Review
Lipotoxicity, overnutrition and energy metabolism in aging

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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 β-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.

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-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 non-adipocytes – 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 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.

Section snippets

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,

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

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

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 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

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

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 PGC1α and PGC1β 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

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 non-oxidative metabolism (Fig. 4) (Unger and Orci, 2002).

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

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 β-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

Lipotoxicity in β-cells

The mechanisms leading to lipotoxic induced β-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

Is cancer facilitated by overnutrition?

The proliferative effect of high levels of long-chain FA on β-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).

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

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    Marc Slawik has been supported by a fellowship from the “Fritz Thyssen Foundation”, Germany.

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