Inhibition of fatty acid oxidation and glucose metabolism does not affect food intake or hunger motivation in syrian hamsters

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)

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

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00518.2005 ◽

2006 ◽

Vol 291 (5) ◽

pp. E1131-E1140 ◽

Cited By ~ 5

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.

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Influence of ketone body and the inhibition of fatty acid oxidation on the food intake of the chick

British Poultry Science ◽

10.1080/00071660120055412 ◽

2001 ◽

Vol 42 (3) ◽

pp. 405-408 ◽

Cited By ~ 5

Author(s):

K. Sashihara ◽

M. Miyamoto ◽

A. Ohgushi ◽

D.M. Denbow ◽

M. Furuse

Keyword(s):

Fatty Acid ◽

Food Intake ◽

Fatty Acid Oxidation ◽

Ketone Body ◽

Acid Oxidation

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Epinephrine increases ATP production in hearts by preferentially increasing glucose metabolism

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1994.267.5.h1862 ◽

1994 ◽

Vol 267 (5) ◽

pp. H1862-H1871 ◽

Cited By ~ 27

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.

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

Endocrinology ◽

10.1210/en.2008-0498 ◽

2008 ◽

Vol 149 (11) ◽

pp. 5432-5439 ◽

Cited By ~ 62

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.

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Systemic stimulation of fatty acid oxidation reduces food intake in diet‐induced obese mice

The FASEB Journal ◽

10.1096/fasebj.20.5.a830-a ◽

2006 ◽

Vol 20 (5) ◽

Author(s):

Jagan N. Thupari ◽

A. Vadlamudi ◽

S. Medghalchi ◽

M. L. Pinn ◽

J, M. McFadden ◽

...

Keyword(s):

Fatty Acid ◽

Food Intake ◽

Fatty Acid Oxidation ◽

Acid Oxidation ◽

Obese Mice ◽

Stimulation Of

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Level of satiety: in vitro energy metabolism in brain during hypophagic and hyperphagic body weight recovery

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1989.257.6.r1322 ◽

1989 ◽

Vol 257 (6) ◽

pp. R1322-R1327 ◽

Cited By ~ 2

Author(s):

T. R. Kasser ◽

R. B. Harris ◽

R. J. Martin

Keyword(s):

Weight Loss ◽

Body Weight ◽

Fatty Acid ◽

Food Intake ◽

Fatty Acid Oxidation ◽

Glucose Oxidation ◽

Area Postrema ◽

Tube Feeding ◽

Acid Oxidation

Rates of in vitro glucose and fatty acid oxidation were examined in four brain sites during hypophagic and hyperphagic recovery of normal body weight. Rats were fed 40, 100, or 160% of normal intake, via gastric intubation, for 3 wk. Another group of rats was starved until body weight loss was equivalent to weight loss in 40%-fed rats. Groups of rats were killed at the conclusion of tube feeding or fasting and at specific periods during recovery of body weight. Brain sites examined were the ventrolateral hypothalamus (VLH), ventromedial hypothalamus (VMH), a caudal brain stem site encompassing the area postrema-nucleus of the solitary tract (AP-NTS), and cortex. During recovery, rats previously fed 160% of normal intake (anorectic) maintained low rates of VLH fatty acid oxidation and were hypophagic until most excess fat was depleted. Conversely, rats previously fed 40% of normal intake (hungry) maintained high rates of VLH fatty acid oxidation and were hyperphagic until most deficient fat was repleted. Rats previously starved maintained high rates of VLH fatty acid oxidation during hyperphagic recovery, although levels of VLH fatty acid oxidation and food intake were initially low on refeeding. Rates of glucose oxidation in the brain sites examined did not relate well to energy balance status and the needed adjustments in food intake. The results indicated that the level of glucose oxidation in the VLH and AP-NTS responded to the level of energy immediately coming into the system (food intake).(ABSTRACT TRUNCATED AT 250 WORDS)

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

Circulation ◽

10.1161/circ.142.suppl_3.15465 ◽

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.

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