ReviewPPARs and the orchestration of metabolic fuel selection
Introduction
Major exogenous sources of lipids include chylomicrons, which transport dietary fatty acids (FA) within their triacylglycerol (TAG) component, very-low-density lipoproteins (VLDL) (which transport FA derived from hepatic TAG, and whose release from liver is suppressed by insulin), non-esterified FA (NEFA), bound to albumin and released from adipose tissue under conditions where insulin's anti-lipolytic action is compromised, and ketone bodies, produced by the liver when hepatic NEFA delivery is high and insulin concentration or action deficient. In addition some tissues, most notably heart and oxidative skeletal muscles, can use endogenous (stored) TAG.
White adipose tissue (WAT) plays an essential role in ‘buffering’ the influx of dietary fat delivered via chylomicrons. According to requirement, WAT stores FA derived from circulating lipoproteins as TAG or releases FA from TAG stored within the adipocyte fat droplet to the bloodstream to support the ATP requirements of other tissues; the latter occurs in conjunction with the release of glycerol, which can provide carbon for gluconeogenesis. Either a deficiency or a surplus of adipose tissue disturbs its fat buffering capacity, resulting in a mismatch between energy availability and TAG storage capacity [1], as well as resulting in abnormal glycerol flux from WAT to liver. Adverse consequences of disturbances in adipose-tissue fat buffering include the ectopic deposition of TAG in other tissues. In liver and muscle this causes insulin resistance [2], a state of reduced responsiveness of insulin-sensitive tissues to insulin that is common to obesity, the metabolic syndrome and type 2 diabetes. As well as increased flux of lipid into non-adipose tissues, a further mechanism by which lipid may accumulate ectopically may be its impaired disposal by oxidation. This has been proposed to be a possible consequence of impaired mitochondrial function and/or a reduced content of mitochondria.
The peroxisome proliferator-activated receptors (PPARs) (α, β/δ and γ) mediate adaptive metabolic responses to increased systemic lipid availability following activation by binding of naturally occurring endogenous or dietary lipids or lipid derivatives [3]. PPARs α and δ promote lipid clearance by increasing tissue fat oxidation. Increased oxidation of accumulated lipids is perceived as one mechanism by which insulin resistance, particularly in skeletal muscle, can be reversed. PPARγ activation promotes lipid storage in WAT, as well as preadipocyte differentiation to mature adipocytes [4]. This augments the ability of WAT to buffer changes in blood lipids, and reduces ectopic TAG deposition (TAG deposition in non-adipose tissue). This contribution describes recent advances in our knowledge of the regulatory interactions between the two major oxidative fuels glucose and lipid, addresses how the metabolic abnormalities associated with insulin resistance and ischemic diseases impair the ability of oxidative tissues – in particular skeletal muscle – to switch between the use of alternative metabolic fuels, and how targeting PPARs might ameliorate this metabolic inflexibility.
Section snippets
The glucose-sparing action of fatty acids
Cross-talk between circulating glucose and FA (derived from adipose-tissue TAG lipolysis, from circulating lipoproteins, or stored TAG), is important for metabolic fuel homeostasis during the fed-to-fasting and fasting-to-fed nutritional transitions. The oxidation of FA is dominant over that of glucose during the fed-to-fasting transition, where glucose becomes scarce, insulin concentrations are low and adipose-tissue TAG lipolysis increases FA delivery to oxidative tissues. Lowered insulin
PDC and PPARα
Inhibition of PDC is achieved by end-product inhibition and activation of the pyruvate dehydrogenase kinases (PDKs) by the increased mitochondrial acetyl-CoA/CoA and NADH/NAD+ ratios generated when FA are oxidised at high rates. The PDKs inactivate PDC by phosphorylation: this can be reversed by PDH phosphatases (reviewed in [12]). We have previously developed the hypothesis that a specific PDK isoform PDK4, whose activity is particularly enhanced by increased NADH/NAD+ concentration ratios
Mitochondrial function in skeletal muscle in prolonged hypoxia is co-ordinated by PPARα
When oxygen supply is limiting and sustained, mitochondrial respiration declines. Mitochondrial performance is further suppressed by oxidative damage as reactive oxygen species (ROS) are generated in excess. A shift to anaerobic ATP production impairs muscle performance and is predicted to impair muscle lipid clearance, but provides protection against lethal ischemia due to reduced generation of oxidative stress. Under hypoxic conditions, levels of the hypoxia-inducible factor-1 (HIF-1)-α
The PDKs and metabolic inflexibility in insulin resistance and in response to hypoxia
Measurement of the respiratory quotient (RQ) across the tissue bed of skeletal muscle in lean healthy subjects reveals a high reliance on fat oxidation (lower RQ) during fasting, but insulin infusion rapidly reverses this preference (a shift to a higher RQ). However, RQ values measured across the tissue bed of the leg during fasting are elevated in type 2 diabetes and in obesity [30]. Thus, there is a constricted range in switching between fat and glucose oxidation in obese, insulin resistant,
Fat partitioning towards lipid storage: the “reverse glucose–fatty acid cycle”
In the well-fed state, where glucose is abundant, a “reverse” glucose–FA cycle operates whereby glucose utilisation blocks FA oxidation [35], [36]. As the PDKs are inhibited by pyruvate, high rates of glucose flux can block PDC inactivation by phosphorylation, facilitating dephosphorylation. This enables PDC to couple glycolysis to the functions of the TCA cycle. Under “physiological” hyperglycemia (e.g. post-prandially) acetyl-CoA production from glucose via PDC may exceed the requirements for
Ectopic lipid accumulation due to increased fatty acid influx in relation to impaired insulin action in muscle
Since elevated glucose flux elicits a relatively decreased degree of intracellular FA oxidation, this may elicit a state of insulin resistance through the accumulation of intracellular lipids. Elevation of muscle malonyl-CoA concentrations in models of rodent obesity occur in conjunction with increased intramyocellular TAG (IMTG) and accumulation of long-chain acyl-CoAs [42], [43]. Mice lacking the muscle ACC isoform (of which malonyl-CoA is the product) are protected against high-fat
Effects of lipid intermediates on insulin signalling
The signalling pathway from the insulin receptor to glucose transport is still incompletely defined, although it is established that IRS-1/phosphatidylinositol 3-kinase (PI3K)/Akt pathway is involved (reviewed in [63]). In skeletal muscle, serine phosphorylation of the insulin receptor leads to decreased IRS-1 tyrosine phosphorylation and IRS-1 associated PI3K activity, thereby inhibiting downstream insulin signalling pathways [64]. Muscle-specific IRS-1 mutant mice, in which Ser302, Ser307 and
Muscle insulin resistance in relation to mitochondrial dysfunction and lipid-induced mitochondrial stress
While increased flux of lipids into non-adipose tissue is one way for lipids to accumulate, impaired disposal of these lipids is also a key factor. In obese or insulin-resistant rodents or humans, mitochondrial oxidative capacity is reduced [72], [73], [74]. This reduction in mitochondrial capacity has been suggested as a primary mechanism that predisposes individuals to the development of insulin resistance and obesity. Thus increased oxidation of accumulated lipids is perceived as one
The enigmatic roles of the PPAR coactivator PGC1α in heart and skeletal muscle
Ligand binding to the PPARs involves the recruitment of coactivators. In particular, PGC1 transcriptional coactivators are major regulators of several metabolic pathways including mitochondrial biogenesis and oxidative metabolism [81]. Cardiac expression of PGC1α, along with that of its target transcription factors PPARα and ERRα are suppressed in animal models of heart failure and in models of cardiac hypertrophy [82], [83]. PGC1α downregulation is associated with increased glucose oxidation
Insulin resistance and the concept that abnormal function of the adipo-muscular axis causes metabolic inflexibility: the role of PPARγ
While a primary function of adipocytes is to store fuel as TAG for distribution to non-adipose tissues in times of need when nutrients are in short supply, a second important function is the compartmentalisation into adipocytes of the surplus calories consumed during overnutrition as TAG [95], [96], [97]. This protects non-adipose organs from abnormalities induced by lipid overload. This is predicted to lead to weight gain, but is perceived to be protective against cardiovascular disease,
Metabolic inflexibility in adipose tissue: a role for PPARγ
In the fed state, insulin increases adipocyte TAG storage by augmenting adipocyte glucose uptake. This allows the production of glycerol 3-phosphate for FA esterification to form TAG, by direct effects to stimulate enzymes in the pathway for esterification of incoming FA, mainly generated from chylomicrons locally via LPL, and by effects to block TAG lipolysis. Adipocyte glucose uptake and its conversion to glycerol 3-phosphate is enhanced by PPARγ activation [111], [112]. PPARγ activation also
Oxidative stress in obesity: metabolic inflexibility induced by a PDK isoform shift towards PDK1?
The augmented glycolytic flux seen in hypoxic/ischemic muscle fibres in the absence of PHD1 is not accompanied by intracellular acidosis [27]. This arises, in part, because loss of PHD1 leads to upregulation of the lactate transporter MCT4, which facilitates lactate efflux. Lactate flux is an overlooked component of adipocyte metabolism. In rat adipocytes, lactate production varies between young lean and older fatter rats (increased by age and fatness), by the adipose-tissue region (higher in
Concluding remarks
There is a complex interplay between the regulation of the two major oxidative fuels glucose and lipid fuels as metabolic fuels in skeletal muscle, including the role of PPARs in modifying gene expression. The development of insulin resistance and ischemic diseases elicit changes in the regulation of nutrient selection that diminish the ability of tissues, including skeletal muscle, to effectively switch between the use of glucose and lipid as oxidative substrate, termed metabolic
Acknowledgements
This study was supported in part by project grants from Diabetes UK (RD06/0003424 and RD03/0002725) to MCS and MJH. MGZ was a recipient of a Diabetes UK studentship.
References (128)
- et al.
The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus
Lancet
(1963) - et al.
CD36-dependent regulation of muscle FoxO1 and PDK4 in the PPAR delta/beta-mediated adaptation to metabolic stress
J Biol Chem
(2008) - et al.
Oxygen sensors at the crossroad of metabolism
Cell Metab
(2009) - et al.
HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption
Cell Metab
(2006) - et al.
HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia
Cell Metab
(2006) - et al.
Induction of pyruvate dehydrogenase kinase-3 by hypoxia-inducible factor-1 promotes metabolic switch and drug resistance
J Biol Chem
(2008) Glucose–fatty acid interactions in health and disease
Am J Clin Nutr
(1998)- et al.
Development and initial evaluation of a novel method for assessing tissue-specific plasma free fatty acid utilization in vivo using (R)-2-bromopalmitate tracer
J Lipid Res
(1999) - et al.
IRS1-independent defects define major nodes of insulin resistance
Cell Metab
(2008) - et al.
Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase activity in muscle
J Biol Chem
(2002)
Ceramide generation is sufficient to account for the inhibition of the insulin-stimulated PKB pathway in C2C12 skeletal muscle cells pretreated with palmitate
J Biol Chem
Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance
Cell Metab
Metabolic control through the PGC-1 family of transcription coactivators
Cell Metab
Peroxisome proliferator activator receptor gamma coactivator-1 expression is reduced in obesity: potential pathogenic role of saturated fatty acids and p38 mitogen-activated protein kinase activation
J Biol Chem
Peroxisome proliferator-activated receptor-gamma co-activator 1alpha-mediated metabolic remodeling of skeletal myocytes mimics exercise training and reverses lipid-induced mitochondrial inefficiency
J Biol Chem
Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia
J Biol Chem
HIF-1 inhibits mitochondrial biogenesis and cellular respiration in VHL-deficient renal cell carcinoma by repression of C-MYC activity
Cancer Cell
Central role of the adipocyte in the insulin-sensitising and cardiovascular risk modifying actions of the thiazolidinediones
Biochimie
Wnt/beta-catenin signaling in adipogenesis and metabolism
Curr Opin Cell Biol
Adipose tissue as a buffer for daily lipid flux
Diabetologia
Disordered lipid metabolism and the pathogenesis of insulin resistance
Physiol Rev
Peroxisome proliferator-activated receptors as sensors of fatty acids and derivatives
Cell Mol Life Sci
Before they were fat: adipocyte progenitors
Cell Metab
Adipose tissue fatty acid metabolism in insulin-resistant men
Diabetologia
Effect of obesity and insulin resistance on myocardial substrate metabolism and efficiency in young women
Circulation
Regulatory interactions between lipids and carbohydrates: the glucose fatty acid cycle after 35 years
Diabetes Metab Rev
The glucose–fatty acid cycle: a physiological perspective
Biochem Soc Trans
Glucose utilization in heart, diaphragm and skeletal muscle during the fed-to-starved transition
Biochem J
Endocrine and nutritional modulation of glucose disposal and storage in muscle
Biochem Soc Trans
Mechanisms underlying regulation of the expression and activities of the mammalian pyruvate dehydrogenase kinases
Arch Physiol Biochem
Recent advances in mechanisms regulating glucose oxidation at the level of the pyruvate dehydrogenase complex by PDKs
Am J Physiol Endocrinol Metab
Starvation and diabetes increase the amount of pyruvate dehydrogenase kinase isoenzyme 4 in rat heart
Biochem J
Evaluation of the role of peroxisome-proliferator-activated receptor alpha in the regulation of cardiac pyruvate dehydrogenase kinase 4 protein expression in response to starvation, high-fat feeding and hyperthyroidism
Biochem J
Up-regulation of pyruvate dehydrogenase kinase isoform 4 (PDK4) protein expression in oxidative skeletal muscle does not require the obligatory participation of peroxisome-proliferator-activated receptor alpha (PPARalpha)
Biochem J
Peroxisome-proliferator-activated receptor-alpha (PPARalpha) deficiency leads to dysregulation of hepatic lipid and carbohydrate metabolism by fatty acids and insulin
Biochem J
Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-alpha, -beta, and -gamma in the adult rat
Endocrinology
Differential regulation in the heart of mitochondrial carnitine palmitoyltransferase-I muscle and liver isoforms
Mol Cell Biochem
Metabolic profiling of PPAR{alpha}−/− mice reveals defects in carnitine and amino acid homeostasis that are partially reversed by oral carnitine supplementation
FASEB J
Oxygen-dependent regulation of mitochondrial respiration by hypoxia-inducible factor 1
Biochem J
Deficiency or inhibition of oxygen sensor Phd1 induces hypoxia tolerance by reprogramming basal metabolism
Nat Genet
Activation of peroxisome proliferator-activated receptor-alpha protects the heart from ischemia/reperfusion injury
Circulation
Peroxisome proliferator-activated receptor-alpha regulates postischemic liver injury
Am J Physiol Gastrointest Liver Physiol
Muscle triglyceride and insulin resistance
Annu Rev Nutr
Fuel selection in human skeletal muscle in insulin resistance: a reexamination
Diabetes
Overexpression of pyruvate dehydrogenase kinase 4 in heart perturbs metabolism and exacerbates calcineurin-induced cardiomyopathy
Am J Physiol Heart Circ Physiol
PDC deletion: the way to a man's heart disease
Am J Physiol Heart Circ Physiol
Evidence for existence of tissue-specific regulation of the mammalian pyruvate dehydrogenase complex
Biochem J
Glucose plus insulin regulate fat oxidation by controlling the rate of fatty acid entry into the mitochondria
J Clin Invest
Malonyl coenzyme A and the regulation of functional carnitine palmitoyltransferase-1 activity and fat oxidation in human skeletal muscle
J Clin Invest
Increased efficiency of fatty acid uptake contributes to lipid accumulation in skeletal muscle of high fat-fed insulin-resistant rats
Diabetes
Cited by (48)
Fatty acid oxidation alleviates the energy deficiency caused by the loss of MPC1 in MPC1<sup>+/−</sup> mice
2018, Biochemical and Biophysical Research CommunicationsCitation Excerpt :ATP production has a major role in the overall metabolism of the cell [2]. Dysregulation of these processes contributes to the pathogenesis of numerous diseases, including diabetes and obesity [3,4], mitochondrial disorders [5], cardiac failure [3], neurodegenerative disorders [6], and cancer [7]. Therefore, a better understanding of how pyruvate fluxes into mitochondria and how to influence the substrate utilization may have therapeutic potential by directly or indirectly influencing glucose, lipid, and amino acid homeostasis.
Principles in the Regulation of Cardiac Metabolism
2015, The Scientist's Guide to Cardiac MetabolismRegulation of substrate utilization by the mitochondrial pyruvate carrier
2014, Molecular CellQuality More Than Quantity: The Use of Carbohydrates in High-Fat Diets to Tackle Obesity in Growing Rats
2022, Frontiers in NutritionExpanding roles of de novo lipogenesis in breast cancer
2021, International Journal of Environmental Research and Public Health