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Adipose tissue expandability, lipotoxicity and the Metabolic Syndrome — An allostatic perspective

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Abstract

While the link between obesity and type 2 diabetes is clear on an epidemiological level, the underlying mechanism linking these two common disorders is not as clearly understood. One hypothesis linking obesity to type 2 diabetes is the adipose tissue expandability hypothesis. The adipose tissue expandability hypothesis states that a failure in the capacity for adipose tissue expansion, rather than obesity per se is the key factor linking positive energy balance and type 2 diabetes. All individuals possess a maximum capacity for adipose expansion which is determined by both genetic and environmental factors. Once the adipose tissue expansion limit is reached, adipose tissue ceases to store energy efficiently and lipids begin to accumulate in other tissues. Ectopic lipid accumulation in non-adipocyte cells causes lipotoxic insults including insulin resistance, apoptosis and inflammation. This article discusses the links between adipokines, inflammation, adipose tissue expandability and lipotoxicity. Finally, we will discuss how considering the concept of allostasis may enable a better understanding of how diabetes develops and allow the rational design of new anti diabetic treatments.

Section snippets

The Metabolic Syndrome

The Metabolic Syndrome (MetS), or Syndrome X, was originally described as a set of four pathogenic states that cluster in individuals with a greater frequency than can be expected by chance alone. The four aspects of the Metabolic Syndrome are obesity, insulin resistance, dyslipidaemia and hypertension [1], [2]. The fact that these four metabolic complications cluster together suggests that there may be a common pathogenic link between them. In this article we explore how adipose tissue

The concept of allostasis and rationalising treatment strategies to combat diabetes

Allostasis is the concept of maintaining stability through change, a change that requires energy and may be associated with unwanted collateral damage. It differs from homeostasis (defined as the stability of physiological parameters) because it incorporates the systems that maintain the homeostatic set point. Indeed, a key concept of allostasis is that the idea of a ‘set point’ for a metabolic parameter is in fact not necessarily true. Over a 24 h period blood glucose in a healthy individual

What causes insulin resistance in the context of obesity?

It has been suggested that development of insulin resistance may be an early event in the development of common forms of type 2 diabetes. It is a clinical fact that the majority of insulin resistant patients are obese. Furthermore, on an epidemiological level, obesity is clearly associated with insulin resistance and diabetes. In the next section of this article potential mechanisms that connect obesity to insulin resistance will be discussed.

The adipose tissue expandability hypothesis

While it is clear that obesity is associated with diabetes based on population studies, there is some controversy as to the mechanisms by which this occurs on an individual level. One hypothesis, which perhaps links many others, is that of limited adipose tissue expandability. The adipose tissue expandability hypothesis can be stated as follows; adipose tissue has a defined limit of expansion for any given individual. As an individual gains weight a point will eventually be reached when their

Preadipocyte to adipocyte differentiation

Mature adipocytes are derived from preadipocyte precursors. The processes involved in terms of preadipocyte to adipocyte conversion have been extensively studied using a variety of in vitro models and genetically modified mice [12], [13]. Perhaps the most important transcription factor in the control of adipogenesis is PPARγ. PPARγ is a nuclear hormone receptor (NHR) super-family member that regulates much of the adipogenic program. While at least 4 different mRNAs have been shown to be

Mechanical limitations on adipose tissue expansion

Although cell culture systems have been used extensively to investigate the mechanisms of preadipocyte to adipocyte conversion, in vivo adipocytes do not exist as a monolayer of identical cells but in a complex milieu of different cell types embedded within an extracellular matrix (ECM). In order for adipocytes to increase in size (hypertrophy) and number (hyperplasia) the extracelullar matrix must be remodelled, if it is not, then these processes cannot occur. The extracelullar matrix is

Angiogenesis as a modulator of adipose tissue expansion

Angiogenesis is the process of new blood vessel formation and is required for expansion of adipose tissue. Unsurprisingly, inhibitors of angiogenesis such as TNP-470, angiostatin and endostatin inhibit adipose tissue expansion and by themselves are sufficient to reverse obesity in dietary and genetic models of obesity [21].

Unexpectedly, from the point of view of the adipose tissue expandability hypothesis, the one study which looked at the metabolic consequences of inhibiting angiogenesis (by

Intrinsic limits on preadipocyte formation

Recently adipose tissue stem cells have been identified [24], [25]. Adipose stem cells appear associated with the vasculature of adipose tissue [25]. At present little is known about the capacity of these stem cells to produce new preadipocytes, or how preadipocyte formation is regulated. If preadipocyte number does differ between individuals this may contribute to an intrinsic limit on adipose tissue expansion. The idea that adipocytes are turned over during the whole lifecycle of humans has

Other hypotheses and how they tie in

Considerable research has focussed on other concepts that can link obesity to diabetes. Perhaps two of the most popular hypotheses are the adipokine hypothesis and the low grade inflammatory state hypothesis. The low grade inflammatory state hypothesis posits that obesity is associated with inflammation in adipose tissue and liver, which leads to an increase in pro-inflammatory cytokine production by immune cells such as macrophages. Pro-inflammatory cytokines can directly impair insulin

Evidence to support the adipose tissue expandability hypothesis from humans

While the above sections have summarised much of the experimental data from rodent models that support the concept of adipose tissue expansion, there is some intriguing evidence from human studies that supports the adipose tissue expansion hypothesis.

Firstly, as mentioned briefly above, a number of human mutations that cause lipodystrophy (a lack of adipose tissue) result in severe insulin resistance. Mutations in multiple different genes have been found to cause congenital lipodystrophy,

Lipotoxicity and how insulin resistance occurs

In the next section of this article the reasons why a failure in adipose tissue expansion leads to insulin resistance will be discussed. A failure in adipose tissue expansion can be observed when there is a slowing in the rate of adipose tissue mass expansion, coupled with insulin resistance within adipose tissue. Under these conditions adipocytes tend to hypertrophy and the appropriate physiological functions of adipose tissue are diminished. Adipose tissue no longer appropriately buffers

Specific lipid species and how they cause lipotoxicity in specific organs

Muscle is the major site of insulin-stimulated glucose disposal in humans and rodents. Several studies have looked at the effects of intramyocellular lipid deposition and found that increased levels of lipid accumulation correlate with insulin resistance [45], [46], [47], [48]. This would seem to agree well with the concept of lipotoxicity induced insulin resistance. However, a substantial and outstanding question was raised by the ‘athletes paradox’. The athletes paradox is the fact that

The role of specific fatty acids in liver

In liver, analogous to muscle, there has generally been observed a strong correlation between hepatosteatosis (macroscopic lipid accumulation) and insulin resistance. Rates of hepatosteatosis in type 2 diabetics are much higher than those found in the general population or non-diabetic obese subjects. Equally, several mouse models have shown that insulin sensitivity can be improved by reducing hepatosteatosis. However, as with muscle, it may be the case that TAG accumulation (seen as

Allostasis, energy balance and insulin resistance — an historical perspective

The term allostasis was first coined in the 1980s. Allostasis encompasses both the processes that control homeostasis and the concept of stability through change. A key aspect of allostasis is that it includes a predictive element to the body's responses to the environment with the brain setting new ‘homeostatic’ set points based on environmental cues. Examples of cues that can affect allostatic set points in a predictive manner are the circadian clock, which will drive a rise in blood pressure

At what stage does it make sense to intervene? An allostatic perspective

In this section we will discuss how applying the concept of allostasis may help to inform where it is of benefit to intervene in the treatment of type 2 diabetes, paying particular regard to the concept of lipotoxicity.

In general terms, when trying to intervene in any disease state the fundamental question that arises is at which level should it be targeted. It is possible to envisage treating specific signs of a disease (such as elevated blood glucose in the case of diabetes) or alternatively

Preventing lipid accumulation in non-adipose organs

In theory preventing organs such as liver from accumulating lipid could have some value. The issue would be what would be the fate of the lipid that was not accumulated in non-adipose organs? An example of the issues that could occur can be seen in hepatocyte-specific PPARγ KO mice crossed onto an ob/ob background. Mice lacking PPARγ in liver on an ob/ob background do not accumulate fat in their livers and as a result have improved hepatic insulin sensitivity. However, on a whole-organism level

Storage of ectopic lipids in less harmful forms

There is increasing evidence that the type of ectopic lipid accumulated in tissues is more important than the amount of lipid accumulated. To that end it is possible to envisage treating insulin resistance by driving lipids in ectopic depots into safe storage forms (such as TAG) and away from more harmful forms, such as ceramides, DAGs and LPCs. Redirecting lipids into safer storage forms has already been shown to be beneficial in muscle [44] and conversely preventing storage in the form of TAG

Preventing glucolipotoxic effects on the beta cell

There is a large body of evidence that TG accumulation in beta cells leads to beta cell failure. Whether the TGs themselves are toxic, or if they are markers of the accumulation of other harmful lipid species such as ceramides is more debatable, but some evidence does point to TGs being directly toxic. Overexpression of DGAT1 in isolated islets (analogous to over expression of DGAT1 in muscle) dramatically reduced islet function while increasing islet TG levels [58]. Furthermore, blocking lipid

Other treatment modalities

One of the most commonly used antidiabetic drugs is metformin. While the mode of metformin action remains somewhat controversial it is now largely believed to act via activating AMPK. In humans the beneficial metabolic effects of metformin seem to be largely focussed on reducing hepatic glucose output [71]. In rodents, AMPK activation by compounds such as AICAR have shown beneficial effects in multiple organs including adipose tissue, muscle, liver and brown adipose tissue. One possible reason

Conclusions

Overall this article discusses how a state of positive energy balance can lead to insulin resistance via a principle failure in the body's ability to store excess lipid appropriately in adipose tissue. We attempt to rephrase these processes, which have been reviewed extensively elsewhere, in the context of allostasis. Thinking of the steps leading from the initiation of positive energy balance through to ultimate beta-cell failure and Type 2 diabetes in terms of a series of processes being

Acknowledgements

We thank the MRC, Diabetes UK and the EU HEPADIP consortium for funding this work.

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