Lipotoxicity, overnutrition and energy metabolism in aging

Ageing Research Reviews 5 (2006) 144–164 www.elsevier.com/locate/arr

Review

Lipotoxicity, overnutrition and energy metabolism in aging Marc Slawik 1, Antonio J. Vidal-Puig * Department of Clinical Biochemistry, University of Cambridge, UK

Abstract The safest place to store lipids is the white adipose tissue, but its storage capacity may become saturated resulting in excess of fat ‘‘overspilled’’ to non-adipose tissues. This overspill of fat occurs in apparently opposite pathological states such as lipodistrophy or obesity. When the excess of energy is redirected towards peripheral organs, their initial response is to facilitate the storage of the surplus in the form of triacylglycerol, but the limited triacylglycerol buffer capacity becomes saturated soon. Under these conditions excess of lipids enter alternative non-oxidative pathways that result in production of toxic reactive lipid species that induce organ-specific toxic responses leading to apoptosis. Reactive lipids can accumulate in non-adipose tissues of metabolically relevant organs such as pancreatic b-cells, liver, heart and skeletal muscle leading to lipotoxicity, a process that contributes substantially to the pathophysiology of insulin resistance, type 2 diabetes, steatotic liver disease and heart failure. The effects of this lipotoxic insult can be minimised by several strategies: (a) decreased incorporation of energy, (b) a less orthodox approach such as increased adipose tissue expandability and/or (c) increased oxidation of fat in peripheral organs. Aging should be considered as physiological degenerative process potentially accelerated by concomitant lipotoxic insults. Conversely, the process of aging can sensitise cells to effects of lipid toxicity. # 2006 Elsevier Ireland Ltd. All rights reserved. Keywords: Energy homoeostasis; Leptin; Lipoapoptosis; Fatty acid oxidation; de novo lipogenesis; SREBP1c

1. Introduction Aging is a physiological degenerative process that in the presence of pre-existing pathological conditions may act as an accelerating factor of these diseases. Similarly pre* Corresponding author at: Clinical Biochemistry, Box 232, Addenbrooke’s Hospital, Cambridge CB2 2QR, UK. Tel.: +44 1223 762790. E-mail address: [email protected] (A.J. Vidal-Puig). 1 Marc Slawik has been supported by a fellowship from the ‘‘Fritz Thyssen Foundation’’, Germany. 1568-1637/$ – see front matter # 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.arr.2006.03.004

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existing medical conditions may accelerate the physiological decay experienced during aging. Energy homeostasis is a highly integrated, redundant network that ensures the maintenance of the entropy of the biological system. In this respect, maintenance of energy homeostasis during aging requires biological allostatic changes to maintain the function of progressively inefficient systems. These adaptive allostatic mechanisms increase the stress load of the homeostatic mechanisms increasing their vulnerability to further stress load. Obesity is one of these diseases that can modify the dynamics of the aging process by increasing the allostatic load of the energy homeostatic mechanisms. In fact, the current epidemic of obesity has been suggested as the leading cause for the decreased life expectancy forecasted for the next generation (Olshansky et al., 2005). How obesity contributes to the development of age-related diseases such as diabetes and cardiovascular diseases remains an important question. Roger Unger in the mid 1990s (Unger et al., 1999), suggested that an important causative link between fat distribution and the metabolic syndrome reside in the accumulation of lipids in extra adipocyte sites, in cells that constitute the organs and tissues traditionally recognised as lean body mass—notably in the pancreas, liver, skeletal muscle and heart. As Unger elegantly argues (Unger et al., 1999), the small intracellular reserve of lipids for essential housekeeping functions in nonadipocytes – such as for the maintenance of membrane structure, fluidity and intracellular signalling – is tightly regulated, and if overloaded would lead to cell dysfunction (lipotoxicity) and lipid-induced programmed cell death (lipoapoptosis). The theme ‘‘lipotoxicity’’ encompasses toxicity that results not only from lipid overloading induced by excess delivery versus oxidation of circulating FFA (free fatty acids) but also from lipids synthesized from an overload of glucose by the process of de novo lipogenesis occurring in adipocytes or in non-adipocytes. In our opinion, overnutrition defined as a chronic state of positive energy balance can saturate the adipose tissue normal storage capacity of the organism resulting in ectopic deposition of reactive lipid species outside adipose tissues depots. Accumulation of lipids in skeletal muscle, heart, liver, pancreas, kidneys, or blood vessels has the potential to cause organ-specific toxic reactions that compromise their normal functionality. This process caused by lipids and its moieties in non-adipose tissue is referred to as lipotoxicity. Intriguingly, aging is associated with a ‘‘physiological’’ increase in lipid accumulation in non-adipose tissues, even in lean individuals. This might be a causal link for increased prevalence of chronic diseases like type 2 diabetes, fatty liver and cardiovascular disease which also substantially increase in prevalence with age. Conversely, obesity could be considered as a potentiating factor of processes normally associated with aging through its effects promoting lipotoxicity. The causes of increased lipid accumulation in non-adipose tissues with special reference to aging are addressed in this review. Our point of view is that aging can be considered as a physiological degenerative process that potentially can be accelerated by the degenerative processes associated with lipotoxic insults. Similarly aging may increase the susceptibility to the toxic effects of lipid overload associated with overnutrition. Thus individuals that have been able to deal efficiently with excess of fuel (e.g. by being very active) may, as they age and lose their fitness become more sensitive to the deleterious metabolic effects associated with lipotoxicity. For instance the well-recognised age-related reduction in lean body mass may facilitate changes in energy balance favouring fat deposition versus fatty acid oxidation. We have proposed three therapeutic strategies to minimise the effects of overnutrition

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induced lipotoxicity. These include: (a) Decrease energy availability through decreased food intake, (b) a less orthodox approach such as to increase adipose tissue expandability and/or (c) to increase oxidation of fat in peripheral organs (see also Fig. 3). Aging may exacerbate the effects of lipotoxicity by directly affecting these factors: by increasing food intake, decreasing energy expenditure, and impairing adipose tissue expandability (Elia, 1992; Baumgartner et al., 1995; Horber et al., 1997). For instance a physiological reduction of lean body mass associated with aging may facilitate changes in energy balance promoting fat deposition versus fatty acid oxidation. Increased fat availability may increase the pool of lipids redirected to form reactive lipid species in ectopic locations. Lipotoxicity is a relatively new disease, that has emerged only recently probably as a sequel of overnutrition. Therefore it is quite unlikely that physiological mechanisms have evolved to specifically prevent the excess of energy derived from overnutrition. However the same physiological mechanisms that ensure efficient usage of energy could be also targets to prevent the deleterious effects of lipotoxicity. For instance, transcriptions factors such as SREBP1c or PPARs that control genetic programs in response to nutritional signals, may be used under conditions of overnutrition to control fuel partitioning and prevent ectopic lipid accumulation. Other example is leptin, an adipocyte derived hormone that also acts as an antisteatotic hormone, thereby protecting non-adipose tissues from lipid accumulation. Therefore, age induced defects in leptin signalling (e.g. leptin resistance) may primarily or secondarily lead to increased susceptibility to steatosis and lipotoxicity in elderly man. As indicated above, the salutary effects of calorie restriction and exercise through their effects on energy balance may in fact reflect a reduction in lipid toxicity in non-adipose tissues. In our opinion certain degree of lipotoxicity may be inherent to the physiological age-related failure of the mechanisms of energy homeostasis and energy balance even in the absence of obesity. However, when aging is associated with positive energy balance these lipotoxic effects may be exacerbated resulting in a pervasive vicious cycle leading to accelerated profiles in the development of age-related diseases like type 2 diabetes, dyslipiaemia and heart-related diseases.

2. Effect of age on body weight, BMI and body composition In the absence of more direct measures, the amount of body fat is estimated by combining measures of height and weight. The most common method is to divide body weight in kilograms by height in meters multiplied by itself. This is called body mass index (BMI: kg/m2). On the BMI scale, people with an index >25 but <30 are said to be overweight, and with an index >30 are defined obese. The BMI gradually rises during most of adult life, peaks at 60 years, and then declines (Lehmann and Bassey, 1996). The relevant age-related changes in male body composition are related to the progressive decrease in the level of circulating anabolic hormones, among which testosterone (T) is rather important (Moretti et al., 2005). After 65 years of age, the rate of weight loss occurs at an average rate of 0–0.65 kg/year. Loss of muscle mass (and to a lesser extend of other lean tissues) begins from 30 to 40 years of age and continues in advanced in old age (Elia, 1992). In contrast, body fat increases through most of adulthood, approximately doubling between 20 and 50–60 year of age and might fall after 70 year of age. Because fat replaces fat free mass with increasing age, older subjects tend to have a greater proportion of fat than

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younger individuals with the same BMI (Baumgartner et al., 1995), especially men (Horber et al., 1997). Thus, lean elderly people have significantly higher body fat mass than younger persons, probably indicating a ‘‘natural’’ process during aging (Baumgartner et al., 1995; Petersen et al., 2003). Interestingly, with aging fat not only accumulates in the adipose tissue, but also in and around non-adipose organs like heart, liver, pancreas and muscle (Petersen et al., 2003; Unger, 2005).

3. Thermodynamics of obesity From a thermodynamic perspective, the regulation of body weight can be described as a linear equation (Fig. 1), balancing both food intake and energy expenditure to derive the amount of fat stored. While outwardly this energy balance equation may appear simple, it can be modulated by many other factors, particularly the preferential partitioning of energy towards specific tissues and organs. In fact, it could be argued that some individuals may have an enhanced capacity to extract energy from blood into the white adipose tissue (WAT), thus facilitating fat deposition. Conversely, individuals may also preferentially partition fuel into lean and/or oxidative tissues (e.g. muscle) facilitating energy dissipation. While it is still unclear whether defects in the mechanism of fuel partitioning are important causes of human obesity, recently reported genetically modified animal models have provided support for this concept as a potential strategy for the treatment of obesity and its protean complications (Abu-Elheiga et al., 2001; Smith et al., 2000; Tabarin et al., 2005). There is also recent evidence for a role in energy partitioning as another layer of control of food intake (Lin et al., 2005). While it is unclear whether a specific alteration in energy partitioning is vital for the initial development of most forms of obesity, identification of factors involved in the regulation of energy partitioning could be candidates for drugs for the treatment of obesity and lipotoxicity. Globally, energy homeostasis should be considered as a complex, integrated system designed to prevent negative energy balance, as illustrated by the decrease in energy expenditure during fasting. Thus, for the treatment of obesity where a negative energy balance is required, this simple strategy has proved not to be effective. The networks controlling energy homeostasis show both compensatory feedback and redundancy. Thus, alterations of two factors of the energy balance equation, reductions in energy acquisition, combined with increases in energy dissipation, via

Fig. 1. Simplified thermodynamic equation. Partitioning of energy might influence food intake, energy expenditure and the amount of fat stored.

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preferential partitioning of energy to oxidative tissues should produce long-term reductions in the amount of fat storage.

4. Positive energy balance with aging Daily total energy expenditure (TEE) is composed of resting metabolic rate (50–70%; RMR), physical activity (15–30%), thermal effect of feeding (8–12%) and other e.g. brown adipose tissue and skeletal muscle derived thermogenesis. Early studies suggested that resting metabolic rate and energy expenditure decline with aging (Poehlman et al., 1992). These studies suggested a decrease of 13–20% in RMR between the ages of 30 and 80 year, with men exhibiting greater decrease and an earlier onset in the decline in RMR. Because fat-free mass accounts for over one-half of the observed interindividual variation in RMR, age-related sarcopenia (loss of muscle with aging) is an attractive explanation for this observation (Weinsier et al., 1992). This is in accordance with studies showing increase of RMR of 10% in older man subjected to endurance training. Moreover, there is also a small intrinsic loss of RMR because of decline in the Na+–K+–ATPase activity, decrease in muscle protein turnover, and possible changes in mitochondrial membrane permeability (Wilson and Morley, 2003). It has been calculated that daily total energy expenditure (TEE) decreases by 165 kcal/decade in men and 103 kcal/decade in women. This was partly due to decreased basal metabolic rate, but primarily due to decreased physical activity (Elia et al., 2000). This decline in physical activity with aging contributes substantially to reduce TEE and is most pronounced in very old individuals (>90 year old) (Rothenberg et al., 2000). Differences in the ability to accurately regulate energy balance have been explored in over- and underfeeding studies in young and old healthy individuals. Changes in maintenance energy expenditure (RER + thermic effect of feeding) were significantly lower in old subjects and associated with the decreased fat-free mass in elderly subjects (Elia, 2001). This suggests that the elderly are at increased risk of impairments in energy regulation (body weight gain or loss) (Roberts et al., 1994). There is also evidence mainly form rodent studies that the underlying cause of age-related changes in energy homeostasis may be associated with the impairment in the central melanocortin system. Proopiomelanocortin (POMC) expressing neurons in the hypothalamus sense total body adiposity by sampling circulating leptin; it has been shown in rats that POMC expression decreases with aging (Gruenewald and Matsumoto, 1991). Increased obesity and fat mass can be mimicked in animal models by induction of progressive loss of POMC neurons (Xu et al., 2005). These mice show increased obesity with aging, indicating that changes in the central regulation of the energy balance are involved during aging (Xu et al., 2005). Therefore these changes in energy balance may contribute to a state of age-related ‘‘overnutrition’’ that could facilitate the development of obesity-related lipotoxicity.

5. Overnutrition, a conflict between carbohydrate and lipid metabolism The current state of chronic overnutrition or positive energy balance has created a previously unknown metabolic conflict between carbohydrates and lipids. Cells are able to

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switch between fuels depending on specific metabolic conditions and specialised demands. For instance most cells can oxidise lipids to spare glucose for brain usage when carbohydrates are limited. In fact, carbohydrates and lipids rarely coincided at cellular level so cells were forced to develop specialised systems to regulate the efficient metabolic switch between fuels. Therefore FA oxidation and carbohydrate induced de novo lipogenesis have evolved as highly integrated processes. Furthermore, efficient usage of fuels also requires cross-talk between organs to establish energy fluxes between skeletal muscle, WAT and liver. This is illustrated by elegant genetic experiments showing that genetically modified mouse models with inhibition of FA storage in WAT compensate by upregulating FA oxidation in skeletal muscle. One example is the diacylglycerol acyltransferase (DGAT) knockout mouse, showing reduced fat deposition and resistance to diet-induced obesity (DGAT is the enzyme that catalyses the final acylation step of triglyceride synthesis) (Cases et al., 1998; Smith et al., 2000). Similarly, deletion of acetylCoA carboxylase 2 (ACC2), a key enzyme for de novo FA synthesis, leads to a lean mouse showing an increase in FA oxidation (Abu-Elheiga et al., 2001). This is due to the fall in malonyl-CoA, the product of ACC reaction. Malonyl-CoA is a potent inhibitor of carnitine-palmitoyl transferase 1 (CPT1), which transports FA moieties into the mitochondria for b-oxidation (Kerner and Hoppel, 2000). Thus, the absence of ACC2 reduces the cellular concentration of malonyl-CoA, removes the inhibition of CPT1 and allows FA oxidation to be maintained (Fig. 2). Conversely, increased fluxes of carbohydrates may through inappropriate induction of the de novo lipogenic pathway and accumulation of malonyl-CoA impair fatty acid oxidation. Under conditions of chronic overnutrition resulting in simultaneous exposure to both, carbohydrates and lipids, a metabolic conflict develops characterised by facilitation of de novo lipogenesis, decreased fatty acid oxidation and accumulation of toxic non oxidised long chain fatty acids as the basis for a generalised lipotoxic state.

Fig. 2. Regulation of fatty acid oxidation vs. FA synthesis (e.g. palmitate).

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6. Adipose tissue expandability and lipotoxicity Adipose tissue expandability in response to positive energy balance has been considered traditionally an adaptive passive process. However recent evidences suggest that the expandability of the adipose tissue is not an unlimited process. In fact, adipose tissue expandability may be an important factor determining the appearance of obesity associated co-morbilities (Medina-Gomez et al., 2005). The importance of the adipose tissue in maintaining energy homeostasis is illustrated by the severity of metabolic defects associated with two apparently opposite syndromes: lipodistrophy and obesity. Lipodystrophy is a syndrome characterised by substantial reduction in fat storage capacity secondary to poor differentiation and expandability of adipose tissue in response to nutritional demands for storage. Such patients lack three crucial adipocyte functions, normal lipid storage capacity, leptin-mediated anorectic effects and leptin-mediated antilipotoxic protection of non-adipose tissues. Despite normal energy intake, lack of adipose tissue results in insulin resistance, elevated serum free fatty acids (FFA) and accumulation of FAs in tissues such as the liver, skeletal muscle and the pancreas (Fig. 3b). Intriguingly, it has been shown recently that patients with lipodystrophy show an increased energy expenditure and FA oxidation after hypercaloric fat load, reflecting a compensatory mechanism to prevent toxic effects (Savage et al., 2005). Insufficient attempts by oxidative tissues to dispose the excess of FAs leads to chronic FA deposition and lipotoxicity, followed by insulin resistance, fatty liver and b-cell failure (Garg, 2000). The other extreme of the spectrum is the obese state, a syndrome resulting from positive energy balance leading to hypertrophic expansion of the WAT (Fig. 3c). Evidence suggests, that hypertrophic obesity is associated with insulin resistance (Molina et al., 1989; Holm et al., 2000; Olefsky, 1977), leptin resistance and a spectrum of clinical symptoms that recapitulates the symptomatology observed in lipodystrophy patients. The common link between both of them probably is the defective storage capacity in adipose tissue depots, in the case of lipodistrophy due to lack of proper adipose tissue, in the case of obesity due to saturation of storage capacity due to excessive fat load. How aging may affect storage capacity in adipose tissue? There is evidence that fat mass, adipocyte size, metabolic responsiveness, and preadipocyte differentiation capability decrease between middle and old age. Also expression of proadipogenic transcription factors (e.g. C/EBPa and PPARg) seems to decline with aging (Karagiannides et al., 2001) resulting in decreased differentiating potential of preadipocytes. It has also been shown that aging is associated with increased expression of anti-adipogenic C/EBP family members (Kirkland and Dobson, 1997). This suggest that age-related decline in adipose tissue expandability may under conditions of positive energy balance fail to accommodate increasing needs of fat storage leading to ectopic fat deposition redistributed to muscle, bone marrow, and other tissues. Obesity at the expense of hypertrophic adipocytes is associated with insulin resistance (Fig. 3c). Conversely individuals expanding adipose tissue at the expense of increasing the number of adipocytes through a hyperplastic response remain insulin sensitive and healthier (Fig. 3d). Hyperplastic changes have the advantage of retaining insulin sensitivity and a favourable pattern of signalling molecules secretion (Weyer et al., 2000). In this regard hypertrophy could be a marker of failure in the mechanisms of preadipocyte recruitment (Medina-Gomez et al., 2005). Furthermore, pharmacological

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Fig. 3. (a) Balance between triglyceride accumulation in adipose tissue and FA oxidation in lean tissues, due to reduced energy intake or increased physical activity. (b) Reduced lipid storage capacity due to lipodystrophy resulting in an imbalance of FA accumulation in non-adipose tissues. (c) Overnutrition leading to overspill of lipids from adipose tissue to pancreas, muscle and liver, etc. (d) Hyperplastic adipocytes increasing lipid storage capacity resulting balanced energy flux.

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Fig. 3. (Continued ).

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remodulation of the adipose tissue facilitating preadipocyte recruitment by thiazolidinediones has been shown at least in rodent models to promote hyperplastic remodulation of the adipose tissue (Okuno et al., 1998). This is fully supported by the evidence that onset of obesity in young age (<20 year), when the adipocytes are probably able to proliferate and/ or differentiate, results in a reduced likelihood of metabolic syndrome (Brochu et al., 2001). There is little evidence that aging alone has any effect on the development of adipocyte hypertrophy, however it is conceivable that in individuals predisposed to develop hypertrophic forms of obesity through defective adipocyte function, aging may facilitate the early development of its deleterious metabolic effects. In our opinion age may decrease the threshold for efficient storage in adipose tissue. In those individuals with tendency to develop obesity, age may become an important factor for the development of complications, whereas in other individuals with fat storage well below this threshold, age may not pose any further metabolic risk. The association between defects in adipose tissue expandability and metabolic complications may depend on other factors, such as the oxidative capacity of skeletal muscle. Apart from increasing storage capacity of fat in ‘‘healthy’’ adipocytes, increasing FA oxidation in muscle can also prevent lipotoxicity. This is illustrated by a transgenic mouse model overexpressing UCP-3 in skeletal muscle (Wang et al., 2003) or mice overexpressing PGC1a (Lin et al., 2002). In this case, the driving force of the phenotype is increased FA oxidation that could act as an energy sink, diverting FA away from storage tissues such as WAT (resulting in a lean phenotype), and also away from other tissues less capable of handling FAs adequately (e.g. liver and bcells). Evidence from epidemiological studies indicate, that people with an increased FA oxidation, proved by lower RQ (respiratory quotient) show a reduced probability of obesity (Froidevaux et al., 1993). Combining the both strategies, prevention of excess fat deposition in WAT and increasing FA oxidation may facilitate safe weight loss and is a target for drug development.

7. Aging, oxidative capacity and lipotoxicity Age is associated with a reduction in skeletal muscle oxidative capacity (Petersen et al., 2003). Recent evidence has identified coactiavtors PGC1a and PGC1b as key regulators of the genetic program controlling mitochondrial number and function. These coactivators are involved in processes such as adaptive thermogenesis, glucose and fatty acid oxidation. The expression and activity of PGCs decrease in parallel with aging (Ling et al., 2004) resulting in a decrease in the threshold for efficient nutrient utilisation and oxidation in skeletal muscle. Of interest decreased levels and activity in PGC1a and b and oxidative metabolism have been associated with insulin resistance and diabetes (Ling et al., 2004). This physiological decrease in oxidative capacity associated with aging should not pose a metabolic problem as long as the demands for oxidation are below the new threshold of oxidative capacity. However, under conditions of positive energy balance there is an increase in the demands of the oxidative machinery potentially resulting in impaired fatty acid oxidation, and accumulation of reactive lipid species. Therefore aging may be a triggering factor for metabolic failure in individuals in whom their adaptive oxidative response to excess of nutrients is close to its maximal capacity. Globally the combination of

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positive energy balance with age-related defects in energy dissipation and adipose tissue expandability may in selected susceptible individuals lead to metabolic failure through potentiation of a lipotoxic mechanism (Fig. 5).

8. Mechanisms of lipotoxicity and lipoapoptosis One of the key remaining questions about the mechanisms leading to lipotoxicity is whether accumulation of TGs is the cause of lipotoxicity per se, or simply a marker of excess of fuel availability. Once FAs such as palmitate enter non-adipose tissues, they may be directed towards: (1) FA oxidation, (2) storage as TGs and (3) synthesis of structural lipids or particularly under conditions of FA surplus towards cell-specific pathways of nonoxidative metabolism (Fig. 4) (Unger and Orci, 2002). In our opinion, TGs probably do not harm the cell. In fact, this is the safest way to accumulate the excess of energy although ultimately, hydrolysis of these TG stores will add to the already expanded pool of fatty acyl-CoA, providing additional substrate for non-oxidative FA metabolism (Fig. 4) (Unger and Orci, 2002). Visualisation of TGs in a tissue (e.g. liver or muscle) has been identified as a marker of lipotoxicity. However this should be considered as a protective response to excess of fuel in the system. Organs different from adipose tissue have a limited buffer capacity to accumulate triacyl glycerol and once this buffer capacity is saturated lipids are shuttled to other more dangerous metabolic pathways. As such TG accumulation indicates that other more reactive lipid species may be formed and in this respect it may be a suitable marker of overexposure to nutrients and potential lipotoxicity (Fig. 4). The reactive lipid derivates that damage non-adipocytes may be generated via more than one pathway and in some way may depend at least partially on the repertoire of metabolic pathways present in the specific organ where they are ectopically accumulated. In the pancreatic islets (Shimabukuro et al., 1998), and in the hearts of ZDF rats (Zhou et al., 2000) lipotoxicity involves an increase in ceramide formation via condensation of unoxidised palmityl-CoA and serine, catalysed by the enzyme serine palmityl-CoA (Unger, 2005). Increased ceramide is accompanied by upregulation of inducible nitric oxide synthase (iNOS), thereby enhancing nitric oxide and peroxynitrite formation (Unger, 2005). Other pathways like ROS are certainly involved though not carefully delineated so far.

Fig. 4. Possible metabolic pathways FAs (e.g. palmitate) might undergo. Pathological reactions are depicted on the grey background.

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Ectopic accumulation of lipids in a specific organ depends on lipid availability and transport, storage and oxidative capacity of the organ. Oxidative capacity can be modulated by physiological (e.g. exercise) and pharmacologically interventions that promote fatty acid disposal through promotion of oxidation such as AMP-activated protein kinase agents such as leptin (Minokoshi et al., 2002), thiazolidinediones (Saha et al., 2004; Fryer et al., 2002), metformin (Zhou et al., 2001; Fryer et al., 2002) and AICAR (Iglesias et al., 2002). The adipose tissue also contributes directly to control the oxidative capacity of peripheral organs through hormones synthesized and secreted by adipose tissue such as leptin (see below), adiponectin and TNFa that directly affect insulin sensitivity and fuel oxidation (Sethi and Hotamisligil, 1999; Jequier, 2002; Yamauchi et al., 2001).

9. Leptin and lipotoxicity Leptin is a hormone secreted by adipocytes, leading to central suppression of appetite, peripheral increase in fatty oxidation and protection of lipid accumulation in non-adipose tissues. Recently, evidence favouring the antisteatotic role of leptin has been obtained (Lee et al., 2001). During high-fat diet (60%) leptin plasma concentrations rise within 24 h in normal animals and increases progressively in remarkable correlations with the increase in body weight. However, lipid deposition is rising only minimally in heart, liver, islets and muscle, despite the 150-fold expansion of adipocyte fat. By contrast, in rodents lacking leptin action, non-adipose tissues rapidly accumulate abnormal quantities of lipids even on a normal fat intake (6%) (Lee et al., 2001). Moreover, transgenic overexpression of the leptin receptor in the liver of ZDF fa/fa rats (leptin receptor defective) selectively reduced TG content in the liver (Lee et al., 2001). In summary, when leptin action is lacking, de novo lipogenesis in non-adipose tissues is inappropriate high, irrespective of FA availability (Unger, 2002). Conversely, blocking of leptin action occurs in adipose tissue during overnutrition, which is crucial for adipocytes to undergo hypertrophy and hyperplasia and to enable lipid storage (Wang et al., 2005). This is due to a combination of postreceptor and receptor-level blockade which appears to minimise potential leptinergic interference with fat storage (Wang et al., 2005). The mechanisms for decompensation of antilipotoxic protection in diet-induced obesity are probably a combination of decreasing leptin sensitivity together with a level of hyperleptinenmia that is insufficient relative to the required levels of leptin action (relative hypoleptinemia). Aging is one of the most common causes of impaired leptin sensitivity on both, hypothalamic and peripheral levels (Wang et al., 2001). It has been shown in aging rats, that leptin exhibits only a small fraction of the anorexic response to adenovirally induced hyperleptinemia compared to young rats. Moreover, the loss in body fat was 90% smaller in old than in young animals. The same may occur in humans; young humans exhibit a strong correlation between body fat and plasma leptin. However in middle-aged and elderly humans, the ages in which the complications of obesity are most likely to develop, the correlation is lost (Moller et al., 1998). On a molecular level this might be explained by increased expression of SOCS-3 (suppressor of cytokine signalling) in leptin-unresponsive fat cells of aged rats (Wang et al., 2001).

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10. SREBP-1c, a gatekeeper for lipotoxicity Another level of control of the lipotoxic insult in peripheral organs may be the control of lipid transport and functional compartmentalisation into a specific organ. In theory it should be possible in individuals with organ-specific susceptibilities to develop b-cell failure, fatty liver or heart failure to devise strategies to spare lipids and protect these organs from lipotoxic insults. This may be accomplished through direct modulation of specific targets involved in lipid-related metabolic pathways controlling lipid transport, deposition and specific metabolism in these organs. Our studies defining the metabolic pathways involved in fatty acid metabolism have identified SREBP1c as a potential gatekeeper for lipotoxicity (Sewter et al., 2002). SREBP-1c is one of three SREBPs that control transcription of genes encoding enzymes of lipid biosynthesis in animal cells. The SREBPs are bound to membranes of the nuclear envelope and endoplasmic reticulum. In cholesterol-deprived cells, the transcriptionally active amino-terminal fragments of the SREBPs are released by proteolysis. They enter the nucleus and activate genes encoding enzymes involved in the synthesis of cholesterol and unsaturated fatty acids and in the uptake from low-density lipoprotein (LDL) particles. When sterols accumulate in cells, proteolysis is blocked and transcription of the target genes declines (Brown and Goldstein, 1997). Interestingly SREBP1c is the nutritionally regulated form of SREBP1. This isoform regulates the major genes encoding the primary enzymes of the de novo FA synthesis, ACC and FAS (Shimano et al., 1997), fatty acid resterification, lipid unsaturation and structural phospholipids formation. We and other groups have established that insulin upregulates SREBP1c mRNA and maturation of SREBP1 protein in parallel with increased expression of FA biosynthesis gene expression (Sewter et al., 2002; Le Lay et al., 2002; Kim et al., 1998). Activation of SREBP increases ACC-catalysed reactions, leading to increased levels of malonyl-CoA, and inhibition of mitochondrial FA oxidation (Fig. 2). We have shown that SREBP1c mRNA expression is regulated heterogeneously in adipose tissue and skeletal muscle. In fact, whereas SREBP1 mRNA is reduced in adipose tissue of morbidly obese and diabetic patients (Sewter et al., 2002) levels of expression of SREBP1 mRNA in skeletal muscle are maintained. Also recently it has been suggested that SREBP1 mRNA levels may decrease in adipose tissue in response to aging (Hotta et al., 1999) suggesting that obesity and aging may have a synergistic effect impairing efficient fat deposition in adipose tissue. This indicates that whereas further lipid accumulation in adipose tissue may be limited, partitioning of free fatty acids towards other tissues such as skeletal muscle should be facilitated. Similar processes may also occur with respect to pancreas, or liver where partitioning of fuel towards these organs may facilitate the development of fatty liver and b-cell failure (Sewter et al., 2002; Unger and Orci, 2001). Moreover, SREBP1c expression was highly correlated with intramyocellular lipid content, before and after weight loss. It is unclear whether SREBP1 activation in skeletal muscle may have positive or negative effects with respect to lipotoxicity. On one hand maintained SREBP1 expression under conditions of lipotoxicity may increase fat partitioning towards a specific organ but also contribute to its safe deposition in the form of triacylglycerol. Alternatively we may consider that decreased activity of SREBP1 in muscle in the context of an overload of lipids may increase the lipotoxic insult if triacylglycerol synthesis is prevented. For these reasons we argue that the

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best strategy to prevent lipotoxicity besides increasing oxidative capacity may be on one hand to prevent the transport of lipids and simultaneously facilitate storage as TG of any surplus of lipids. Finally, we need to consider the possibility that pathways physiologically not relevant may under conditions of overnutrition become pathophysiologically relevant. For instance it has been shown in contracting myotubes that high glucose is able to induce de novo lipogenesis via activation of SREBP1c (Guillet-Deniau et al., 2004). This might start a vicious circle of lipogenesis, impaired oxidation leading to lipotoxicity and insulin resistance. In summary selective activation of SREBP1 regulated pathways in adipose tissue may provide a suitable strategy to prevent or reverse the deleterious effects of age and obesity induced lipotoxicity.

11. Organ-specific lipotoxic response and aging 11.1. Lipotoxicity in b-cells The mechanisms leading to lipotoxic induced b-cell failure have only recently started to be clarified. The leptin signalling deficient rat (‘‘ZDF’’; leptin receptor defective) is an animal model of extreme obesity, caused by hyperphagia and reduced energy expenditure. During the onset of obesity, the islets of these animals show a 10 increased lipid content, the number and size of islets rises enabling sufficient insulin secretion to maintain normal blood glucose (Higa et al., 1999). However, as a result of aging these homeostatic mechanisms fail leading to subsequent mitochondrial alterations and apoptosis, resulting in b-cell failure and diabetes (Higa et al., 1999). The increase of TGs in the islets of this model is exceptional high, in part because FA export in impaired. Intriguingly, overexpression of WT leptin receptor in islets of diabetic fa/fa rats reduces TG content, and restores b-cell function and viability (Shimabukuro et al., 1998). Recently, in islets an alternative mechanism of lipotoxicity has been identified. In fact, activation of GPR40, a fatty acid activated receptor located in the cell membrane of the pancreatic b-cell mediates the ability of fatty acids to promote glucose-induced insulin secretion (Steneberg et al., 2005). In short term, FAs induce insulin secretion; however, over the long term, chronic activation of GPR40 by fatty acids promotes a lipotoxic state that results in b-cell failure (Steneberg et al., 2005; Medina-Gomez and Vidal-Puig, 2005). Intriguingly, GPR40 KO mice are protected against development of lipotoxic induced b-cell failure (Steneberg et al., 2005). 11.2. Lipotoxicity in liver and aging Non-alcoholic steatohepatitis (NASH) is a common feature of the metabolic syndrome resulting from an unbalance amongst the mechanisms of lipid uptake and synthesis, lipid oxidation, triglyceride synthesis and secretion as lipoproteins and disposal through bile acid synthesis. The liver plays a key role facilitating mitochondrial b-oxidation of fatty acids. Non-alcoholic fatty liver disease (NAFLD) encompasses a broad spectrum ranging from simple steatosis to non-alcoholic steatohepatitis (NASH) (Falck-Ytter et al., 2001). NAFLD has a high prevalence of 20%, is most commonly diagnosed in adults aged 45–55

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years and strongly associated with insulin resistance (Rashid and Roberts, 2000). The physiological capacity of the liver to control lipid metabolism is impaired by aging resulting in increased lipid content even in lean individuals (Petersen et al., 2003). However, this accumulation of triacyl glycerol may not pose a major metabolic challenge to the liver unless the lipid load outweighs the liver adaptive metabolic capacity left to metabolise the surplus of energy. Mice with a heterozygous defect of MTP (mitochondrial trifunctional protein) showed an accelerated and increased steatosis with aging, which was highly associated with the development of insulin resistance and increased FFA (Ibdah et al., 2005). Moreover, the MTP mutant mice had swollen mitochondria and signs of increased ROS and oxidative stress. In conclusion, the human and animal data are indicative, that increased lipid accumulation in the liver (steatosis) develops in aging, but is accelerated in states of reduced b-oxidation and insulin resistance. 11.3. Aging and the lipotoxic muscle Skeletal muscle, which accounts for 30–40% of body mass in mammals, is an important site of glucose disposal, lipid oxidation and thermogenesis whose impairments contribute to the pathogenesis of obesity and type 2 diabetes. It has been shown recently that leptin increases thermogenesis in skeletal muscle by 20%, specifically via FA oxidation thereby reducing lipid accumulation (Dulloo et al., 2002; Solinas et al., 2004). Thus leptin resistance in aging could lead to lipid accumulation and insulin resistance in skeletal muscle (Dulloo et al., 2002; Solinas et al., 2004). This is accordance with data using NMR spectroscopy to compare intramyocellular lipid content (ICML) and mitochondrial function in healthy young and elderly persons (BMI < 25 kg/m2). Elderly volunteers showed significant higher ICML (45%), but reduced mitochondrial ATP synthesis and higher plasma insulin concentration during oral glucose tolerance test (Petersen et al., 2003). This increased ICML might induce apoptosis via high NO generation (Fig. 4) and be a causal link for skeletal muscle loss in the elderly, which occurs in association with an increasing adipose mass (Elia, 1992; Baumgartner et al., 1995; Horber et al., 1997). PPARg coactivator 1a (PGC-1a) was found to drive the formation of oxidative type 1 myofibres and activate genes of mitochondrial oxidative metabolism (Lin et al., 2002). It has been shown recently that PGC-1a expression and protein level decrease with aging, which might be a causal molecular link for decreased oxidative capacity (Ling et al., 2004). Thus, susceptibility for lipid accumulation might be increased by changes of key metabolic transcription factors in parallel with age. This effect of aging on lipid metabolism may also explain the increased age-related insulin resistance. In fact, lipid infusions designed to increase plasma fatty acid concentration in humans and rodents can directly reduce insulinstimulated glucose disposal (Boden and Shulman, 2002; Boden, 2001). Furthermore, the fall in insulin sensitivity during such clamp procedures only occurs several hours after elevations in FA concentrations, in keeping with the idea that FA accumulation in skeletal muscle and liver is responsible for this phenomenon (Boden, 2001). On a molecular level this has been explained by reduced tyrosine phosphorylation of IRS-1 (insulin receptor substrate 1) (Fig. 4) (Dresner et al., 1999). It has been hypothesised that hyperinsulinemia, in the state of insulin resistance, may be involved in driving de novo lipogenesis in muscle and liver by increasing SREBP1c expression (c.f. ‘‘10. SREBP-1c, a gatekeeper for

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lipotoxicity’’ and Fig. 2) (Shimomura et al., 2000). As the skeletal muscle accounts for >80% of insulin stimulated glucose uptake small disturbances might initiate a vicious circle of increased lipid accumulation thereby further increasing insulin resistance in aging. Therefore overnutrition may under conditions of deficient lipid handling induced by age induce even a more severe insulin resistance. 11.4. Age and the lipotoxic heart Age is a major risk factor for the development of heart failure (Wei, 1992). ZDF fa/fa rats are used as a model to study effects of aging on the heart. Myorcardial contractility is reduced by 50% in 20-week-old animals compared to 7 weeks of age. This is accompanied by an increase in TG and ceramide. Intriguingly, these leptin receptor defective animals show a reduction of lipid content in the heart when the receptor function is restored in young age, but not in old animals (Zhou et al., 1997). This indicates that also in the heart leptin resistance develops in aging, thereby losing its antisteatotic and protective effect. Moreover, treatment of old rats with thiazolidinediones reduced TG content, normalizes contractility and DNA laddering, an indicator of apoptosis. It has been shown that in a subgroup of patients with non-ischemic heart failure intramyocardial lipid deposition was substantially increased (Sharma et al., 2004). The balance between fatty acid uptake and its oxidation may become critical in the aging heart. A mismatch between uptake and utilisation can lead to accumulation of intracellular fatty acyl intermediates and increased triglyceride stores. In a transgenic mouse model with increased FA uptake due to overexpression of ACS1 in the heart lipid content was increased resulting in hypertrophy, heart failure and premature death (Chiu et al., 2001). Similar pathological changes take place in diabetic heart failure, indicating that states of insulin resistance are involved in lipid accumulation in the heart (Lopaschuk, 1989). With aging, humans exhibit a decline in myocardial fatty acid oxidation capacity and relative increase in glucose utilisation (Kates et al., 2003). This might increase susceptibility to lipotoxicity. Moreover, hypertrophy and increased heart lipid content appears to be a characteristic of aging hearts, even in otherwise healthy individuals. In conclusion, increased lipid content due to obesity or diabetes might accelerate heart failure resembling premature aging. 11.5. Age-related lipotoxicity in kidney It has been shown that age-related renal matrix deposition and proteinuria were associated with increased SREBP1 expression and increased renal accumulation of triglycerides and cholesterol. Intriguingly, in calorie restricted animals proteinuria and extracellular matrix accumulation was decreased and associated with lower levels of plasminogen activator inhibitor 1 (PAI-1) and vascular endothelial growth factor (VEGF) (Jiang et al., 2005a). Moreover, renal SREBP1c expression and triglyceride content were also decreased during calorie restriction (Jiang et al., 2005a). Conversely, in animal models of obesity renal lipid accumulation and proteinuria are increased. However, it has been demonstrated that mice with a deletion for SREBP1c are protected from this obesity associated renal disease (Jiang et al., 2005b). In humans, obesity-related glomeropathy is

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now considered as an isolated complication in obese patients and characterised by enlarged glomerular size, glomerulosclerosis and proteinuria. Intriguingly, expression of genes, as TNF-a, IL-6, SREBP1, VEGF and PAI-1 were upregulated indicating similar processes involved in this disease, as in adipose tissue (Wu et al., 2005). In conclusion, this indicates that age-related lipid accumulation in the kidney is promoted by SREBP1c activation and accelerated in obesity.

12. Is cancer facilitated by overnutrition? The proliferative effect of high levels of long-chain FA on b-cells (Milburn et al., 1995) raises the possibility that exposure to TG has mitotic effects that increase the risk of neoplasia in other cells. Considerable evidence suggests a link between a high-fat diet and cancer of the colon (Correa, 1975). Moreover, there is significant increase of malignancy with increasing body weight (Calle et al., 1999; Milburn et al., 1995).

13. Summary Aging decreases the functional reserve of important metabolic organs. When these aged organs are challenged with excess of fuel as a result of overnutrition associated to impaired adipose tissue expandability, oxidative capacity and dysregulated energy homeostasis, this results in increased exposure and accumulation of lipids in non-adipose tissues and leptin resistance. These conditions can increase the susceptibility of aged organs to nutritionally related lipotoxic effects (Fig. 5). States of metabolic imbalance such as overnutrition, obesity and insulin resistance by itself challenge these homeostatic mechanisms synergising with age-related lipotoxic susceptibility (Fig. 5). In conclusion, preventing overnutrition and its deleterious effects should make the aging experience a more bearable process.

Fig. 5. Pathophysiological changes associated with lipotoxicity and aging. The interconnection of both might initiate a vicious circle accelerating development of diseases such as diabetes and heart failure.

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