- Email: [email protected]
Lipid mediators and inflammation in glucose intolerance and insulin resistance
Drug Discovery Today: Disease Mechanisms
DRUG DISCOVERY
TODAY
Vol. 7, No. 3–4 2010
Editors-in-Chief Toren Finkel – National Heart, Lung and Blood Institute, National Institutes of Health, USA Charles Lowenstein – University of Rochester Medical Center, Rochester, NY.
DISEASE Endocrinology/mechanisms of obesity MECHANISMS
Lipid mediators and inflammation in glucose intolerance and insulin resistance Abishek Iyer1, Lindsay Brown1,2,* 1 2
School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia Department of Biological and Physical Sciences, University of Southern Queensland, Toowoomba, QLD 4350, Australia
Clinical and epidemiological studies suggest that patients who are overweight or obese are at greater risk to develop glucose intolerance and insulin resis-
Section editor: Vincenzo Di Marzo – CNR, Institute of Biomolecular Chemistry, Napoli, Italy
tance leading to type II diabetes and cardiovascular disease. Despite many hypotheses, it has been difficult to pin-point the precise causes of insulin resistance or impaired glucose tolerance. This commentary aims to stimulate debate by providing some mechanistic insights into a unifying hypothesis by which disturbed lipid metabolism, increased circulating lipid-derived mediators and excess accumulation of toxic lipid metabolites in adipose, muscle, liver and pancreatic beta cells contribute to inflammation, insulin resistance and beta cell dysfunction in type II diabetes. This understanding will direct future drug discovery research to identify and develop novel compounds that can regulate both metabolic and immune/inflammatory systems to provide a dual strategy to combat metabolic disease, especially insulin resistance and type II diabetes.
*Corresponding author: L. Brown ([email protected]) 1740-6765/$ ß 2010 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.ddmec.2010.12.001
Introduction As glucose is a major source of energy for cells, precise control of glucose concentrations by the hormone, insulin, is essential. Impaired glucose tolerance is a delayed normalisation of blood glucose concentrations after glucose intake despite adequate insulin concentrations. The combination of increased glucose and insulin concentrations defines insulin resistance, typically characterised as the insensitivity to insulin in peripheral tissues such as skeletal muscle, liver and adipose and reduced function of the pancreatic beta cells [1]. In patients, insulin resistance is characterised by obesity, type II diabetes mellitus and the associated metabolic and cardiovascular dysfunction, a major cause of morbidity and mortality throughout the world [1–3]. The metabolic syndrome, also termed the insulin resistance syndrome, combines the clinical signs of fasting and post-prandial hyperglycaemia, centrally distributed abdominal fat, dyslipidaemia and hypertension [4–6]. Clinical and epidemiological studies suggest that patients who are overweight or obese are more at risk in developing glucose intolerance and insulin resistance leading to type II diabetes and cardiovascular disease. Many hypotheses have been proposed to explain the underlying mechanisms of insulin resistance. Traditionally, insulin resistance and type II diabetes have been rationalised as a dysfunction of glucose metabolism and this has been the e191
Drug Discovery Today: Disease Mechanisms | Endocrinology/mechanisms of obesity
primary therapeutic target in type II diabetes. This glucocentric view then changed towards an emphasis on induction of the dysfunction of glucose homeostasis by free fatty acids and other lipid mediators [7]. Activation of inflammatory lipid mediators associated with the altered release of adipokines and cytokines to alter adipocyte and immune cell function has now become the prevailing hypothesis to explain the mechanisms of insulin resistance [2]. This commentary aims to stimulate debate by providing some mechanistic insights into a unifying hypothesis by which disturbed lipid metabolism, increased circulating lipidderived mediators and excess accumulation of toxic lipid metabolites in adipose, muscle, liver and pancreatic beta cells contribute to inflammation, insulin resistance and beta cell dysfunction in type II diabetes.
Insulin resistance, obesity and inflammation Evidence linking inflammation and type II diabetes mellitus has been accumulating since the first report in 1876 that high dose sodium salicylate decreased glucosuria in patients presumably with type II diabetes [8,9]. Clinical, animal and in vitro studies support links between insulin resistance, obesity, metabolic dysfunction and inflammation [2]. Insulin resistance is associated with increased pro-inflammatory proteins in the circulation and metabolic tissues [1]. Adipose tissue releases many bioactive mediators, including inflammatory cytokines, that alter body weight homeostasis and induce changes in cardiovascular structure and function, glucose metabolism, blood pressure, lipid metabolism, coagulation, fibrinolysis and inflammation, leading to endothelial dysfunction and atherosclerosis [1]. Plasma concentrations of inflammatory markers derived from immune and other cell types, including adipocytes, correlate with body mass index in morbidly obese patients [10,11]. Obesity and insulin resistance are also associated with high circulating concentrations of free fatty acids, particularly following meals, that are ligands for immune receptors such as Toll-like receptors and G-protein coupled receptors, thus initiating and perpetuating an innate immune response [2]. There is increasing pre-clinical and clinical evidence that anti-inflammatory compounds including salicylates and other non-steroidal anti-inflammatory drugs may be helpful in improving metabolic dysfunction [2,12]. Drugs with pleiotropic anti-inflammatory effects such as statins, ACE inhibitors and PPARg agonists are also effective in metabolic syndrome; this effectiveness cannot be explained only by lowering lipid concentrations or blood pressure or improving insulin sensitivity [1,2]. The proposal that chronic low-grade inflammation underlies obesity, insulin resistance and metabolic dysfunction has become credible in recent years. Inflammation is usually described as the short-term primary response of the body to deal with injuries and so it is crucial for tissue repair, involving many complex signals in distinct cells and organ e192
www.drugdiscoverytoday.com
Vol. 7, No. 3–4 2010
systems [13]. If prolonged, this response turns pathological, damaging cells [13]. In the case of metabolic diseases, this has been termed ‘meta-inflammation’ or ‘chronic low-grade inflammation’ that can be described as a long-term inflammatory response triggered by nutrients and metabolic surplus [14]. This process utilises a similar set of molecules and signalling pathways to those involved in classical inflammation but might also regulate energy storage and metabolism [14]. Current studies would argue that molecules such as the lipid mediators and their signalling pathways, known to play immune/inflammatory roles, participate in the accumulation of toxic lipid mediators in metabolically relevant tissues thereby hampering the normal functioning of these tissues. This understanding will direct future drug discovery research to identify and develop novel compounds that can regulate both metabolic and immune systems to provide a dual strategy to combat metabolic disease, especially insulin resistance. The identification of novel therapeutic agents for insulin resistance and metabolic disease requires immunologists and drug discovery scientists to distinguish the key differences between the inflammatory/immune components underling metabolic disease and those described in the classic literature.
Inflammation, lipid signalling and insulin resistance It has been difficult to pin-point the precise causes of insulin resistance or impaired glucose tolerance. Nevertheless, clinical and epidemiological data suggest that insulin resistance is primarily caused by an imbalance resulting from excessive nutrient intake as overeating and insufficient energy expenditure as a lack of physical activity or metabolic dysfunction [1,2]. This imbalance in energy homeostasis can lead to metabolic dysfunction in three ways: (i) direct alterations in primary metabolism by altering synthesis and action of metabolic hormones such as insulin, leptin, adiponectin, glucocorticoids and also lipid catabolism, transportation and distribution; (ii) ectopic synthesis and deposition of toxic lipid mediators including fatty acyl CoA, diacylglycerol, triacylglycerol and ceramides in metabolically relevant tissues such as muscle, liver, adipose and pancreatic beta cells; (iii) directly increasing synthesis and action of more specialised lipid signalling molecules such as endocannabinoids, resolvins, protectins, prostaglandins, thromboxanes, leukotrienes, lipoxins, epoxyeicosatrienoic acids, other fatty acid epoxides, platelet activating factor (PAF; 1-O-alkyl-2-acetylsn-glycero-3-phosphorylcholine), lysophosphatidic acid, sphingosine 1-phosphate, 2-arachidonoylglycerol and other lipid amides, thus contributing to insulin resistance, beta cell dysfunction and reduced insulin sensitivity in type II diabetes [7,15,16] (Fig. 1). Although systemic inflammation is not always accompanied by impaired insulin action and obesity, the traditional immune/inflammatory and lipid-derived mediators could play a role in causing or aggravating insulin
Vol. 7, No. 3–4 2010
Drug Discovery Today: Disease Mechanisms | Endocrinology/mechanisms of obesity
PLAs TXA2
Phospholipids
Arachidonate
COX
PLAs
P450s PGG2 TXB2
LOX
LysoPAF
14,15 EET
PGH2
sEH
5HpETE 12 (S) HETE
PAF 15 (S) HETE
PGE2
14,15 DHET
LTA4
PGI2 LTB4
PGF2α
Lipoxin A4/B4
16, 20 HETE
EPA/DHA
LTC4
LTD4
PGF1α
Resolvins
Protectins
LTE4
5-OXOETE
IP
DP
CysLT1
TP
FP
EP4 EP3
CysLT2
EP2 PAF EP1 GRP34
TGR5 Bile acid receptor
LPA4
CB2
Lipid G-protein coupled receptors
p2y5 GPR41
Lipid Toll-like receptors
CB1 LPA3
Short-Chain Fatty acid receptor
GPR40
LPA2
Long-Chain Fatty acid receptor
LPA1
CRTH2 ChemR23
S1P5
FPRL1
TLR2
TLR1
TLR6
TLR4
S1P4 BLT1
BLT2
S1P1 S1P2
S1P3 Drug Discovery Today: Mechanisms
Figure 1. Lipid-derived mediators and their receptors currently suspected to be involved in obesity and metabolic dysfunction. PLA – phospholipase; COX – cyclooxygenase; LOX – lipoxygenase; P450 – cytochrome P450 epoxygenase; sEH – soluble epoxyhydrolase; TX – thromboxane; PG – prostaglandin; LT – leukotriene; HETE – hydroxyeicosatetranoic acid; EET – epoxyeicosatrienoic acid; DHET – hydroxyeicosatrienoicacid; PAF – platelet activating factor; EPA – eicosapentaenoic acid; DHA – docosahexaenoic acid; TLR – Toll-like receptor; EP – E-prostanoid; FP – F-prostanoid; TP – Tprostanoid; DP – D-prostanoid; IP – I-prostanoid; GPR – G-protein receptor; CB – cannabinoid; S1P – sphingosine 1-phosphate; LPA – lysophospholipid.
resistance and contributing to its establishment in a feedforward mechanism [8]. Important cells and organ systems such as adipose tissue, hepatocytes and leukocytes that control key metabolic and
immune functions in humans might have evolved from single structures in lower organisms, such as the drosophila fat body, involved in both immune and metabolic functions [2,14]. Further, organ systems involved in metabolism such as www.drugdiscoverytoday.com
e193
Drug Discovery Today: Disease Mechanisms | Endocrinology/mechanisms of obesity
the mammalian liver and adipose tissue have comparable structural blueprints in which cells such as adipocytes and hepatocytes are in close proximity to immunoregulatory cells such as Kupffer cells or immune cells or both with immediate access to a vast network of blood vessels [2,14]. Because initiation and maintenance of immunity is a metabolically expensive affair, this structural blueprint appears necessary to sustain continuous dynamic interactions between immune and metabolic response. This arrangement will regulate signalling networks such as cytokine-insulin signalling that communicates with sites in adipose tissue, pancreatic islets and muscle to organise and redistribute energy resources to regulate immunity [2,14]. Unfortunately, this structural blueprint is a disadvantage during excessive nutrient intake or storage as these changes can overload the signalling networks to disturb the delicate homeostatic balance between energy utilization and immune responses thereby inducing metabolic disease probably by lipotoxicity. The adipocyte has evolved into a site for storage, allowing other organ systems to perform normal physiological functions. It is now clear that adipocytes have an additional role to protect non-adipocytes from excessive fat intake and provide protection from lipotoxicity [17]. Hence, excessive nutrient intake probably initially results in accumulation of visceral fat and, when there is continued nutritional surplus, excess fat either directly disturbs primary metabolism by altering synthesis and action of metabolic hormones or gets deposited in liver, heart, muscle and pancreatic beta cells causing lipotoxicity or initiates specialised extracellular and intracellular signalling through lipid-derived mediators leading to systemic inflammation and insulin resistance [17]. For example, constant increases in free fatty acids for 24–48 h alter insulin gene expression, impair glucose-stimulated insulin secretion and induce apoptosis in beta cells both in vitro and in vivo [18–20]. Pancreatic beta cells are more vulnerable to lipotoxicity because of their inability to store excess free fatty acids completely as triglycerides [20]. After a limited storage of triglycerides, free fatty acid overload is converted into toxic lipid mediators such as ceramides, diacylglycerols, triacylglycerols and acyl CoAs leading to harmful metabolic products and pathways [20]. Chronic excessive free fatty acid deposition may activate NFkB pathways, formation of reactive oxygen species and lipid-induced beta cell apoptosis leading to beta cell failure, type II diabetes and insulin resistance [18,20]. Further, lipid-derived mediators can act as ligands for important immune receptors such as class A G-proteincoupled receptors and Toll-like receptors, and this receptor activation can initiate and perpetuate an innate immune response [2].
Lipid metabolism, cellular stress and lipid signalling Lipid mediators are involved in many human diseases, including rheumatoid and other forms of arthritis, multiple e194
www.drugdiscoverytoday.com
Vol. 7, No. 3–4 2010
sclerosis, reproductive disorders, intestinal polyposis, bronchial asthma, pulmonary and cardiac fibrosis, and chronic inflammatory diseases [21]. Lipid mediators are energy sources, although the importance of lipid mediators as intracellular signalling molecules in metabolism and immune defence is now appreciated [21]. Lipid catabolism involves lipolysis, beta-oxidation and the transport and distribution of lipids as free fatty acids and lipoproteins. As mentioned above, insulin resistance is a condition of energy imbalance between intake and expenditure. Free energy in multi-cellular organisms is traded in adenosine triphosphate (ATP) [22]. Food once acquired is converted into nutrients including glucose, free fatty acids and amino acids [22]. These nutrients are either directly metabolised to ATP or become precursors for lipids or proteins [22]. Lipids and proteins are also metabolised to ATP but this involves several energy-expensive metabolic steps [22]. In an obesity/insulin resistance setting, the efficiency of lipid to ATP conversion is compromised; in other words, obese individuals have a deficit of energy in the form of ATP with simultaneous over-synthesis of lipids resulting in excess adiposity [22]. The process for some people of diverting fuel from food to lipid synthesis before all their energetic needs in the body are satisfied seems logical from an evolutionary perspective [2]. When an organism encounters excess food, it conserves the nutrients either as glycogen for short-term storage or as lipids for longer storage duration because lipid combustion yields more energy than almost any other source [2]. During evolution, limited or spasmodic nutrient supply forced organisms to manage the need for portable energy with the need to efficiently store fatty acids, and to develop effective transcriptional machineries such as PPARs and NFkB that are activated by fatty acids and regulate the cellular response including physiological processes and fighting infection [2]. However, for 21st century humans, dietary calorie intake is no longer limited for most individuals in developed societies, which has led to an epidemic of obesity and associated metabolic disturbances [2]. Obese people often experience tiredness [23] even with a constant high energy food supply. During physical exercise, obese people become fatigued faster than lean people [22] and have decreased exercise capacity [22]. Thus, the paradox seems to be that obese people have at the same time too much and too little energy for the normal physiological needs of the body. The answer to this paradox may be that energy from food is diverted to fat synthesis before all of the energetic needs in the body are satisfied [22]. Fat and proteins may be metabolised to ATP but this is not an automatic conversion and involves several energy-consuming steps. The metabolic steps involved in fat synthesis and in beta-oxidation may be disturbed in obesity and insulin resistance [22]. Apart from fat synthesis and beta-oxidation, lipid transportation and distribution may be disturbed in obesity and
Vol. 7, No. 3–4 2010
Drug Discovery Today: Disease Mechanisms | Endocrinology/mechanisms of obesity
Chylomicrons Lipoprotein lipase
IDL
Used in the synthesis of hormones and membranes
VLDL
Fatty acids and monoglycerides
LDL Liver cells
Peripheral cells
Cholesterol extracted
LDL
Lysosomal breakdown
High cholesterol
HDL
Excess cholesterol excreted in hike
HDL
Low cholesterol
cholesterol released cholesterol absorption by HDL Drug Discovery Today: Mechanisms
Figure 2. Lipid transportation and distribution may be disturbed in obesity and insulin resistance. Free fatty acids and lipoproteins such as high, intermediate, low and very low-density lipoproteins, and chylomicrons determine which cells absorb the associated lipids for metabolism and storage. In an obesity setting, ectopic accumulation of lipid stores in metabolically relevant tissues leads to deleterious non-oxidative pathways producing fatty acyl CoA, diacylglycerols, triacylglycerols and ceramides in adipose and non-adipose tissues which may trigger apoptosis of lipid-laden cells leading to insulin resistance.
insulin resistance. In general, free fatty acids and lipoproteins such as high, intermediate, low and very low-density lipoproteins, and chylomicrons determine which cells absorb the associated lipids for metabolism and storage (Fig. 2). There is unequivocal data to suggest that increased plasma concentrations of long-chain saturated and unsaturated fatty acids referred to as free fatty acids are associated with obesity and insulin resistance [24]. Free fatty acids are lipids that can easily diffuse across plasma membranes. When free fatty acids are not used for triglyceride synthesis, they diffuse out of the intestinal epithelium into the circulation. As with glucose, lipids are needed throughout the body to maintain plasma membranes and also as precursors of steroid hormones. In an obesity setting, nutrient surplus and increased lipolysis from lipid stores such as liver and adipose tissue disturb this delicate balance between healthy membrane remodelling and circulating free fatty acid concentrations leading to the development of ectopic lipid stores in metabolically relevant tissues. This disturbance in lipid metabolism, apart from directly altering primary metabolism as an alteration of the synthesis and action of metabolic hormones such as insulin, leptin, adiponectin, glucocorticoids, also leads to ineffective oxidation of lipids when excessively accumulated in non-adipose tissue [7,17,24]. These free fatty acids provide
the substrate for deleterious non-oxidative pathways to products such as fatty acyl CoA, diacylglycerols, triacylglycerols and ceramides in adipose and non-adipose tissues which may trigger apoptosis of lipid-laden cells through increased nitric oxide expression and production [7]. This detrimental ectopic accumulation of reactive lipid mediators in non-adipose tissues such as liver, skeletal muscle, pancreas and heart is now commonly referred to as lipotoxicity that ultimately leads to insulin resistance [7]. Lipotoxicity-induced programmed death is termed as lipoapoptosis. Although the exact underlying metabolic events that result in lipotoxicity leading to lipoapoptosis are yet to be completely unravelled, evidence so far suggests a dysfunction in the mitochondria, lysosomes, endoplasmic reticulum, C-Jun N-terminal kinase, death receptors, ceramide synthesis, oxidative stress and inflammatory Toll-like receptor pathways. Furthermore, observations that cellular lipid loading is an initiator of inflammation have encouraged studies of the underlying mechanisms [7,17,24]; lipid-derived mediators being key suspects in this initiation process given their precursor status to inflammatory pathways. The importance of the lipid-derived mediators in Fig. 1 as intracellular signalling molecules in metabolism and immune defence is now appreciated. These lipid-derived mediators can act as ligands for important immune receptors www.drugdiscoverytoday.com
e195
Drug Discovery Today: Disease Mechanisms | Endocrinology/mechanisms of obesity
such as class A G-protein-coupled receptors and Toll-like receptors (Fig. 1), and receptor activation can initiate and perpetuate an innate immune response. In obesity and metabolic dysfunction, these lipid-derived mediators localised in adipose tissue and in circulation may bind to these immune receptors and induce low-grade tissue inflammation. This process may lead to adipocyte and metabolic dysfunction, without overt signs of inflammation. Current research focuses on clarifying the emerging roles of these circulating and adipose tissue localised lipid mediators in obesity and metabolic dysfunction (Fig. 1). We have reviewed the likely molecular mechanisms whereby lipid-derived mediators, receptors and intracellular signalling pathways affect adipocyte function, glucose metabolism and insulin resistance [2]. In summary, the metabolic steps involved in fat synthesis, beta-oxidation and lipid transportation and distribution are disturbed in obesity and insulin resistance. These disturbances probably result from stress and dysfunction of important cellular organelles including mitochondria, peroxisomes and endoplasmic reticulum which are involved in many different cellular functions associated with lipid metabolism [24–27].
Lipid metabolism, inflammation and insulin resistance Investigating the nexus between lipids, inflammation and adipocyte function should identify the roles of circulating lipid mediators in obesity, insulin resistance and metabolic dysfunction. Current studies do not establish that inflammation causes adiposity, rather that inflammation and adiposity
Vol. 7, No. 3–4 2010
co-exist. The question is whether inflammation precedes obesity so that metabolic dysfunction results from a low-grade chronic inflammatory state or whether inflammation merely contributes to insulin resistance and metabolic disease. Many of the metabolic defects including insulin resistance in muscle and lipid accumulation in the liver can be observed in preobese states without overt signs of systemic inflammation. The reasons behind this paradox remain to be identified. We speculate that this cellular stress initiated by lipid overloading, together with the excess lipid, initiates and perpetuates an inflammatory response detrimental to the metabolic status of the organism. The currently favoured paradigm is that excess nutrient intake disrupts normal lipid metabolism resulting in accumulation of visceral fat, initially triggering local adipose tissue inflammation. With continued nutritional surplus, excess fat either directly disturbs primary metabolism by altering synthesis and action of metabolic hormones or gets deposited in liver, heart, muscle and pancreatic beta cells causing lipotoxicity or initiates specialised extracellular and intracellular signalling through lipid-derived mediators leading to systemic inflammation and insulin resistance. In general, all conditions that increase circulating free fatty acids and cause lipid overloading such as obesity, lipodystrophy and lipoatrophy induce a lipotoxic state in non-adipose tissue giving rise to insulin resistance [26,27]. In obesity, chronic nutrient surplus causes an increase in the formation of triglycerides and other toxic lipid mediators such as fatty acyl CoA, triacylglycerols and ceramides in adipocytes con-
Chronic lipid loading Healthy Cellular stress Adipocytes
Adipocyte Hypertrophy
Inflammatory cell infiltration & activation
Insulin resistant adipocytes Lipids ↑ Adipokines ↑ Cytokines ↑ Insulin ↑ Adiponectin ↓ Leptin ↑
Lipotoxicity
Insulin resistance & metabolic syndrome Drug Discovery Today: Mechanisms
Figure 3. Adipocyte dysfunction and local inflammation leading to lipotoxicity-induced insulin resistance. Chronic overloading of adipocytes induces cellular stress such as endoplasmic reticulum stress that also contributes to the chronic inflammatory state in the adipose tissue, further recruiting macrophages and other inflammatory cells into the adipose tissue to feed-forward the release of free fatty acids, adipokines and inflammatory cytokines. Increase in circulating concentrations of free fatty acids, lipid mediators, inflammatory cytokines/adipokines, insulin and leptin, together with reductions in circulating adiponectin concentrations, leads to ectopic lipid stores, lipotoxicity and insulin resistance in non-adipose tissues.
e196
www.drugdiscoverytoday.com
Vol. 7, No. 3–4 2010
tributing to adipocyte hypertrophy [26,27]. Chronic overloading of adipocytes induces cellular stress such as endoplasmic reticulum stress that also contributes to the chronic inflammatory state in the adipose tissue, further recruiting macrophages and other inflammatory cells into the adipose tissue to feed-forward the release of adipokines and inflammatory cytokines [26,27]. This local inflammatory state of the adipose tissue induces adipocytes to become insulin-resistant and extends the insulin-resistant state to non-adipose tissues [26]. Insulin-resistant adipocytes readily release free fatty acids as they are characterised by low liposynthetic capacity and high lipolytic capacity [26]. These free fatty acids and lipid-derived mediators are ligands for immune receptors such as Toll-like receptors and G-protein coupled receptors and can thus initiate and perpetuate an innate immune response as seen in obesity and insulin resistance [2]. This increase in circulating concentrations of free fatty acids, lipidderived mediators, inflammatory cytokines/adipokines, insulin and leptin, together with reductions in circulating adiponectin concentrations, leads to ectopic lipid stores, lipotoxicity and insulin resistance in non-adipose tissues (Fig. 3) [26]. Further, molecules that are involved in lipid transportation and distribution such as HDL-cholesterol influence adipocyte metabolism and adiponectin expression [28]. An important feature of dyslipidaemia in insulin resistance and obesity is the decrease in HDL-cholesterol [28], whose primary role is to transport excess lipids from peripheral tissues back to liver for storage or excretion in the bile, thereby decreasing the risk of lipotoxicity in peripheral tissues (Fig. 2). In vivo administration of lipopolysaccharide (LPS), an agent used to induce an inflammatory response, reduced HDL-cholesterol and adiponectin concentrations reaffirming the link between lipid metabolism, inflammation and insulin resistance [28]. Increasing HDL in vivo by transferring human apo A-I gene in mice affected the expression of genes involved in fatty acid and triglyceride metabolism in adipose tissue, together with attenuation of increased triglycerides and free fatty acids by LPS administration [28]. HDL also elevates plasma adiponectin concentrations and expression in adipocytes in a phosphatidylinositol-3-kinase dependent manner in vivo [28]. Taken together, these findings suggest that molecules that traditionally play a role in lipid metabolism may exert direct effects on adipocyte metabolism and on molecules that alter immune responses such as adiponectin in insulin resistance.
Conclusion The anabolic and catabolic pathways in lipid metabolism are disturbed in obesity and insulin resistance. This disturbance together with local adipocyte inflammation and dysfunction probably allows excess accumulation of toxic lipid metabolites in adipose, muscle, liver and pancreatic beta cells contributing to systemic inflammation, insulin resistance
Drug Discovery Today: Disease Mechanisms | Endocrinology/mechanisms of obesity
and beta cell dysfunction in type II diabetes. A better understanding of both the molecular mechanisms that underpin metabolic dysfunction and the key roles played by inflammatory/immune components on metabolism should lead to new therapeutic strategies for obesity and insulin resistance.
References 1 Van Gaal, L.F. et al. (2006) Mechanisms linking obesity with cardiovascular disease. Nature 444, 875–880 2 Iyer, A. et al. (2010) Inflammatory lipid mediators in adipocyte function and obesity. Nat. Rev. Endocrinol. 6, 71–82 3 Powell, K. (2007) Obesity: the two faces of fat. Nature 447, 525–527 4 Eckel, R.H. et al. (2005) The metabolic syndrome. Lancet 365, 1415–1428 5 Alberti, K.G. et al. (2005) The metabolic syndrome – a new worldwide definition. Lancet 366, 1059–1062 6 Dandona, P. et al. (2005) Metabolic syndrome: a comprehensive perspective based on interactions between obesity, diabetes, and inflammation. Circulation 111, 1448–1454 7 Kusminski, C.M. et al. (2009) Diabetes and apoptosis: lipotoxicity. Apoptosis 14, 1484–1495 8 Pedersen, B.K. and Febbraio, M.A. (2010) Diabetes: Treatment of diabetes mellitus: new tricks by an old player. Nat. Rev. Endocrinol. 6, 482–483 9 Shoelson, S.E. et al. (2006) Inflammation and insulin resistance. J. Clin. Invest. 116, 1793–1801 10 Visser, M. et al. (1999) Elevated C-reactive protein levels in overweight and obese adults. JAMA 282, 2131–2135 11 Esposito, K. et al. (2003) Cytokine milieu tends toward inflammation in type 2 diabetes. Diabetes Care 26, 1647 12 Larsen, C.M. et al. (2009) Sustained effects of interleukin-1 receptor antagonist treatment in type 2 diabetes. Diabetes Care 32, 1663–1668 13 Nathan, C. (2002) Points of control in inflammation. Nature 420, 846–852 14 Hotamisligil, G.S. (2006) Inflammation and metabolic disorders. Nature 444, 860–867 15 Muoio, D.M. (2010) Intramuscular triacylglycerol and insulin resistance: guilty as charged or wrongly accused? Biochim. Biophys. Acta 1801, 281– 288 16 Taube, A. et al. (2009) Role of lipid-derived mediators in skeletal muscle insulin resistance. Am. J. Physiol. Endocrinol. Metab. 297, E1004–E1012 17 Li, L.O. et al. (2010) Acyl-CoA synthesis, lipid metabolism and lipotoxicity. Biochim. Biophys. Acta 1801, 246–251 18 Unger, R.H. and Zhou, Y.T. (2001) Lipotoxicity of beta-cells in obesity and in other causes of fatty acid spillover. Diabetes 50 (Suppl. 1), S118–S121 19 Butler, A.E. et al. (2003) Increased beta-cell apoptosis prevents adaptive increase in beta-cell mass in mouse model of type 2 diabetes: evidence for role of islet amyloid formation rather than direct action of amyloid. Diabetes 52, 2304–2314 20 Cusi, K. (2010) The role of adipose tissue and lipotoxicity in the pathogenesis of type 2 diabetes. Curr. Diab. Rep. 10, 306–315 21 Shimizu, T. (2009) Lipid mediators in health and disease: enzymes and receptors as therapeutic targets for the regulation of immunity and inflammation. Annu. Rev. Pharmacol. Toxicol. 49, 123–150 22 Wlodek, D. and Gonzales, M. (2003) Decreased energy levels can cause and sustain obesity. J. Theor. Biol. 225, 33–44 23 Lean, M.E. (2000) Pathophysiology of obesity. Proc. Nutr. Soc. 59, 331–336 24 Malhi, H. and Gores, G.J. (2008) Molecular mechanisms of lipotoxicity in nonalcoholic fatty liver disease. Semin. Liver Dis. 28, 360–369 25 Wanders, R.J. (2004) Peroxisomes, lipid metabolism, and peroxisomal disorders. Mol. Genet. Metab. 83, 16–27 26 Lionetti, L. et al. (2009) From chronic overnutrition to insulin resistance: the role of fat-storing capacity and inflammation. Nutr. Metab. Cardiovasc. Dis. 19, 146–152 27 Virtue, S. and Vidal-Puig, A. (2010) Adipose tissue expandability, lipotoxicity and the Metabolic Syndrome – an allostatic perspective. Biochim. Biophys. Acta 1801, 338–349 28 Van Linthout, S. et al. (2010) Impact of HDL on adipose tissue metabolism and adiponectin expression. Atherosclerosis 210, 438–444 www.drugdiscoverytoday.com
e197
DRUG DISCOVERY
TODAY
Vol. 7, No. 3–4 2010
Editors-in-Chief Toren Finkel – National Heart, Lung and Blood Institute, National Institutes of Health, USA Charles Lowenstein – University of Rochester Medical Center, Rochester, NY.
DISEASE Endocrinology/mechanisms of obesity MECHANISMS
Lipid mediators and inflammation in glucose intolerance and insulin resistance Abishek Iyer1, Lindsay Brown1,2,* 1 2
School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia Department of Biological and Physical Sciences, University of Southern Queensland, Toowoomba, QLD 4350, Australia
Clinical and epidemiological studies suggest that patients who are overweight or obese are at greater risk to develop glucose intolerance and insulin resis-
Section editor: Vincenzo Di Marzo – CNR, Institute of Biomolecular Chemistry, Napoli, Italy
tance leading to type II diabetes and cardiovascular disease. Despite many hypotheses, it has been difficult to pin-point the precise causes of insulin resistance or impaired glucose tolerance. This commentary aims to stimulate debate by providing some mechanistic insights into a unifying hypothesis by which disturbed lipid metabolism, increased circulating lipid-derived mediators and excess accumulation of toxic lipid metabolites in adipose, muscle, liver and pancreatic beta cells contribute to inflammation, insulin resistance and beta cell dysfunction in type II diabetes. This understanding will direct future drug discovery research to identify and develop novel compounds that can regulate both metabolic and immune/inflammatory systems to provide a dual strategy to combat metabolic disease, especially insulin resistance and type II diabetes.
*Corresponding author: L. Brown ([email protected]) 1740-6765/$ ß 2010 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.ddmec.2010.12.001
Introduction As glucose is a major source of energy for cells, precise control of glucose concentrations by the hormone, insulin, is essential. Impaired glucose tolerance is a delayed normalisation of blood glucose concentrations after glucose intake despite adequate insulin concentrations. The combination of increased glucose and insulin concentrations defines insulin resistance, typically characterised as the insensitivity to insulin in peripheral tissues such as skeletal muscle, liver and adipose and reduced function of the pancreatic beta cells [1]. In patients, insulin resistance is characterised by obesity, type II diabetes mellitus and the associated metabolic and cardiovascular dysfunction, a major cause of morbidity and mortality throughout the world [1–3]. The metabolic syndrome, also termed the insulin resistance syndrome, combines the clinical signs of fasting and post-prandial hyperglycaemia, centrally distributed abdominal fat, dyslipidaemia and hypertension [4–6]. Clinical and epidemiological studies suggest that patients who are overweight or obese are more at risk in developing glucose intolerance and insulin resistance leading to type II diabetes and cardiovascular disease. Many hypotheses have been proposed to explain the underlying mechanisms of insulin resistance. Traditionally, insulin resistance and type II diabetes have been rationalised as a dysfunction of glucose metabolism and this has been the e191
Drug Discovery Today: Disease Mechanisms | Endocrinology/mechanisms of obesity
primary therapeutic target in type II diabetes. This glucocentric view then changed towards an emphasis on induction of the dysfunction of glucose homeostasis by free fatty acids and other lipid mediators [7]. Activation of inflammatory lipid mediators associated with the altered release of adipokines and cytokines to alter adipocyte and immune cell function has now become the prevailing hypothesis to explain the mechanisms of insulin resistance [2]. This commentary aims to stimulate debate by providing some mechanistic insights into a unifying hypothesis by which disturbed lipid metabolism, increased circulating lipidderived mediators and excess accumulation of toxic lipid metabolites in adipose, muscle, liver and pancreatic beta cells contribute to inflammation, insulin resistance and beta cell dysfunction in type II diabetes.
Insulin resistance, obesity and inflammation Evidence linking inflammation and type II diabetes mellitus has been accumulating since the first report in 1876 that high dose sodium salicylate decreased glucosuria in patients presumably with type II diabetes [8,9]. Clinical, animal and in vitro studies support links between insulin resistance, obesity, metabolic dysfunction and inflammation [2]. Insulin resistance is associated with increased pro-inflammatory proteins in the circulation and metabolic tissues [1]. Adipose tissue releases many bioactive mediators, including inflammatory cytokines, that alter body weight homeostasis and induce changes in cardiovascular structure and function, glucose metabolism, blood pressure, lipid metabolism, coagulation, fibrinolysis and inflammation, leading to endothelial dysfunction and atherosclerosis [1]. Plasma concentrations of inflammatory markers derived from immune and other cell types, including adipocytes, correlate with body mass index in morbidly obese patients [10,11]. Obesity and insulin resistance are also associated with high circulating concentrations of free fatty acids, particularly following meals, that are ligands for immune receptors such as Toll-like receptors and G-protein coupled receptors, thus initiating and perpetuating an innate immune response [2]. There is increasing pre-clinical and clinical evidence that anti-inflammatory compounds including salicylates and other non-steroidal anti-inflammatory drugs may be helpful in improving metabolic dysfunction [2,12]. Drugs with pleiotropic anti-inflammatory effects such as statins, ACE inhibitors and PPARg agonists are also effective in metabolic syndrome; this effectiveness cannot be explained only by lowering lipid concentrations or blood pressure or improving insulin sensitivity [1,2]. The proposal that chronic low-grade inflammation underlies obesity, insulin resistance and metabolic dysfunction has become credible in recent years. Inflammation is usually described as the short-term primary response of the body to deal with injuries and so it is crucial for tissue repair, involving many complex signals in distinct cells and organ e192
www.drugdiscoverytoday.com
Vol. 7, No. 3–4 2010
systems [13]. If prolonged, this response turns pathological, damaging cells [13]. In the case of metabolic diseases, this has been termed ‘meta-inflammation’ or ‘chronic low-grade inflammation’ that can be described as a long-term inflammatory response triggered by nutrients and metabolic surplus [14]. This process utilises a similar set of molecules and signalling pathways to those involved in classical inflammation but might also regulate energy storage and metabolism [14]. Current studies would argue that molecules such as the lipid mediators and their signalling pathways, known to play immune/inflammatory roles, participate in the accumulation of toxic lipid mediators in metabolically relevant tissues thereby hampering the normal functioning of these tissues. This understanding will direct future drug discovery research to identify and develop novel compounds that can regulate both metabolic and immune systems to provide a dual strategy to combat metabolic disease, especially insulin resistance. The identification of novel therapeutic agents for insulin resistance and metabolic disease requires immunologists and drug discovery scientists to distinguish the key differences between the inflammatory/immune components underling metabolic disease and those described in the classic literature.
Inflammation, lipid signalling and insulin resistance It has been difficult to pin-point the precise causes of insulin resistance or impaired glucose tolerance. Nevertheless, clinical and epidemiological data suggest that insulin resistance is primarily caused by an imbalance resulting from excessive nutrient intake as overeating and insufficient energy expenditure as a lack of physical activity or metabolic dysfunction [1,2]. This imbalance in energy homeostasis can lead to metabolic dysfunction in three ways: (i) direct alterations in primary metabolism by altering synthesis and action of metabolic hormones such as insulin, leptin, adiponectin, glucocorticoids and also lipid catabolism, transportation and distribution; (ii) ectopic synthesis and deposition of toxic lipid mediators including fatty acyl CoA, diacylglycerol, triacylglycerol and ceramides in metabolically relevant tissues such as muscle, liver, adipose and pancreatic beta cells; (iii) directly increasing synthesis and action of more specialised lipid signalling molecules such as endocannabinoids, resolvins, protectins, prostaglandins, thromboxanes, leukotrienes, lipoxins, epoxyeicosatrienoic acids, other fatty acid epoxides, platelet activating factor (PAF; 1-O-alkyl-2-acetylsn-glycero-3-phosphorylcholine), lysophosphatidic acid, sphingosine 1-phosphate, 2-arachidonoylglycerol and other lipid amides, thus contributing to insulin resistance, beta cell dysfunction and reduced insulin sensitivity in type II diabetes [7,15,16] (Fig. 1). Although systemic inflammation is not always accompanied by impaired insulin action and obesity, the traditional immune/inflammatory and lipid-derived mediators could play a role in causing or aggravating insulin
Vol. 7, No. 3–4 2010
Drug Discovery Today: Disease Mechanisms | Endocrinology/mechanisms of obesity
PLAs TXA2
Phospholipids
Arachidonate
COX
PLAs
P450s PGG2 TXB2
LOX
LysoPAF
14,15 EET
PGH2
sEH
5HpETE 12 (S) HETE
PAF 15 (S) HETE
PGE2
14,15 DHET
LTA4
PGI2 LTB4
PGF2α
Lipoxin A4/B4
16, 20 HETE
EPA/DHA
LTC4
LTD4
PGF1α
Resolvins
Protectins
LTE4
5-OXOETE
IP
DP
CysLT1
TP
FP
EP4 EP3
CysLT2
EP2 PAF EP1 GRP34
TGR5 Bile acid receptor
LPA4
CB2
Lipid G-protein coupled receptors
p2y5 GPR41
Lipid Toll-like receptors
CB1 LPA3
Short-Chain Fatty acid receptor
GPR40
LPA2
Long-Chain Fatty acid receptor
LPA1
CRTH2 ChemR23
S1P5
FPRL1
TLR2
TLR1
TLR6
TLR4
S1P4 BLT1
BLT2
S1P1 S1P2
S1P3 Drug Discovery Today: Mechanisms
Figure 1. Lipid-derived mediators and their receptors currently suspected to be involved in obesity and metabolic dysfunction. PLA – phospholipase; COX – cyclooxygenase; LOX – lipoxygenase; P450 – cytochrome P450 epoxygenase; sEH – soluble epoxyhydrolase; TX – thromboxane; PG – prostaglandin; LT – leukotriene; HETE – hydroxyeicosatetranoic acid; EET – epoxyeicosatrienoic acid; DHET – hydroxyeicosatrienoicacid; PAF – platelet activating factor; EPA – eicosapentaenoic acid; DHA – docosahexaenoic acid; TLR – Toll-like receptor; EP – E-prostanoid; FP – F-prostanoid; TP – Tprostanoid; DP – D-prostanoid; IP – I-prostanoid; GPR – G-protein receptor; CB – cannabinoid; S1P – sphingosine 1-phosphate; LPA – lysophospholipid.
resistance and contributing to its establishment in a feedforward mechanism [8]. Important cells and organ systems such as adipose tissue, hepatocytes and leukocytes that control key metabolic and
immune functions in humans might have evolved from single structures in lower organisms, such as the drosophila fat body, involved in both immune and metabolic functions [2,14]. Further, organ systems involved in metabolism such as www.drugdiscoverytoday.com
e193
Drug Discovery Today: Disease Mechanisms | Endocrinology/mechanisms of obesity
the mammalian liver and adipose tissue have comparable structural blueprints in which cells such as adipocytes and hepatocytes are in close proximity to immunoregulatory cells such as Kupffer cells or immune cells or both with immediate access to a vast network of blood vessels [2,14]. Because initiation and maintenance of immunity is a metabolically expensive affair, this structural blueprint appears necessary to sustain continuous dynamic interactions between immune and metabolic response. This arrangement will regulate signalling networks such as cytokine-insulin signalling that communicates with sites in adipose tissue, pancreatic islets and muscle to organise and redistribute energy resources to regulate immunity [2,14]. Unfortunately, this structural blueprint is a disadvantage during excessive nutrient intake or storage as these changes can overload the signalling networks to disturb the delicate homeostatic balance between energy utilization and immune responses thereby inducing metabolic disease probably by lipotoxicity. The adipocyte has evolved into a site for storage, allowing other organ systems to perform normal physiological functions. It is now clear that adipocytes have an additional role to protect non-adipocytes from excessive fat intake and provide protection from lipotoxicity [17]. Hence, excessive nutrient intake probably initially results in accumulation of visceral fat and, when there is continued nutritional surplus, excess fat either directly disturbs primary metabolism by altering synthesis and action of metabolic hormones or gets deposited in liver, heart, muscle and pancreatic beta cells causing lipotoxicity or initiates specialised extracellular and intracellular signalling through lipid-derived mediators leading to systemic inflammation and insulin resistance [17]. For example, constant increases in free fatty acids for 24–48 h alter insulin gene expression, impair glucose-stimulated insulin secretion and induce apoptosis in beta cells both in vitro and in vivo [18–20]. Pancreatic beta cells are more vulnerable to lipotoxicity because of their inability to store excess free fatty acids completely as triglycerides [20]. After a limited storage of triglycerides, free fatty acid overload is converted into toxic lipid mediators such as ceramides, diacylglycerols, triacylglycerols and acyl CoAs leading to harmful metabolic products and pathways [20]. Chronic excessive free fatty acid deposition may activate NFkB pathways, formation of reactive oxygen species and lipid-induced beta cell apoptosis leading to beta cell failure, type II diabetes and insulin resistance [18,20]. Further, lipid-derived mediators can act as ligands for important immune receptors such as class A G-proteincoupled receptors and Toll-like receptors, and this receptor activation can initiate and perpetuate an innate immune response [2].
Lipid metabolism, cellular stress and lipid signalling Lipid mediators are involved in many human diseases, including rheumatoid and other forms of arthritis, multiple e194
www.drugdiscoverytoday.com
Vol. 7, No. 3–4 2010
sclerosis, reproductive disorders, intestinal polyposis, bronchial asthma, pulmonary and cardiac fibrosis, and chronic inflammatory diseases [21]. Lipid mediators are energy sources, although the importance of lipid mediators as intracellular signalling molecules in metabolism and immune defence is now appreciated [21]. Lipid catabolism involves lipolysis, beta-oxidation and the transport and distribution of lipids as free fatty acids and lipoproteins. As mentioned above, insulin resistance is a condition of energy imbalance between intake and expenditure. Free energy in multi-cellular organisms is traded in adenosine triphosphate (ATP) [22]. Food once acquired is converted into nutrients including glucose, free fatty acids and amino acids [22]. These nutrients are either directly metabolised to ATP or become precursors for lipids or proteins [22]. Lipids and proteins are also metabolised to ATP but this involves several energy-expensive metabolic steps [22]. In an obesity/insulin resistance setting, the efficiency of lipid to ATP conversion is compromised; in other words, obese individuals have a deficit of energy in the form of ATP with simultaneous over-synthesis of lipids resulting in excess adiposity [22]. The process for some people of diverting fuel from food to lipid synthesis before all their energetic needs in the body are satisfied seems logical from an evolutionary perspective [2]. When an organism encounters excess food, it conserves the nutrients either as glycogen for short-term storage or as lipids for longer storage duration because lipid combustion yields more energy than almost any other source [2]. During evolution, limited or spasmodic nutrient supply forced organisms to manage the need for portable energy with the need to efficiently store fatty acids, and to develop effective transcriptional machineries such as PPARs and NFkB that are activated by fatty acids and regulate the cellular response including physiological processes and fighting infection [2]. However, for 21st century humans, dietary calorie intake is no longer limited for most individuals in developed societies, which has led to an epidemic of obesity and associated metabolic disturbances [2]. Obese people often experience tiredness [23] even with a constant high energy food supply. During physical exercise, obese people become fatigued faster than lean people [22] and have decreased exercise capacity [22]. Thus, the paradox seems to be that obese people have at the same time too much and too little energy for the normal physiological needs of the body. The answer to this paradox may be that energy from food is diverted to fat synthesis before all of the energetic needs in the body are satisfied [22]. Fat and proteins may be metabolised to ATP but this is not an automatic conversion and involves several energy-consuming steps. The metabolic steps involved in fat synthesis and in beta-oxidation may be disturbed in obesity and insulin resistance [22]. Apart from fat synthesis and beta-oxidation, lipid transportation and distribution may be disturbed in obesity and
Vol. 7, No. 3–4 2010
Drug Discovery Today: Disease Mechanisms | Endocrinology/mechanisms of obesity
Chylomicrons Lipoprotein lipase
IDL
Used in the synthesis of hormones and membranes
VLDL
Fatty acids and monoglycerides
LDL Liver cells
Peripheral cells
Cholesterol extracted
LDL
Lysosomal breakdown
High cholesterol
HDL
Excess cholesterol excreted in hike
HDL
Low cholesterol
cholesterol released cholesterol absorption by HDL Drug Discovery Today: Mechanisms
Figure 2. Lipid transportation and distribution may be disturbed in obesity and insulin resistance. Free fatty acids and lipoproteins such as high, intermediate, low and very low-density lipoproteins, and chylomicrons determine which cells absorb the associated lipids for metabolism and storage. In an obesity setting, ectopic accumulation of lipid stores in metabolically relevant tissues leads to deleterious non-oxidative pathways producing fatty acyl CoA, diacylglycerols, triacylglycerols and ceramides in adipose and non-adipose tissues which may trigger apoptosis of lipid-laden cells leading to insulin resistance.
insulin resistance. In general, free fatty acids and lipoproteins such as high, intermediate, low and very low-density lipoproteins, and chylomicrons determine which cells absorb the associated lipids for metabolism and storage (Fig. 2). There is unequivocal data to suggest that increased plasma concentrations of long-chain saturated and unsaturated fatty acids referred to as free fatty acids are associated with obesity and insulin resistance [24]. Free fatty acids are lipids that can easily diffuse across plasma membranes. When free fatty acids are not used for triglyceride synthesis, they diffuse out of the intestinal epithelium into the circulation. As with glucose, lipids are needed throughout the body to maintain plasma membranes and also as precursors of steroid hormones. In an obesity setting, nutrient surplus and increased lipolysis from lipid stores such as liver and adipose tissue disturb this delicate balance between healthy membrane remodelling and circulating free fatty acid concentrations leading to the development of ectopic lipid stores in metabolically relevant tissues. This disturbance in lipid metabolism, apart from directly altering primary metabolism as an alteration of the synthesis and action of metabolic hormones such as insulin, leptin, adiponectin, glucocorticoids, also leads to ineffective oxidation of lipids when excessively accumulated in non-adipose tissue [7,17,24]. These free fatty acids provide
the substrate for deleterious non-oxidative pathways to products such as fatty acyl CoA, diacylglycerols, triacylglycerols and ceramides in adipose and non-adipose tissues which may trigger apoptosis of lipid-laden cells through increased nitric oxide expression and production [7]. This detrimental ectopic accumulation of reactive lipid mediators in non-adipose tissues such as liver, skeletal muscle, pancreas and heart is now commonly referred to as lipotoxicity that ultimately leads to insulin resistance [7]. Lipotoxicity-induced programmed death is termed as lipoapoptosis. Although the exact underlying metabolic events that result in lipotoxicity leading to lipoapoptosis are yet to be completely unravelled, evidence so far suggests a dysfunction in the mitochondria, lysosomes, endoplasmic reticulum, C-Jun N-terminal kinase, death receptors, ceramide synthesis, oxidative stress and inflammatory Toll-like receptor pathways. Furthermore, observations that cellular lipid loading is an initiator of inflammation have encouraged studies of the underlying mechanisms [7,17,24]; lipid-derived mediators being key suspects in this initiation process given their precursor status to inflammatory pathways. The importance of the lipid-derived mediators in Fig. 1 as intracellular signalling molecules in metabolism and immune defence is now appreciated. These lipid-derived mediators can act as ligands for important immune receptors www.drugdiscoverytoday.com
e195
Drug Discovery Today: Disease Mechanisms | Endocrinology/mechanisms of obesity
such as class A G-protein-coupled receptors and Toll-like receptors (Fig. 1), and receptor activation can initiate and perpetuate an innate immune response. In obesity and metabolic dysfunction, these lipid-derived mediators localised in adipose tissue and in circulation may bind to these immune receptors and induce low-grade tissue inflammation. This process may lead to adipocyte and metabolic dysfunction, without overt signs of inflammation. Current research focuses on clarifying the emerging roles of these circulating and adipose tissue localised lipid mediators in obesity and metabolic dysfunction (Fig. 1). We have reviewed the likely molecular mechanisms whereby lipid-derived mediators, receptors and intracellular signalling pathways affect adipocyte function, glucose metabolism and insulin resistance [2]. In summary, the metabolic steps involved in fat synthesis, beta-oxidation and lipid transportation and distribution are disturbed in obesity and insulin resistance. These disturbances probably result from stress and dysfunction of important cellular organelles including mitochondria, peroxisomes and endoplasmic reticulum which are involved in many different cellular functions associated with lipid metabolism [24–27].
Lipid metabolism, inflammation and insulin resistance Investigating the nexus between lipids, inflammation and adipocyte function should identify the roles of circulating lipid mediators in obesity, insulin resistance and metabolic dysfunction. Current studies do not establish that inflammation causes adiposity, rather that inflammation and adiposity
Vol. 7, No. 3–4 2010
co-exist. The question is whether inflammation precedes obesity so that metabolic dysfunction results from a low-grade chronic inflammatory state or whether inflammation merely contributes to insulin resistance and metabolic disease. Many of the metabolic defects including insulin resistance in muscle and lipid accumulation in the liver can be observed in preobese states without overt signs of systemic inflammation. The reasons behind this paradox remain to be identified. We speculate that this cellular stress initiated by lipid overloading, together with the excess lipid, initiates and perpetuates an inflammatory response detrimental to the metabolic status of the organism. The currently favoured paradigm is that excess nutrient intake disrupts normal lipid metabolism resulting in accumulation of visceral fat, initially triggering local adipose tissue inflammation. With continued nutritional surplus, excess fat either directly disturbs primary metabolism by altering synthesis and action of metabolic hormones or gets deposited in liver, heart, muscle and pancreatic beta cells causing lipotoxicity or initiates specialised extracellular and intracellular signalling through lipid-derived mediators leading to systemic inflammation and insulin resistance. In general, all conditions that increase circulating free fatty acids and cause lipid overloading such as obesity, lipodystrophy and lipoatrophy induce a lipotoxic state in non-adipose tissue giving rise to insulin resistance [26,27]. In obesity, chronic nutrient surplus causes an increase in the formation of triglycerides and other toxic lipid mediators such as fatty acyl CoA, triacylglycerols and ceramides in adipocytes con-
Chronic lipid loading Healthy Cellular stress Adipocytes
Adipocyte Hypertrophy
Inflammatory cell infiltration & activation
Insulin resistant adipocytes Lipids ↑ Adipokines ↑ Cytokines ↑ Insulin ↑ Adiponectin ↓ Leptin ↑
Lipotoxicity
Insulin resistance & metabolic syndrome Drug Discovery Today: Mechanisms
Figure 3. Adipocyte dysfunction and local inflammation leading to lipotoxicity-induced insulin resistance. Chronic overloading of adipocytes induces cellular stress such as endoplasmic reticulum stress that also contributes to the chronic inflammatory state in the adipose tissue, further recruiting macrophages and other inflammatory cells into the adipose tissue to feed-forward the release of free fatty acids, adipokines and inflammatory cytokines. Increase in circulating concentrations of free fatty acids, lipid mediators, inflammatory cytokines/adipokines, insulin and leptin, together with reductions in circulating adiponectin concentrations, leads to ectopic lipid stores, lipotoxicity and insulin resistance in non-adipose tissues.
e196
www.drugdiscoverytoday.com
Vol. 7, No. 3–4 2010
tributing to adipocyte hypertrophy [26,27]. Chronic overloading of adipocytes induces cellular stress such as endoplasmic reticulum stress that also contributes to the chronic inflammatory state in the adipose tissue, further recruiting macrophages and other inflammatory cells into the adipose tissue to feed-forward the release of adipokines and inflammatory cytokines [26,27]. This local inflammatory state of the adipose tissue induces adipocytes to become insulin-resistant and extends the insulin-resistant state to non-adipose tissues [26]. Insulin-resistant adipocytes readily release free fatty acids as they are characterised by low liposynthetic capacity and high lipolytic capacity [26]. These free fatty acids and lipid-derived mediators are ligands for immune receptors such as Toll-like receptors and G-protein coupled receptors and can thus initiate and perpetuate an innate immune response as seen in obesity and insulin resistance [2]. This increase in circulating concentrations of free fatty acids, lipidderived mediators, inflammatory cytokines/adipokines, insulin and leptin, together with reductions in circulating adiponectin concentrations, leads to ectopic lipid stores, lipotoxicity and insulin resistance in non-adipose tissues (Fig. 3) [26]. Further, molecules that are involved in lipid transportation and distribution such as HDL-cholesterol influence adipocyte metabolism and adiponectin expression [28]. An important feature of dyslipidaemia in insulin resistance and obesity is the decrease in HDL-cholesterol [28], whose primary role is to transport excess lipids from peripheral tissues back to liver for storage or excretion in the bile, thereby decreasing the risk of lipotoxicity in peripheral tissues (Fig. 2). In vivo administration of lipopolysaccharide (LPS), an agent used to induce an inflammatory response, reduced HDL-cholesterol and adiponectin concentrations reaffirming the link between lipid metabolism, inflammation and insulin resistance [28]. Increasing HDL in vivo by transferring human apo A-I gene in mice affected the expression of genes involved in fatty acid and triglyceride metabolism in adipose tissue, together with attenuation of increased triglycerides and free fatty acids by LPS administration [28]. HDL also elevates plasma adiponectin concentrations and expression in adipocytes in a phosphatidylinositol-3-kinase dependent manner in vivo [28]. Taken together, these findings suggest that molecules that traditionally play a role in lipid metabolism may exert direct effects on adipocyte metabolism and on molecules that alter immune responses such as adiponectin in insulin resistance.
Conclusion The anabolic and catabolic pathways in lipid metabolism are disturbed in obesity and insulin resistance. This disturbance together with local adipocyte inflammation and dysfunction probably allows excess accumulation of toxic lipid metabolites in adipose, muscle, liver and pancreatic beta cells contributing to systemic inflammation, insulin resistance
Drug Discovery Today: Disease Mechanisms | Endocrinology/mechanisms of obesity
and beta cell dysfunction in type II diabetes. A better understanding of both the molecular mechanisms that underpin metabolic dysfunction and the key roles played by inflammatory/immune components on metabolism should lead to new therapeutic strategies for obesity and insulin resistance.
References 1 Van Gaal, L.F. et al. (2006) Mechanisms linking obesity with cardiovascular disease. Nature 444, 875–880 2 Iyer, A. et al. (2010) Inflammatory lipid mediators in adipocyte function and obesity. Nat. Rev. Endocrinol. 6, 71–82 3 Powell, K. (2007) Obesity: the two faces of fat. Nature 447, 525–527 4 Eckel, R.H. et al. (2005) The metabolic syndrome. Lancet 365, 1415–1428 5 Alberti, K.G. et al. (2005) The metabolic syndrome – a new worldwide definition. Lancet 366, 1059–1062 6 Dandona, P. et al. (2005) Metabolic syndrome: a comprehensive perspective based on interactions between obesity, diabetes, and inflammation. Circulation 111, 1448–1454 7 Kusminski, C.M. et al. (2009) Diabetes and apoptosis: lipotoxicity. Apoptosis 14, 1484–1495 8 Pedersen, B.K. and Febbraio, M.A. (2010) Diabetes: Treatment of diabetes mellitus: new tricks by an old player. Nat. Rev. Endocrinol. 6, 482–483 9 Shoelson, S.E. et al. (2006) Inflammation and insulin resistance. J. Clin. Invest. 116, 1793–1801 10 Visser, M. et al. (1999) Elevated C-reactive protein levels in overweight and obese adults. JAMA 282, 2131–2135 11 Esposito, K. et al. (2003) Cytokine milieu tends toward inflammation in type 2 diabetes. Diabetes Care 26, 1647 12 Larsen, C.M. et al. (2009) Sustained effects of interleukin-1 receptor antagonist treatment in type 2 diabetes. Diabetes Care 32, 1663–1668 13 Nathan, C. (2002) Points of control in inflammation. Nature 420, 846–852 14 Hotamisligil, G.S. (2006) Inflammation and metabolic disorders. Nature 444, 860–867 15 Muoio, D.M. (2010) Intramuscular triacylglycerol and insulin resistance: guilty as charged or wrongly accused? Biochim. Biophys. Acta 1801, 281– 288 16 Taube, A. et al. (2009) Role of lipid-derived mediators in skeletal muscle insulin resistance. Am. J. Physiol. Endocrinol. Metab. 297, E1004–E1012 17 Li, L.O. et al. (2010) Acyl-CoA synthesis, lipid metabolism and lipotoxicity. Biochim. Biophys. Acta 1801, 246–251 18 Unger, R.H. and Zhou, Y.T. (2001) Lipotoxicity of beta-cells in obesity and in other causes of fatty acid spillover. Diabetes 50 (Suppl. 1), S118–S121 19 Butler, A.E. et al. (2003) Increased beta-cell apoptosis prevents adaptive increase in beta-cell mass in mouse model of type 2 diabetes: evidence for role of islet amyloid formation rather than direct action of amyloid. Diabetes 52, 2304–2314 20 Cusi, K. (2010) The role of adipose tissue and lipotoxicity in the pathogenesis of type 2 diabetes. Curr. Diab. Rep. 10, 306–315 21 Shimizu, T. (2009) Lipid mediators in health and disease: enzymes and receptors as therapeutic targets for the regulation of immunity and inflammation. Annu. Rev. Pharmacol. Toxicol. 49, 123–150 22 Wlodek, D. and Gonzales, M. (2003) Decreased energy levels can cause and sustain obesity. J. Theor. Biol. 225, 33–44 23 Lean, M.E. (2000) Pathophysiology of obesity. Proc. Nutr. Soc. 59, 331–336 24 Malhi, H. and Gores, G.J. (2008) Molecular mechanisms of lipotoxicity in nonalcoholic fatty liver disease. Semin. Liver Dis. 28, 360–369 25 Wanders, R.J. (2004) Peroxisomes, lipid metabolism, and peroxisomal disorders. Mol. Genet. Metab. 83, 16–27 26 Lionetti, L. et al. (2009) From chronic overnutrition to insulin resistance: the role of fat-storing capacity and inflammation. Nutr. Metab. Cardiovasc. Dis. 19, 146–152 27 Virtue, S. and Vidal-Puig, A. (2010) Adipose tissue expandability, lipotoxicity and the Metabolic Syndrome – an allostatic perspective. Biochim. Biophys. Acta 1801, 338–349 28 Van Linthout, S. et al. (2010) Impact of HDL on adipose tissue metabolism and adiponectin expression. Atherosclerosis 210, 438–444 www.drugdiscoverytoday.com
e197