Metabolism of Free Fatty Acids and Ketone Bodies in Skeletal Muscle

1971 ◽  
pp. 153-163 ◽  
Author(s):  
L. Hagenfeldt ◽  
J. Wahren
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acids ◽  
Free Fatty Acids ◽  
Ketone Bodies

Net substrates balance across hindlimb in conscious rabbit during late pregnancy

1986 ◽  
Vol 251 (1) ◽  
pp. E42-E47 ◽  
Author(s):  
M. Bouisset ◽  
M. C. Pere ◽  
M. Gilbert
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acids ◽  
Free Fatty Acids ◽  
Glucose Uptake ◽  
Ketone Bodies ◽  
Late Pregnancy ◽  
Gravid Uterus ◽  
Minor Importance ◽  
Insulin Effect ◽  
Increase Glucose Uptake

The present work performed in rabbits was designed to investigate whether changes in skeletal muscle metabolism could contribute to glucose homeostasis during late pregnancy a time at which there is a large glucose demand of the gravid uterus. We therefore studied the net substrate balance of glucose, lactate, free fatty acids, and ketone bodies across the hindlimb of pregnant animals (days 24 and 30) and virgin animals. Our data show that on day 24 the basal rate of glucose uptake is similar to that observed in virgin rabbits, but it decreases by approximately 60% on day 30 despite comparable levels of blood glucose and plasma insulin at both gestational ages. A moderate hyperglycemia (20% above basal level) and hyperinsulinemia (2- to 3-fold above basal level) sustained for 80 min failed to increase glucose uptake except in virgin animals. Estimates of the contribution of substrates to oxidative metabolism indicate that free fatty acids could represent the major fuel in all groups, whereas glucose would be of minor importance especially at term. It is concluded that in pregnancy a) under normoglycemia there is a reduced insulin effect on glucose uptake and b) under moderate hyperglycemia and hyperinsulinemia the insulin resistance results from an impaired stimulation of glucose uptake. Sparing glucose from the skeletal muscle, the mother can direct more glucose toward the uterus without marked increase in her production rate.

scholarly journals Effects of 3-hydroxybutyrate and free fatty acids on muscle protein kinetics and signaling during LPS-induced inflammation in humans: anticatabolic impact of ketone bodies

2018 ◽  
Vol 108 (4) ◽  
pp. 857-867 ◽  
Author(s):  
Henrik H Thomsen ◽  
Nikolaj Rittig ◽  
Mogens Johannsen ◽  
Andreas B Møller ◽  
Jens Otto Jørgensen ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Free Fatty Acids ◽  
Acute Inflammation ◽  
Ketone Bodies ◽  
Muscle Protein ◽  
Initiation Factor ◽  
Whole Body ◽  
Protein Breakdown ◽  
Protein Kinetics ◽  
Nonesterified Fatty Acids

Abstract Background Acute inflammation, and subsequent release of bacterial products (e.g. LPS), inflammatory cytokines, and stress hormones, is catabolic, and the loss of lean body mass predicts morbidity and mortality. Lipid intermediates may reduce protein loss, but the roles of free fatty acids (FFAs) and ketone bodies during acute inflammation are unclear. Objective We aimed to test whether infusions of 3-hydroxybutyrate (3OHB), FFAs, and saline reduce protein catabolism during exposure to LPS and Acipimox (to restrict and control endogenous lipolysis). Design A total of 10 healthy male subjects were randomly tested 3 times, with: 1) LPS, Acipimox (Olbetam) and saline, 2) LPS, Acipimox, and nonesterified fatty acids (Intralipid), and 3) LPS, Acipimox, and 3OHB, during a 5-h basal period and a 2-h hyperinsulinemic, euglycemic clamp. Labeled phenylalanine, tyrosine, and urea tracers were used to estimate protein kinetics, and muscle biopsies were taken for Western blot analysis of protein metabolic signaling. Results 3OHB infusion increased 3OHB concentrations (P < 0.0005) to 3.5 mM and decreased whole-body phenylalanine-to-tyrosine degradation. Basal and insulin-stimulated net forearm phenylalanine release decreased by >70% (P < 0.005), with both appearance and phenylalanine disappearance being profoundly decreased. Phosphorylation of eukaryotic initiation factor 2α at Ser51 was increased in skeletal muscle, and S6 kinase phosphorylation at Ser235/236 tended (P = 0.074) to be decreased with 3OHB infusion (suggesting inhibition of protein synthesis), whereas no detectable effects were seen on markers of protein breakdown. Lipid infusion did not affect phenylalanine kinetics, and insulin sensitivity was unaffected by interventions. Conclusion During acute inflammation, 3OHB has potent anticatabolic actions in muscle and at the whole-body level; in muscle, reduction of protein breakdown overrides inhibition of synthesis. This trial was registered at clinicaltrials.gov as NCT01752348.

Elevated plasma free fatty acids decrease basal protein synthesis, but not the anabolic effect of leucine, in skeletal muscle

2006 ◽  
Vol 291 (3) ◽  
pp. E666-E674 ◽  
Author(s):  
Charles H. Lang
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acids ◽  
Protein Synthesis ◽  
Free Fatty Acids ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Short Term ◽  
Lipid Infusion ◽  
Igf I ◽  
Plasma Ffas

Elevations in free fatty acids (FFAs) impair glucose uptake in skeletal muscle. However, there is no information pertaining to the effect of elevated circulating lipids on either basal protein synthesis or the anabolic effects of leucine and insulin-like growth factor I (IGF-I). In chronically catheterized conscious rats, the short-term elevation of plasma FFAs by the 5-h infusion of heparin plus Intralipid decreased muscle protein synthesis by ∼25% under basal conditions. Lipid infusion was associated with a redistribution of eukaryotic initiation factor (eIF)4E from the active eIF4E·eIF4G complex to the inactive eIF4E·4E-BP1 complex. This shift was associated with a decreased phosphorylation of eIF4G but not 4E-BP1. Lipid infusion did not significantly alter either the total amount or phosphorylation state of mTOR, TSC2, S6K1, or the ribosomal protein S6 under basal conditions. In control rats, oral leucine increased muscle protein synthesis. This anabolic response was not impaired by lipid infusion, and no defects in signal transduction pathways regulating translation initiation were detected. In separate rats that received a bolus injection of IGF-I, lipid infusion attenuated the normal redistribution of eIF4E from the active to inactive complex and largely prevented the increased phosphorylation of 4E-BP1, eIF4G, S6K1, and S6. This IGF-I resistance was associated with enhanced Ser307 phosphorylation of insulin receptor substrate-1 (IRS-1). These data indicate that the short-term elevation of plasma FFAs impairs basal protein synthesis in muscle by altering eIF4E availability, and this defect may be related to impaired phosphorylation of eIF4G, not 4E-BP1. Moreover, hyperlipidemia impairs IGF-I action but does not produce leucine resistance in skeletal muscle.

Rapid impairment of skeletal muscle glucose transport/phosphorylation by free fatty acids in humans

Diabetes ◽  
1999 ◽  
Vol 48 (2) ◽  
pp. 358-364 ◽  
Author(s):  
M. Roden ◽  
M. Krssak ◽  
H. Stingl ◽  
S. Gruber ◽  
A. Hofer ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acids ◽  
Free Fatty Acids ◽  
Glucose Transport ◽  
Muscle Glucose Transport

scholarly journals A Clinical Case of Clozapine-Induced Fatal Diabetic Ketoacidosis

2016 ◽  
Vol 7 ◽  
pp. CMPsy.S30532
Author(s):  
Eric Romney ◽  
Vinay J. Nagaraj ◽  
Amie Kafer
Keyword(s):  
Fatty Acids ◽  
Weight Gain ◽  
Free Fatty Acids ◽  
Diabetic Ketoacidosis ◽  
Ketone Bodies ◽  
Pancreatic Beta Cell ◽  
Metabolic Effects ◽  
Psychotic Symptoms ◽  
Life Threatening ◽  
Altered Metabolism

Introduction Clozapine, a second generation medication, has become the atypical antipsychotic drug of choice for refractory or treatment-resistant schizophrenia. In addition to the high risk of agranulocytosis and seizures, clozapine treatment is increasingly associated with significant metabolic effects, such as hyperglycemia, central weight gain and adiposity, hypertriglyceridemia, and elevated low-density lipoprotein cholesterol. A potentially life-threatening complication of altered metabolism is diabetic ketoacidosis (DKA). This report details a case of fatal DKA in a schizophrenic patient undergoing treatment with clozapine. Case Description An African–American male in his 20s with a medical history significant for schizophrenia was presented to the psychiatric inpatient ward with severe paranoid thoughts and aggressive behavior. After trials of risperidone, olanzapine, and haloperidol—all of which failed to adequately control his psychotic symptoms—clozapine titration was initiated and he showed significant improvement. Weight gain was observed throughout hospitalization, but all blood and urine test results showed no metabolic or hematological abnormalities. The patient was discharged for outpatient treatment on clozapine (125 mg morning and 325 mg evening) along with divalproex sodium and metoprolol. Six days post-discharge, the patient died. A medical autopsy later ruled that the death was due to DKA without any evidence of contributory injuries or natural disease. Results and Conclusion Significant increase in body mass index from 28.7 to 33.5 was observed during hospitalization. The blood glucose level, measured after his death, was found to be 500 mg/dL. Altered metabolism due to clozapine can lead to dyslipidemia-mediated-pancreatic-beta-cell damage, decreased insulin secretion as well as insulin resistance. In DKA, low levels of insulin lead to an increased release of free fatty acids from adipose tissue. Acetyl coenzyme A (CoA), derived from the breakdown of free fatty acids, is metabolized by the Kreb's cycle. In hepatocytes, excess acetyl-CoA is converted into ketone bodies (acetoacetate and β-hydroxybutyrate) and released into circulation. Ketone bodies have a low p Ka value and their high serum concentrations lead to DKA. In this patient, DKA was most probably clozapine induced and had fatal consequences. Thus, recognizing potential risk factors, providing patient education, and increasing monitoring of patients on clozapine and other atypical antipsychotics are critical to prevent the life-threatening effects of DKA.

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