 compartments, age, and diet as modifiers of DPP-4 activity linked to control of gut lipid metabolism

The brown adipose tissue glucagon receptor is functional but not essential for control of energy homeostasis in mice

Objective: Administration of glucagon (GCG) or GCG-containing co-agonists reduces body weight and increases energy expenditure. These actions appear to be transduced by multiple direct and indirect GCG receptor (GCGR)-dependent mechanisms. Although the canonical GCGR is expressed in brown adipose tissue (BAT) the importance of BAT GCGR activity for the physiological control of body weight, or the response to GCG agonism, has not been defined. Methods: We studied the mechanisms linking GCG action to acute increases in oxygen consumption using wildtype (WT), Ucp1−/− and Fgf21−/− mice. The importance of basal GCGR expression within the Myf5+ domain for control of body weight, adiposity, glucose and lipid metabolism, food intake, and energy expenditure was examined in GcgrBAT−/− mice housed at room temperature or 4 °C, fed a regular chow diet (RCD) or after a prolonged exposure to high fat diet (HFD). Results: Acute GCG administration induced lipolysis and increased the expression of thermogenic genes in BAT cells, whereas knockdown of Gcgr reduced expression of genes related to thermogenesis. GCG increased energy expenditure (measured by oxygen consumption) both in vivo in WT mice and ex vivo in BAT and liver explants. GCG also increased acute energy expenditure in Ucp1−/− mice, but these actions were partially blunted in Ffg21−/− mice. However, acute GCG administration also robustly increased oxygen consumption in GcgrBAT−/− mice. Moreover, body weight, glycemia, lipid metabolism, body temperature, food intake, activity, energy expenditure and adipose tissue gene expression profiles were normal in GcgrBAT−/− mice, either on RCD or HFD, whether studied at room temperature, or chronically housed at 4 °C. Conclusions: Exogenous GCG increases oxygen consumption in mice, also evident both in liver and BAT explants ex vivo, through UCP1-independent, FGF21-dependent pathways. Nevertheless, GCGR signaling within BAT is not physiologically essential for control of body weight, whole body energy expenditure, glucose homeostasis, or the adaptive metabolic response to cold or prolonged exposure to an energy dense diet. Keywords: Glucagon, brown adipose tissue, Energy expenditure, Adiposity, Lipolysis, Thermogenesi

Naringenin Decreases Progression of Atherosclerosis by Improving Dyslipidemia in High-Fat-Fed Low-Density Lipoprotein Receptor-Null Mice

OBJECTIVE: Naringenin is a citrus flavonoid that potently inhibits the assembly and secretion of apolipoprotein B100-containing lipoproteins in cultured hepatocytes and improves the dyslipidemia and insulin resistance in a mouse model of the metabolic syndrome. In the present study, we used low-density lipoprotein receptor-null mice fed a high-fat diet (Western, TD96125) to test the hypothesis that naringenin prevents atherosclerosis. METHODS AND RESULTS: Three groups (chow, Western, and Western plus naringenin) were fed ad libitum for 6 months. The Western diet increased fasting plasma triglyceride (TG) (5-fold) and cholesterol (8-fold) levels compared with chow, whereas the addition of naringenin significantly decreased both lipids by 50%. The Western-fed mice developed extensive atherosclerosis in the aortic sinus because plaque area was increased by 10-fold compared with chow-fed animals. Quantitation of fat-soluble dye (Sudan IV)-stained aortas, prepared en face, revealed that Western-fed mice also had a 10-fold increase in plaque deposits throughout the arch and in the abdominal sections of the aorta, compared with chow. Atherosclerosis in both areas was significantly decreased by more than 70% in naringenin-treated mice. Consistent with quantitation of aortic lesions, the Western-fed mice had a significant 6-fold increase in cholesterol and a 4-fold increase in TG deposition in the aorta compared with chow-fed mice. Both were reduced more than 50% by naringenin. The Western diet induced extensive hepatic steatosis, with a 10-fold increase in both TG and cholesteryl ester mass compared with chow. The addition of naringenin decreased both liver TG and cholesteryl ester mass by 80%. The hyperinsulinemia and obesity that developed in Western-fed mice was normalized by naringenin to levels observed in chow-fed mice. CONCLUSIONS: These in vivo studies demonstrate that the citrus flavonoid naringenin ameliorates the dyslipidemia in Western-fed low-density lipoprotein receptor-null mice, leading to decreased atherosclerosis; and suggests a potential therapeutic strategy for the hyperlipidemia and increased risk of atherosclerosis associated with insulin resistance

Naringenin prevents obesity, hepatic steatosis, and glucose intolerance in male mice independent of fibroblast growth factor 21

Copyright © 2015 by the Endocrine Society. The molecular mechanisms and metabolic pathways whereby the citrus flavonoid, naringenin, reduces dyslipidemia and improves glucose tolerance were investigated in C57BL6/J wild-type mice and fibroblast growth factor 21 (FGF21) null (Fgf21 -/-) mice. FGF21 regulates energy homeostasis and the metabolic adaptation to fasting. One avenue of this regulation is through induction of peroxisome proliferator-activated receptor-γ coactivator-1α (Pgc1a), a regulator of hepatic fatty acid oxidation and ketogenesis. Because naringenin is a potent activator of hepatic FA oxidation, we hypothesized that induction of FGF21 might be an integral part of naringenin\u27s mechanism of action. Furthermore, we predicted that FGF21 deficiency would potentiate high-fat diet (HFD)- induced metabolic dysregulation and compromise metabolic protection by naringenin. The absence of FGF21 exacerbated the response to a HFD. Interestingly, naringenin supplementation to the HFD robustly prevented obesity in both genotypes. Gene expression analysis suggested that naringenin was not primarily targeting fatty acid metabolism in white adipose tissue. Naringenin corrected hepatic triglyceride concentrations and normalized hepatic expression of Pgc1a, Cpt1a, and Srebf1c in both wild-type and Fgf21 -/- mice. HFD-fed Fgf21 -/- mice displayed greater muscle triglyceride deposition, hyperinsulinemia, and impaired glucose tolerance as compared with wild-type mice, confirming the role of FGF21 in insulin sensitivity; however, naringenin supplementation improved these metabolic parameters in both genotypes. We conclude that FGF21 deficiency exacerbates HFD-induced obesity, hepatic steatosis, and insulin resistance. Furthermore, FGF21 is not required for naringenin to protect mice from HFD-induced metabolic dysregulation. Collectively these studies support the concept that naringenin has potent lipid-lowering effects and may act as an insulin sensitizer in vivo