Elsevier

Pharmacological Research

Volume 60, Issue 3, September 2009, Pages 141-150
Pharmacological Research

Review
PPARs and the orchestration of metabolic fuel selection

https://doi.org/10.1016/j.phrs.2009.03.014Get rights and content

Abstract

This contribution describes recent advances in our knowledge of the regulatory interactions between the two major oxidative fuels glucose and lipid. It also addresses how the metabolic abnormalities associated with insulin resistance and ischemic diseases impair the ability of skeletal muscle to switch between the use of alternative metabolic fuels and the ability of adipose tissue to function appropriately in relation to the body's requirements for triglyceride mobilisation or storage, as appropriate to nutritional status. We discuss how targeting PPARs might ameliorate metabolic inflexibility in muscle through altered expression of pyruvate dehydrogenase kinase (PDK) isoforms and impact the functions of the adipocyte in lipid buffering and energy homeostasis. Focus has been placed on the participation of the regulatory pyruvate dehydrogenase kinases, PPAR targets, both in the beneficial and the potentially adverse actions of the PPARs in metabolic control.

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.

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