Regulation Of Fat Oxidation Research Articles

Branched-Chain Amino Acid Levels Are Related with Surrogates of Disturbed Lipid Metabolism among Older Men.

Existing studies suggest that decreased branched-chain amino acid (BCAA) catabolism and thus elevated levels in blood are associated with metabolic disturbances. Based on such information, we have developed a hypothesis how BCAA degradation mechanistically connects to tricarboxylic acid cycle, intramyocellular lipid storage, and oxidation, thus allowing more efficient mitochondrial energy production from lipids as well as providing better metabolic health. We analyzed whether data from aged Finnish men are in line with our mechanistic hypothesis linking BCAA catabolism and metabolic disturbances. Older Finnish men enriched with individuals having been athletes in young adulthood (n = 593; mean age 72.6 ± 5.9 years) responded to questionnaires, participated in a clinical examination including assessment of body composition with bioimpedance and gave fasting blood samples for various analytes as well as participated in a 2-h 75 g oral glucose tolerance test. Metabolomics measurements from serum included BCAAs (isoleucine, leucine, and valine). Out of the 593 participants, 59 had previously known type 2 diabetes, further 67 had screen-detected type 2 diabetes, 127 impaired glucose tolerance, and 125 impaired fasting glucose, while 214 had normal glucose regulation and one had missing glucose tolerance information. There were group differences in all of the BCAA concentrations (p ≤ 0.005 for all BCAAs), such that those with normal glucose tolerance had the lowest and those with diabetes mellitus had the highest BCAA concentrations. All BCAA levels correlated positively with body fat percentage (r = 0.29-0.34, p < 0.0001 for all). Expected associations with high BCAA concentrations and unfavorable metabolic profile indicators from metabolomics analysis were found. Except for glucose concentrations, the associations were stronger with isoleucine and leucine than with valine. The findings provided further support for our hypothesis by strengthening the idea that the efficiency of BCAA catabolism may be mechanistically involved in the regulation of fat oxidation, thus affecting the levels of metabolic disease risk factors.

Metformin for Lithium-induced Weight Gain: A Case Report.

Lithium is the first line treatment for maintenance treatment of bipolar disorder. Among the long term adverse effects, weight gain is likely to affect a subset of patients. There is no specific guideline for the treatment of lithium-induced weight gain. We report a young male with bipolar disorder who had significant weight gain with lithium (25 kg), which responded to metformin treatment at 500 mg twice daily. The proposed mechanism of weight lowering effect of metformin includes changes in hypo-thalamic physiology, including leptin and insulin sensitivity, as well as circadian rhythm changes affecting food intake, regulation of fat oxidation and storage in liver, skeletal muscle, and adipose tissue.

Effects of metformin on weight loss: potential mechanisms.

Despite the known glucose-lowering effects of metformin, more recent clinical interest lies in its potential as a weight loss drug. Herein, we discuss the potential mechanisms by which metformin decreases appetite and opposes unfavorable fat storage in peripheral tissues. Many individuals struggle to maintain clinically relevant weight loss from lifestyle and bariatric surgery interventions. Long-term follow-up from the Diabetes Prevention Program demonstrates that metformin produces durable weight loss, and decreased food intake by metformin is the primary weight loss mechanism. Although the effect of metformin on appetite is likely to be multifactorial, changes in hypothalamic physiology, including leptin and insulin sensitivity, have been documented. In addition, novel work in obesity highlights the gastrointestinal physiology and circadian rhythm changes by metformin as not only affecting food intake, but also the regulation of fat oxidation and storage in liver, skeletal muscle, and adipose tissue. Metformin induces modest weight loss in overweight and obese individuals at risk for diabetes. A more detailed understanding of how metformin induces weight loss will likely lead to optimal co-prescription of lifestyle modification with pharmacology for the treatment of obesity independent of diabetes.

Abstract 677: The PPARdelta Agonist GW501516: Influence on Features of the Metabolic Syndrome

Hypertriglyceridemia and insulin resistance in the setting of obesity, i.e. the metabolic syndrome, are thought related to ectopic fat storage and impaired regulation of fat oxidation. Rodent models suggest that increased PPARdelta function may correct these abnormalities. Design/Methods: Double-blind, randomized, 3-parallel group (n = 6 in each group), 2-week study of PPARdelta agonist ( GW501516 –10mg), PPARalpha agonist ( GW590735 –20ug) and placebo. Men with a waist &gt; 95cm, BMI &gt; 27, TG &gt; 100mg/dl &lt; 400mg/dl, and HDLc &lt; 50 mg/dl were included. Blood lipids, fatty acids, serum insulin and liver fat content (MRI) were measured at baseline and termination of study, while oral 13 C-palmitate-labeled fat-feeding allowed post-meal examination of plasma NEFA metabolism and oxidation ( 13 CO 2 exhalation). Skeletal muscle biopsies were taken to monitor transcript regulation of fat oxidation pathways. Results: The PPARdelta group revealed reduction of LDLc, apoB and TG by 23%, 21%, and 31%, respectively and of plasma NEFA, without any deterioration of insulin and glucose homeostasis. Comparable TG reduction in PPARalpha (27%), with modest apoB reductions (−13%) were not accompanied by NEFA reductions. Hepatic fat was significantly reduced in the PPARdelta group only (p = 0.04). After the labeled fat meal, cumulative exhaled 13 CO 2 was increased (p = 0.03; enhanced fat catabolism) and accompanied by increased mRNA expression of skeletal muscle CPT1b only in the PPARδ group. Summary: Short term administration of a selective PPARdelta agonist decreased TG, apoB, LDL-C and NEFA concentrations. Increased peripheral fatty acid uptake and oxidation may partly explain these benefits.

Transforming growth factor-beta in the brain enhances fat oxidation via noradrenergic neurons in the ventromedial and paraventricular hypothalamic nucleus

We have previously reported that intracisternal administration of TGF-beta induces an increase in fat oxidation and that intracisternal administration of anti-TGF-beta antibody partially inhibits an increase in fat oxidation during treadmill running in rats. These results indicate a regulatory role of that TGF-beta in the brain on fat oxidation during exercise. However, it is not clear how TGF-beta in the brain enhance fat oxidation. We hypothesized that TGF-beta in the brain elicits its regulatory effects on fat oxidation via hypothalamic noradrenergic neurons, because some reports have demonstrated the important role of hypothalamic noradrenergic neurons in the regulation of fat oxidation during and after exercise. To examine this hypothesis, we measured the extracellular noradrenaline (NA) levels in the paraventricular hypothalamic nucleus (PVH), ventromedial hypothalamic nucleus (VMH) and lateral hypothalamic area, which are especially important in the regulation of energy metabolism, after intracisternal administration of TGF-beta by using an in vivo brain microdialysis. Microdialysis study revealed that intracisternal administration of TGF-beta3 caused increases in the NA levels in the PVH and VMH. Then, we investigated the impact of impairment of noradrenergic neurons in the PVH and VMH by neurotoxin 6-hydroxydopamine microinjection (NA-lesion) on the action of intracisternal administration of TGF-beta. The NA lesion completely abolished the regulatory effect of TGF-beta on fat oxidation. These results suggest that TGF-beta in the brain enhances fat oxidation via noradrenergic neurons in the PVH and VMH.

Aging-Associated Reductions in AMP-Activated Protein Kinase Activity and Mitochondrial Biogenesis

SummaryRecent studies have demonstrated a strong relationship between aging-associated reductions in mitochondrial function, dysregulated intracellular lipid metabolism, and insulin resistance. Given the important role of the AMP-activated protein kinase (AMPK) in the regulation of fat oxidation and mitochondrial biogenesis, we examined AMPK activity in young and old rats and found that acute stimulation of AMPK-α2 activity by 5′-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) and exercise was blunted in skeletal muscle of old rats. Furthermore, mitochondrial biogenesis in response to chronic activation of AMPK with β-guanidinopropionic acid (β-GPA) feeding was also diminished in old rats. These results suggest that aging-associated reductions in AMPK activity may be an important contributing factor in the reduced mitochondrial function and dysregulated intracellular lipid metabolism associated with aging.

Exercising women throw a wrench in the gears of the AMPK–lipid oxidation link

Several studies, including one in this issue of The Journal of Physiology (Roepstorff et al. 2006), have found that women oxidize more lipid than men during endurance exercise (Friedlander et al. 1999; Carter et al. 2001). The carefully controlled study reported in this issue (Roepstorff et al. 2006) evaluated AMPK signalling as a mechanism for a sex difference in metabolism by evaluating the potential role of AMPK in the regulation of skeletal muscle fat oxidation during exercise. It has been suggested that AMPK is a skeletal muscle energy sensor responding to elevated free AMP content during muscle contraction, which, in turn, inactivates acetyl CoA carboxylase, decreases malonyl CoA and removes its inhibitory effect on CPT1 activity (for review see Hardie & Sakamoto, 2006). Roepstorff et al. had moderately trained males and females complete 90 min of cycling at 60% VO2peak and found that skeletal muscle AMPK Thr172 and α2AMPK activity increased significantly with a concomitant increase in free AMP, the AMP/ATP ratio and free creatine in men, but not women (Roepstorff et al. 2006). These data suggested the higher lipid oxidation seen in women during submaximal endurance exercise was associated with lower ‘cellular energy stress’, but not with AMPK status (Roepstorff et al. 2006). Consequently, the results of the current study suggest that either the AMPK–fat oxidation relationship is more complicated than originally proposed, or that the regulation of fat oxidation is independent of AMPK in women. They also confirmed earlier reports of a higher proportion of type 1 muscle fibres in women (Carter et al. 2001), and added novel data showing a correspondingly higher capillarization (∼23%). These latter findings suggest that fibre type and capillarization can partially explain the sex difference in metabolism; however, there must be other factors at work given that acute 17-β-oestradiol administration can influence exercise substrate selection within days (Devries et al. 2005), which is far too rapid for capillarization or fibre type transformation to occur. In the future, it will be of great interest to determine the role of 17-β-oestradiol on AMPK activity and its ultimate effect on capillarization and fibre type. Initial insight into this could be gleaned from the AMPK mRNA and protein abundance and phosphorylation status in response to acute 17-β-oestradiol administration; however, fibre type and capillarization influences will likely require longer term animal studies. As is the case with every study done well, more questions and research ideas are generated, particularly with respect to the AMPK–fat oxidation relationship in human skeletal muscle. Researchers in every aspect of exercise physiology will be further reminded of the need to control for potential sex differences and metabolism in all aspects of research design.

The Impact of Carbohydrate Ingestion on the Regulation of Fat Oxidation Following Exercise

The level of obesity has reached epidemic proportions in recent years. Fat is an important fuel for muscle metabolism during recovery from exercise. A comprehensive understanding of the effect of carbohydrate on post-exercise lipid oxidation could have important implications for exercise recommendations to prevent weight gain. PURPOSE: To determine the impact of carbohydrate ingestion on the regulation of fat oxidation following a glycogen depleting bout of exercise. METHODS: Six trained males (age 22.7 ± 3.4 yrs; VO2peak 55.8 ± 5.0ml·kg−1. min−1) volunteered to participate in the study. On two separate days, subjects cycled at 75%VO2peak for 90 mins. Upon completion of exercise, subjects consumed either a carbohydrate drink (10% solution; 1.5g kg−1) or a flavoured placebo. Substrate oxidation rates were measured at 1-hr post exercise using indirect calorimetry. RESULTS:The relative exercise intensity was similar for the carbohydrate (72 ± 2%VO2peak) and placebo (73 ± 2%VO2peak) trials. Total energy expenditure during exercise was similar for the two trials. Post exercise carbohydrate ingestion increased the rate of carbohydrate oxidation at 1-hr recovery (0.30 ± 0.02 vs. 0.17 ± 0.02 g.min−1). The rate of fat oxidation was decreased in comparison to placebo (0.12 ± 0.02 vs. 0.07 ± 0.02 g.min−1) but the rate of whole body energy expenditure was similar between trials. CONCLUSIONS: The ingestion of a large amount of carbohydrate in the recovery from prolonged exercise significantly decreased, but did not suppress, fat oxidation. It has been proposed that the rate of fat oxidation is determined by the availability of glucose, rather than the rate of lipolysis. These results indicate that factors other than carbohydrate availability control post-exercise fat oxidation. Further research on the regulation of malonyl-CoA and triglyceride re-esterification following exercise is required.

Effect of elevated lipid concentrations on human skeletal muscle gene expression

Dietary fatty acids regulate the abundance and activity of various proteins involved in the regulation of fat oxidation by functioning as regulators of gene transcription. To determine whether the transcription of key lipid metabolic proteins necessary for fat metabolism within human skeletal muscle are regulated by acute elevations in circulating free fatty acid (FFA) concentrations, 7 healthy men underwent 3 randomized resting infusions of Intralipid (20%) with heparin sodium, saline and heparin sodium, or saline only for 5 hours. These infusions significantly elevated plasma FFA concentrations by 15-fold (to 1.67 ± 0.13 mmol/L) in the Intralipid infusion trial, with modest elevations observed in the saline and heparin sodium and saline alone infusion groups (0.67 ± 0.09 and 0.49 ± 0.087 mmol/L, P < .01 both vs Intralipid infusion). Analysis of messenger RNA (mRNA) concentration demonstrated that pyruvate dehydrogenase kinase isoform 4 (PDK4) mRNA, a key negative regulator of glucose oxidation, was increased in all trials with a 24-fold response after Intralipid infusion, 15-fold after saline and heparin infusion, and 9-fold after saline alone. The PDK4 increases were not significantly different between the 3 trials. The mRNA concentration of the major uncoupling protein within skeletal muscle, uncoupling protein 3, was not elevated in parallel to the increased plasma FFA as similar (∼2-fold) increases were evident in all trials. Additional genes involved in lipid transport (fatty acid translocase/CD36), oxidation (carnitine palmitoyltransferase I), and metabolism (1-acylglycerol-3-phosphate O-acyltransferase 1, hormone-sensitive lipase, and peroxisomal proliferator-activated receptor-γ coactivator-1α) were not altered by increased circulating FFA concentrations. The present data demonstrate that of the genes analyzed that encode proteins that are key regulators of lipid homeostasis within skeletal muscle, only the PDK4 gene is uniquely sensitive to increasing FFA concentrations after increased plasma FFA achieved by intravenous lipid infusion.

Malonyl-CoA and carnitine in regulation of fat oxidation in human skeletal muscle during exercise.

Intracellular mechanisms regulating fat oxidation were investigated in human skeletal muscle during exercise. Eight young, healthy, moderately trained men performed bicycle exercise (60 min, 65% peak O2 consumption) on two occasions, where they ingested either 1) a high-carbohydrate diet (H-CHO) or 2) a low-carbohydrate diet (L-CHO) before exercise to alter muscle glycogen content as well as to induce, respectively, low and high rates of fat oxidation. Leg fat oxidation was 122% higher during exercise in L-CHO than in H-CHO (P < 0.001). In keeping with this, the activity of alpha2-AMP-activated protein kinase (alpha2-AMPK) was increased twice as much in L-CHO as in H-CHO (P < 0.01) at 60 min of exercise. However, acetyl-CoA carboxylase (ACC)beta Ser221 phosphorylation was increased to the same extent (6-fold) under the two conditions. The concentration of malonyl-CoA was reduced 13% by exercise in both conditions (P < 0.05). Pyruvate dehydrogenase activity was higher during exercise in H-CHO than in L-CHO (P < 0.01). In H-CHO only, the concentrations of acetyl-CoA and acetylcarnitine were increased (P < 0.001), and the concentration of free carnitine was decreased (P < 0.01), by exercise. The data suggest that a decrease in the concentration of malonyl-CoA, secondary to alpha2-AMPK activation and ACC inhibition (by phosphorylation), contributes to the increase in fat oxidation observed at the onset of exercise regardless of muscle glycogen levels. They also suggest that, with high muscle glycogen, the availability of free carnitine may limit fat oxidation during exercise, due to its increased use for acetylcarnitine formation.

Symposium: Limits to fat oxidation by skeletal muscle during exercise--introduction.

Lipids, in the form of adipose tissue triacylglycerol (TG), intramuscular triglyceride (IMTG), and dietary-derived fatty acids (FA) from plasma TG (chylomicrons), and very low-density lipoproteins (VLDL), represent the largest store of nutrient energy in humans. Yet despite the abundance of endogenous TG, there is limited capacity for FA oxidation during exercise: there are no mechanisms that match the availability and metabolism of FA to the rate of energy expenditure. Because of the body's limited carbohydrate (CHO) stores, and because depletion of muscle and liver glycogen reserves often coincide with exhaustion, there is interest in several nutritional interventions that increase FA availability and rates of fat oxidation during exercise: such strategies have the potential to slow the rate of glycogen utilization and delay the onset of fatigue. The five papers comprising this symposium provide a synopsis of 1) the regulation of fat oxidation in human skeletal muscle during aerobic exercise; 2) selected nutritional techniques that increase fat oxidation, spare endogenous CHO stores, and modify exercise capacity; and 3) dietary manipulations that alter macronutrient availability and muscle gene expression.

Fat metabolism during exercise: a review--part II: regulation of metabolism and the effects of training.

This part discusses the complex regulation of fat metabolism. Catecholamines as a stimulator of lipolysis and insulin as a suppressor play very important roles in the regulation of fat oxidation. The interaction of carbohydrate and fat metabolism has been extensively studied in the past decennia but the understanding of this multifactorial regulation is complex and still incompletely understood. In 1963, Randle et al. proposed the glucose-fatty acid cycle as a possible mechanism, and more recently, regulation through malonyl-CoA has been put forward as a possible way to explain shifts in carbohydrate and fat metabolism at rest and during exercise. The exercise intensity affects fat oxidation mainly by increasing lipolysis and fatty acid availability during exercise of low to moderate intensity. At high exercise intensities, both a reduction in fatty acid availability (decreased RaFa) and intramuscular factors reduce fat oxidation. These intramuscular factors are largely unknown. The increased mitochondrial density after training and increased oxidative enzymes may partly explain the increased fatty acid oxidation during exercise as observed after training. However, also supply of fatty acids to the mitochondria may be important. The available evidence suggests that the additional fatty acids oxidized after training are primarily derived from intramuscular triacylglycerols and not from adipose tissue derived fatty acids or circulating triacylglycerols.