scholarly journals Interferon-gamma Impairs Human Coronary Artery Endothelial Glucose Metabolism via Tryptophan Catabolism and Activates Fatty Acid Oxidation

Circulation ◽  
2021 ◽  
Author(s):  
Laurel Yong-Hwa Lee ◽  
William M. Oldham ◽  
Huamei He ◽  
Ruisheng Wang ◽  
Ryan Mulhern ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Fatty Acid ◽  
Glucose Metabolism ◽  
Fatty Acid Oxidation ◽  
T Lymphocyte ◽  
Metabolic Effects ◽  
Acid Oxidation ◽  
Human Coronary Artery ◽  
Aryl Hydrocarbon ◽  
Tryptophan Catabolism

Background: Endothelial cells depend on glycolysis for much of their energy production. Impaired endothelial glycolysis has been associated with various vascular pathobiologies, including impaired angiogenesis and atherogenesis. Interferon-gamma (IFN- γ )-producing CD4 + and CD8 + T-lymphocytes have been identified as the predominant pathologic cell subsets in human atherosclerotic plaques. While the immunological consequences of these cells have been extensively evaluated, their IFN- γ -mediated metabolic effects on endothelial cells remain unknown. The purpose of this study was to determine the metabolic consequences of the T-lymphocyte cytokine, IFN- γ , on human coronary artery endothelial cells (HCAEC). Methods: The metabolic effects of IFN- γ on primary HCAEC were assessed by unbiased transcriptomic and metabolomic analyses combined with real-time extracellular flux analyses and molecular mechanistic studies. Cellular phenotypic correlations were made by measuring altered endothelial intracellular cyclic guanosine monophosphate (cGMP) content, wound healing capacity, and adhesion molecule expression. Results: IFN- γ exposure inhibited basal glycolysis of quiescent primary HCAEC by 20% through the global transcriptional suppression of glycolytic enzymes resulting from decreased basal hypoxia inducible factor 1α (HIF1α) nuclear availability in normoxia. The decrease in HIF1α activity was a consequence of IFN- γ -induced tryptophan catabolism resulting in ARNT (aryl hydrocarbon receptor nuclear translocator)/HIF1β sequestration by the kynurenine-activated aryl hydrocarbon receptor (AHR). Additionally, IFN- γ resulted in a 23% depletion of intracellular NAD + in HCAEC. This altered glucose metabolism was met with concomitant activation of fatty acid oxidation, which augmented its contribution to intracellular ATP balance by over 20%. These metabolic derangements were associated with adverse endothelial phenotypic changes, including decreased basal intracellular cGMP, impaired endothelial migration, and a switch to a pro-inflammatory state. Conclusions: IFN- γ impairs endothelial glucose metabolism via altered tryptophan catabolism destabilizing HIF1, depletes NAD + , and results in a metabolic shift toward increased fatty acid oxidation. This work suggests a novel mechanistic basis for pathologic T-lymphocyte-endothelial interactions in atherosclerosis mediated by IFN- γ , linking endothelial glucose, tryptophan, and fatty acid metabolism with NAD(H) and ATP generation, and their adverse endothelial functional consequences.

Effects of blockade of fatty acid oxidation on whole body and tissue-specific glucose metabolism in rats

1993 ◽  
Vol 265 (4) ◽  
pp. E592-E600 ◽  
Author(s):  
A. B. Jenkins ◽  
L. H. Storlien ◽  
G. J. Cooney ◽  
G. S. Denyer ◽  
I. D. Caterson ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Glucose Metabolism ◽  
Fatty Acid Oxidation ◽  
Pyruvate Dehydrogenase ◽  
Glucose Utilization ◽  
Whole Body ◽  
Acid Oxidation ◽  
Tissue Specific ◽  
Glucose Output

We examined the effect of the long-chain fatty acid oxidation blocker methyl palmoxirate (methyl 2-tetradecyloxiranecarboxylate, McN-3716) on glucose metabolism in conscious rats. Fasted animals [5 h with or without hyperinsulinemia (100 mU/l) and 24 h] received methyl palmoxirate (30 or 100 mg/kg body wt po) or vehicle 30 min before a euglycemic glucose clamp. Whole body and tissue-specific glucose metabolism were calculated from 2-deoxy-[3H]-glucose kinetics and accumulation. Oxidative metabolism was assessed by respiratory gas exchange in 24-h fasted animals. Pyruvate dehydrogenase complex activation was determined in selected tissues. Methyl palmoxirate suppressed whole body lipid oxidation by 40-50% in 24-h fasted animals, whereas carbohydrate oxidation was stimulated 8- to 10-fold. Whole body glucose utilization was not significantly affected by methyl palmoxirate under any conditions; hepatic glucose output was suppressed only in the predominantly gluconeogenic 24-h fasted animals. Methyl palmoxirate stimulated glucose uptake in heart in 24-h fasted animals [15 +/- 5 vs. 220 +/- 28 (SE) mumol x 100 g-1 x min-1], with smaller effects in 5-h fasted animals with or without hyperinsulinemia. Methyl palmoxirate induced significant activation of pyruvate dehydrogenase in heart in the basal state, but not during hyperinsulinemia. In skeletal muscles, methyl palmoxirate suppressed glucose utilization in the basal state but had no effect during hyperinsulinemia; pyruvate dehydrogenase activation in skeletal muscle was not affected by methyl palmoxirate under any conditions. The responses in skeletal muscle are consistent with the operation of a mechanism similar to the Pasteur effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Impact of in vivo fatty acid oxidation blockade on glucose turnover and muscle glucose metabolism during low-dose AICAR infusion

2006 ◽  
Vol 291 (5) ◽  
pp. E1131-E1140 ◽  
Author(s):  
Michael Christopher ◽  
Christian Rantzau ◽  
Zhi-Ping Chen ◽  
Rodney Snow ◽  
Bruce Kemp ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Glucose Metabolism ◽  
Fatty Acid Oxidation ◽  
Low Dose ◽  
Whole Body ◽  
Glucose Turnover ◽  
Acid Oxidation ◽  
Metabolic Clearance ◽  
The Impact

AMPK plays a central role in influencing fuel usage and selection. The aim of this study was to analyze the impact of low-dose AMP analog 5-aminoimidazole-4-carboxamide-1-β-d-ribosyl monophosphate (ZMP) on whole body glucose turnover and skeletal muscle (SkM) glucose metabolism. Dogs were restudied after prior 48-h fatty acid oxidation (FAOX) blockade by methylpalmoxirate (MP; 5 × 12 hourly 10 mg/kg doses). During the basal equilibrium period (0–150 min), fasting dogs ( n = 8) were infused with [3-3H]glucose followed by either 2-h saline or AICAR (1.5–2.0 mg·kg−1·min−1) infusions. SkM was biopsied at completion of each study. On a separate day, the same protocol was undertaken after 48-h in vivo FAOX blockade. The AICAR and AICAR + MP studies were repeated in three chronic alloxan-diabetic dogs. AICAR produced a transient fall in plasma glucose and increase in insulin and a small decline in free fatty acid (FFA). Parallel increases in hepatic glucose production (HGP), glucose disappearance (Rd tissue), and glycolytic flux (GF) occurred, whereas metabolic clearance rate of glucose (MCRg) did not change significantly. Intracellular SkM glucose, glucose 6-phosphate, and glycogen were unchanged. Acetyl-CoA carboxylase (ACC∼pSer221) increased by 50%. In the AICAR + MP studies, the metabolic responses were modified: the glucose was lower over 120 min, only minor changes occurred with insulin and FFA, and HGP and Rd tissue responses were markedly attenuated, but MCRg and GF increased significantly. SkM substrates were unchanged, but ACC∼pSer221 rose by 80%. Thus low-dose AICAR leads to increases in HGP and SkM glucose uptake, which are modified by prior FAox blockade.

Epinephrine increases ATP production in hearts by preferentially increasing glucose metabolism

1994 ◽  
Vol 267 (5) ◽  
pp. H1862-H1871 ◽  
Author(s):  
R. L. Collins-Nakai ◽  
D. Noseworthy ◽  
G. D. Lopaschuk
Keyword(s):  
Fatty Acid ◽  
Glucose Metabolism ◽  
Fatty Acid Oxidation ◽  
Glucose Oxidation ◽  
Contractile Function ◽  
Pyruvate Dehydrogenase Complex ◽  
Active Form ◽  
Acid Oxidation ◽  
Complex Activity ◽  
Atp Production

Although epinephrine is widely used clinically, its effect on myocardial energy substrate preference in the intact heart has yet to be clearly defined. We determined the effects of epinephrine on glucose and fatty acid metabolism in isolated working rat hearts perfused with 11 mM glucose, 0.4 mM palmitate, and 100 muU/ml insulin at an 11.5-mmHg left atrial preload and a 60-mmHg aortic afterload. Glycolysis and glucose oxidation were measured in hearts perfused with [5–3H]glucose and [U-14C]glucose, whereas fatty acid oxidation was measured in hearts perfused with [1–14C]palmitate. Addition of 1 microM epinephrine resulted in a 53% increase in the heart rate-developed pressure product. Glycolysis increased dramatically following addition of epinephrine (a 272% increase), as did glucose oxidation (a 410% increase). In contrast, fatty acid oxidation increased by only 10%. Epinephrine treatment did not increase the amount of oxygen required to produce an equivalent amount of ATP; however, epinephrine did increase the uncoupling between glycolysis and glucose oxidation in these fatty acid-perfused hearts, resulting in a significant increase in H+ production from glucose metabolism. Overall ATP production in epinephrine-treated hearts increased 59%. The contribution of glucose (glycolysis and glucose oxidation) to ATP production increased from 13 to 36%, which was accompanied by a reciprocal decrease in the contribution of fatty acid oxidation to ATP production from 83 to 63%. The increase in glucose oxidation was accompanied by a significant increase in pyruvate dehydrogenase complex activity in the active form. We conclude that the increase in ATP required for contractile function following epinephrine treatment occurs through a preferential increase in glucose use.

scholarly journals Leptin Regulates Peripheral Lipid Metabolism Primarily through Central Effects on Food Intake

Endocrinology ◽  
2008 ◽  
Vol 149 (11) ◽  
pp. 5432-5439 ◽  
Author(s):  
Xavier Prieur ◽  
Y. C. Loraine Tung ◽  
Julian L. Griffin ◽  
I. Sadaf Farooqi ◽  
Stephen O'Rahilly ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Lipid Metabolism ◽  
Food Intake ◽  
Fatty Acid Oxidation ◽  
Liver Weight ◽  
Metabolic Effects ◽  
Acid Oxidation ◽  
Mediated Effects ◽  
Expression Of Genes ◽  
Acyl Coenzyme A

The metabolic effects of leptin may involve both centrally and peripherally mediated actions with a component of the central actions potentially independent of alterations in food intake. Ob/ob mice have significant abnormalities in lipid metabolism, correctable by leptin administration. We used ob/ob mice to study the relative importance of the subtypes of actions of leptin (central vs. peripheral; food intake dependent vs. independent) on lipid metabolism. Mice were treated for 3 d with leptin, either centrally [intracerebroventricular (icv)] or peripherally (ip), and compared with mice pair-fed to the leptin-treated mice (PF) and with ad libitum-fed controls (C). All treatment groups (icv, ip, PF) showed indistinguishable changes in liver weight; hepatic steatosis; hepatic lipidemic profile; and circulating free fatty acids, triglycerides, and cholesterol lipoprotein profile. Changes in the expression of genes involved in lipogenesis and fatty acid oxidation in liver, muscle, and white fat were broadly similar in ip, icv, and PF groups. Leptin (both icv and ip) stimulated expression of both mitochondrial and peroxisomal acyl-coenzyme A oxidase (liver) and peroxisomal proliferator-activated receptor-α (skeletal muscle) to an extent not replicated by pair feeding. Leptin had profound effects on peripheral lipid metabolism, but the majority were explained by its effects on food intake. Leptin had additional centrally mediated effects to increase the expression of a limited number of genes concerned with fatty acid oxidation. Whereas we cannot exclude direct peripheral effects of leptin on certain aspects of lipid metabolism, we were unable to detect any such effects on the parameters measured in this study.

Abstract 15465: Upregulation of Mitochondrial Atpase Inhibitory Factor 1 Mediates Increased Glycolysis in Pathological Cardiac Hypertrophy

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Bo Zhou ◽  
Arianne Caudal ◽  
Xiaoting Tang ◽  
Juan D Chavez ◽  
Andrew Keller ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Glucose Metabolism ◽  
Cardiac Hypertrophy ◽  
Fatty Acid Oxidation ◽  
Atp Synthase ◽  
Atp Synthesis ◽  
Inhibitory Factor ◽  
Acid Oxidation ◽  
Mitochondrial Atpase ◽  
Inhibitory Factor 1

Background: During the development of heart failure cardiac fuel metabolism switches from predominantly fatty acid oxidation (FAO) to increased reliance on glucose, especially glycolysis. Mechanisms responsible for the switch are poorly understood but appear to be coupled with impaired mitochondrial function. We recently demonstrated that increased glucose metabolism is required for cardiomyocytes growth during pathological remodeling. Hypothesis: Upregulation of mitochondrial ATPase inhibitory factor 1 (ATPIF1) in hypertrophied hearts suppresses ATP synthesis and shifts cardiac metabolism from fatty acid oxidation towards glucose metabolism. Methods and Results: We report that ATPIF1 expression is upregulated in cardiomyocytes and mouse hearts undergoing pathological hypertrophy. Using genetic models of ATPIF1 gain- and loss-of-function in cardiomyocytes and in mouse hearts,we find that upregulation of ATPIF1 in cardiac hypertrophy inhibits ATP synthesis. Furthermore, quantitative analysis of chemical crosslinking by mass spectrometry revealed that increased expression of ATPIF1 promoted the formation of F o F 1 -ATP synthase nonproductive tetramer. Impairment of F o F 1 -ATP synthase function in respiring mitochondria increasedROS generation resulting in transcriptional activation of glycolysis. Cardiac-specific deletion of ATPIF1 in mice prevented the switch to glycolysis in pressure overload induced cardiac hypertrophy. Conclusions: We show that upregulation of ATPIF1 drives glucose metabolism at the expense of energy supply during the pathological growth of cardiomyocytes. Our study proposes a central role of ATP synthase in toggling anabolic and catabolic metabolism during pathological remodeling, illustrating a new concept for metabolic reprogramming of the heart.

Potential mechanisms and consequences of cardiac triacylglycerol accumulation in insulin-resistant rats

2003 ◽  
Vol 284 (5) ◽  
pp. E923-E930 ◽  
Author(s):  
Laura L. Atkinson ◽  
Ray Kozak ◽  
Sandra E. Kelly ◽  
Arzu Onay-Besikci ◽  
James C. Russell ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Glucose Metabolism ◽  
Fatty Acid Oxidation ◽  
Acid Oxidation ◽  
Fatty Acid Binding ◽  
Insulin Resistant ◽  
Lean Control ◽  
Malonyl Coa ◽  
Significant Difference ◽  
Ampk Activity

The accumulation of intracellular triacylglycerol (TG) is highly correlated with muscle insulin resistance. However, it is controversial whether the accumulation of TG is the result of increased fatty acid supply, decreased fatty acid oxidation, or both. Because abnormal fatty acid metabolism is a key contributor to the pathogenesis of diabetes-related cardiovascular dysfunction, we examined fatty acid and glucose metabolism in hearts of insulin-resistant JCR:LA-cp rats. Isolated working hearts from insulin-resistant rats had glycolytic rates that were reduced to 50% of lean control levels ( P < 0.05). Cardiac TG content was increased by 50% ( P < 0.05) in the insulin-resistant rats, but palmitate oxidation rates remained similar between the insulin-resistant and lean control rats. However, plasma fatty acids and TG levels, as well as cardiac fatty acid-binding protein (FABP) expression, were significantly increased in the insulin-resistant rats. AMP-activated protein kinase (AMPK) plays a major role in the regulation of cardiac fatty acid and glucose metabolism. When activated, AMPK increases fatty acid oxidation by inhibiting acetyl-CoA carboxylase (ACC) and reducing malonyl-CoA levels, and it decreases TG content by inhibiting glycerol-3-phosphate acyltransferase (GPAT), the rate-limiting step in TG synthesis. The activation of AMPK also stimulates cardiac glucose uptake and glycolysis. We thus investigated whether a decrease in AMPK activity was responsible for the reduced cardiac glycolysis and increased TG content in the insulin-resistant rats. However, we found no significant difference in AMPK activity. We also found no significant difference in various established downstream targets of AMPK: ACC activity, malonyl-CoA levels, carnitine palmitoyltransferase I activity, or GPAT activity. We conclude that hearts from insulin-resistant JCR:LA-cp rats accumulate substantial TG as a result of increased fatty acid supply rather than from reduced fatty acid oxidation. Furthermore, the accumulation of cardiac TG is associated with a reduction in insulin-stimulated glucose metabolism.

Fatty acid oxidation and glucose utilization interact to control food intake in rats

1986 ◽  
Vol 251 (5) ◽  
pp. R840-R845 ◽  
Author(s):  
M. I. Friedman ◽  
M. G. Tordoff
Keyword(s):  
Fatty Acid ◽  
Food Intake ◽  
Fatty Acid Oxidation ◽  
Glucose Utilization ◽  
Combined Treatment ◽  
Fat Metabolism ◽  
Metabolic Effects ◽  
Acid Oxidation ◽  
Control Food ◽  
Control Food Intake

To determine whether glucose and fat metabolism interact to control food intake, rats were administered 2-deoxyglucose (2-DG), which inhibits glucose utilization, and methyl palmoxirate (MP), which inhibits fatty acid oxidation. Combined treatment with 2-DG and MP increased food intake in a synergistic fashion. This synergistic effect was observed even at doses of the two agents that alone did not increase food intake, and it was expressed by either an initiation of eating or a prolonged bout of eating, depending on the testing conditions. Metabolic measures of circulating substrates, liver glycogen, and gastric contents confirmed that the drugs had their intended metabolic effects and revealed no evidence that one drug enhanced the direct metabolic action of the other. The results provide direct evidence that glucose and fat metabolism exert a coordinated control over feeding behavior and suggest the existence of a common integrative mechanism in that control.

scholarly journals The SGLT2 inhibitor canagliflozin suppresses lipid synthesis and interleukin-1 beta in ApoE deficient mice

2020 ◽  
Vol 477 (12) ◽  
pp. 2347-2361
Author(s):  
Emily A. Day ◽  
Rebecca J. Ford ◽  
Jessie H. Lu ◽  
Rachel Lu ◽  
Lucie Lundenberg ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Blood Glucose ◽  
Energy Expenditure ◽  
Fatty Acid Oxidation ◽  
Liver Lipid ◽  
Sglt2 Inhibitor ◽  
Lipid Synthesis ◽  
Metabolic Energy ◽  
Metabolic Effects ◽  
Acid Oxidation

Sodium-glucose cotransporter 2 inhibitors such as canagliflozin lower blood glucose and reduce cardiovascular events in people with type 2 diabetes through mechanisms that are not fully understood. Canagliflozin has been shown to increase the activity of the AMP-activated protein kinase (AMPK), a metabolic energy sensor important for increasing fatty acid oxidation and energy expenditure and suppressing lipogenesis and inflammation, but whether AMPK activation is important for mediating some of the beneficial metabolic effects of canagliflozin has not been determined. We, therefore, evaluated the effects of canagliflozin in female ApoE−/− and ApoE−/−AMPK β1−/− mice fed a western diet. Canagliflozin increased fatty acid oxidation and energy expenditure and lowered adiposity, blood glucose and the respiratory exchange ratio independently of AMPK β1. Canagliflozin also suppressed liver lipid synthesis and the expression of ATP-citrate lyase, acetyl-CoA carboxylase and sterol response element-binding protein 1c independently of AMPK β1. Canagliflozin lowered circulating IL-1β and studies in bone marrow-derived macrophages indicated that in contrast with the metabolic adaptations, this effect required AMPK β1. Canagliflozin had no effect on the size of atherosclerotic plaques in either ApoE−/− and ApoE−/−AMPK β1−/− mice. Future studies investigating whether reductions in liver lipid synthesis and macrophage IL-1β are important for the cardioprotective effects of canagliflozin warrant further investigation.

scholarly journals Metabolic Effects of Late Dinner in Healthy Volunteers—A Randomized Crossover Clinical Trial

2020 ◽  
Vol 105 (8) ◽  
pp. 2789-2802 ◽  
Author(s):  
Chenjuan Gu ◽  
Nga Brereton ◽  
Amy Schweitzer ◽  
Matthew Cotter ◽  
Daisy Duan ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Healthy Volunteers ◽  
Fatty Acid Oxidation ◽  
Dietary Fatty Acid ◽  
Metabolic Effects ◽  
Acid Oxidation ◽  
Sleep Phase ◽  
Female Age ◽  
Postprandial Period ◽  
The Impact

Abstract Context Consuming calories later in the day is associated with obesity and metabolic syndrome. We hypothesized that eating a late dinner alters substrate metabolism during sleep in a manner that promotes obesity. Objective The objective of this work is to examine the impact of late dinner on nocturnal metabolism in healthy volunteers. Design and Setting This is a randomized crossover trial of late dinner (LD, 22:00) vs routine dinner (RD, 18:00), with a fixed sleep period (23:00-07:00) in a laboratory setting. Participants Participants comprised 20 healthy volunteers (10 male, 10 female), age 26.0 ± 0.6 years, body mass index 23.2 ± 0.7 kg/m2, accustomed to a bedtime between 22:00 and 01:00. Interventions An isocaloric macronutrient diet was administered on both visits. Dinner (35% daily kcal, 50% carbohydrate, 35% fat) with an oral lipid tracer ([2H31] palmitate, 15 mg/kg) was given at 18:00 with RD and 22:00 with LD. Main Outcome Measures Measurements included nocturnal and next-morning hourly plasma glucose, insulin, triglycerides, free fatty acids (FFAs), cortisol, dietary fatty acid oxidation, and overnight polysomnography. Results LD caused a 4-hour shift in the postprandial period, overlapping with the sleep phase. Independent of this shift, the postprandial period following LD was characterized by higher glucose, a triglyceride peak delay, and lower FFA and dietary fatty acid oxidation. LD did not affect sleep architecture, but increased plasma cortisol. These metabolic changes were most pronounced in habitual earlier sleepers determined by actigraphy monitoring. Conclusion LD induces nocturnal glucose intolerance, and reduces fatty acid oxidation and mobilization, particularly in earlier sleepers. These effects might promote obesity if they recur chronically.

Sign in / Sign up

Export Citation Format

Share Document