The adipocyte in insulin resistance: key molecules and the impact of the thiazolidinediones

Review

TRENDS in Endocrinology and Metabolism

Vol.14 No.3 April 2003

137

The adipocyte in insulin resistance: key molecules and the impact of the thiazolidinediones Peter Arner Dept of Medicine, CME M63, Huddinge University Hospital, S-141 86 Stockholm, Sweden

Globally, the prevalence of obesity is escalating, and insulin resistance resulting from increased (predominantly visceral) adipose tissue mass has been identified as a key factor that could drive parallel rises in type 2 diabetes mellitus (T2DM) prevalence. Correlations between these global epidemics have encouraged investigation into potential molecular links between the related impairments in lipid and glucose homeostasis. This article reviews factors released from adipose tissue that could contribute to the development of insulin resistance and b-cell dysfunction, including tumour necrosis factor a (TNF-a), free fatty acids (FFAs), adiponectin, resistin and leptin. It also considers whether agonists of the peroxisome proliferator-activated receptor g, which is abundant in adipose tissue, might have an important impact on factors associated with adipocyte metabolism. For example, the thiazolidinediones, a class of oral anti-diabetic agents that reduce insulin resistance and improve b-cell function, might mediate these effects by regulating adipocyte-derived factors, in particular TNF-a and FFAs. There is a global epidemic of obesity and diabetes. In the USA, for example, estimates from the large-scale Behavioural Risk Factor Surveillance System (BRFSS) indicated prevalences for obesity and diabetes of 19.8% and 7.3%, respectively, among US adults in 2000 [1]. Compared with estimates of 12.0% for obesity and 5.0% for diabetes in 1991, these figures represent a 50% increase in just under a decade [1,2]. Furthermore, BRFSS data collected from , 150 000 individuals between 1990 and 1998 demonstrated a high correlation between the prevalence of diabetes and the prevalence of obesity (r ¼ 0:64; P , 0:001) [2], supporting the proposal that the increase in diabetes prevalence could be driven by the rising tide of obesity. These results are supported further by findings from the Australian Diabetes, Obesity and Lifestyle Study (AusDiab). Data from . 11 000 subjects indicated a total prevalence (including both known and newly diagnosed diabetes cases) of 7.4%, with an additional 16.4% having abnormal glucose tolerance (either impaired glucose tolerance or impaired fasting glucose) [3]. As with the BRFSS data, findings from the AusDiab study indicated that the escalating numbers of diabetes cases probably result from Corresponding author: P. Arner ([email protected]).

increases in the longevity of the population, coupled with rises in obesity and physical inactivity [3]. Furthermore, it is even more alarming to note that the parallel increases in obesity and diabetes prevalence observed in adults might also be applicable to younger age groups. In AusDiab, the prevalence of abnormal glucose tolerance was found to be high in younger individuals (5.7% prevalence in subjects aged 25 – 34 years) [3] and, globally, it is estimated that , 22 million children under the age of five years are overweight or obese [4]. Childhood obesity is directly linked with increases in the risk of type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD) [5]. What causes this strong and consistent association between obesity and the development of T2DM and CVD? The relationship between obesity and insulin resistance has been likened to a cause and effect association, because weight loss or gain correlates closely with increasing or decreasing insulin sensitivity [6– 9]. Insulin resistance, in turn, is a major underlying factor contributing to the development of T2DM, with skeletal muscle, liver, adipose tissue and pancreas representing important sites of insulin resistance in diabetic individuals. Although earlier reports implicated skeletal muscle as the major site of insulin resistance [10], adipose tissue is now recognized by many as the primary site [11]. In particular, the visceral compartment has been identified as an important contributor to insulin resistance and its related syndrome, the insulin resistance syndrome or metabolic syndrome [12]. Furthermore, visceral depots of fat are much more strongly linked to T2DM and CVD than are subcutaneous fat depots [13]. Here, I review some of the recently defined key processes involved in adipocyte biology that might contribute to the development of insulin resistance, and discuss novel therapeutic interventions that target these factors, and which might therefore have a role in ameliorating insulin resistance in adipose tissue. According to Medline, there are currently .1500 original articles dealing with adipose tissue and insulin resistance. Therefore, in the interest of space, review articles will be utilized wherever possible. Adipose tissue physiology Traditionally, the major function of adipose tissue is considered to be energy storage. When fuel is required

http://tem.trends.com 1043-2760/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved. doi:10.1016/S1043-2760(03)00024-9

138

Review

TRENDS in Endocrinology and Metabolism

(e.g. during periods of fasting, starvation, or long-term muscle work) free fatty acids (FFAs) are released from adipose triglyceride stores into the circulation by lipolysis and oxidized, primarily by skeletal muscle, to provide energy. However, there is increasing evidence to suggest that adipose tissue also plays an important part in other physiological processes; for example, as an endocrine organ [14]. Adipocytes secrete proteins involved in a variety of functions, including glucose homeostasis, inflammation, energy balance, lipid metabolism and the fibrinolytic system/vascular haemostasis (Table 1), many of which are regulated by insulin. Adipose tissue can be divided into two major compartments – subcutaneous and visceral fat – which vary both in their distribution and metabolism. The subcutaneous and visceral compartments constitute ,80% and 10% of total body fat, respectively [15], with other depots, such as retroperitoneal, perirenal and orbital fat, accounting for the remainder. Individuals with central obesity (intraabdominal or visceral fat) have an increased risk of metabolic and cardiovascular complications, whereas those with peripheral obesity (subcutaneous fat) are at low risk. This is linked with regional differences in the rates of lipolysis between the two compartments. In visceral adipocytes, release of FFAs from stored triglycerides is higher than in subcutaneous fat, where antilipolytic hormones, such as insulin, have a more pronounced effect but the lipolytic catecholamines have a less pronounced effect [15]. Because visceral fat drains into the portal vein, rapid visceral lipid metabolism results in the delivery of high FFA concentrations to the liver. This, in turn, leads to stimulation of gluconeogenesis, increased triglyceride synthesis and inhibition of insulin clearance – ultimately resulting in the development of dyslipidaemia, hyperglycaemia and hyperinsulinaemia, which are collectively associated with increased cardiovascular risk [15]. How do increases in circulating factors related to visceral adiposity lead to insulin resistance and related conditions, such as T2DM and CVD? It appears that their impact on insulin signalling pathways in adipose and other insulin-sensitive tissues could play a major role.

Vol.14 No.3 April 2003

Insulin resistance in the adipocyte: the role of insulin signalling Insulin is a crucial regulator of adipose function, with a wide range of actions (e.g. stimulating the differentiation of pre-adipocytes to adipocytes and, in mature adipocytes, enhancing glucose transport and triglyceride synthesis, in addition to inhibiting lipolysis). How does insulin cause these multiple effects? Binding of insulin to its receptor triggers a cascade of signalling events that are strongly conserved across a range of species and in a variety of tissue types. Although downstream elements of the insulinsignalling cascade are generally tissue specific, many of the upstream components are highly conserved [16]. A brief review of insulin signalling in the adipocyte is provided in Fig. 1a, and more detail is given in additional reviews [17 – 19]. In insulin resistance, normal insulin signalling in the adipocyte is impaired, leading to a decrease in insulin-mediated glucose uptake and metabolism (Fig. 1b). What factors in adipose tissue are responsible for overall insulin resistance in obesity? Several factors secreted from adipose tissue, such as tumour necrosis factor a (TNF-a) and FFAs, have been reported to influence insulin signalling in individuals with an increase in adipose mass (more specifically, those with increased visceral fat). Adipose tissue factors involved in insulin resistance TNF-a Adipose tissue synthesizes several cytokines and growth factors, including TNF-a, interleukin 6 and transforming growth factor b. In particular, TNF-a is a key modulator of adipocyte metabolism, with a direct role in several insulinmediated processes, including glucose homeostasis and lipid metabolism [20]. For example, TNF-a regulates the production of several adipocyte-derived factors involved in lipid uptake/metabolism, including lipoprotein lipase (LPL), fatty acid transport protein (FATP) and acetyl CoA synthase (ACS) [20] (Figs 2,3). The net effect of TNF-a is to decrease lipogenesis (FFA uptake and triglyceride synthesis) and to increase lipolysis. TNF-a also regulates the formation of leptin, plasminogen activator inhibitor 1,

Table 1. Factors secreted from the adipocytea Function

Factor(s) released from adipocyte

Inflammatory cytokines

Tumour necrosis factor a Interleukin 6 Transforming growth factor b Free fatty acids Adiponectin Resistin Leptin Plasminogen activator inhibitor 1 Lipoprotein lipase Fatty acid transport protein Acyl-CoA synthetase Cholesteryl ester transfer protein Apolipoprotein E Retinol-binding protein Adipsin Acylation-stimulating protein Angiotensinogen (and other compounds of the renin –angiotensin system)

Energy/signalling Glucose homeostasis Energy balance Fibrinolysis/vascular haemostasis Lipid and lipoprotein uptake/metabolism

Alternative complement system Maintaining vascular tone a

In addition to its conventional role in energy storage, adipose tissue also has a major endocrine function. Some key factors released from the adipocyte are listed here and are reviewed in more detail in [14,20].

http://tem.trends.com

Review

TRENDS in Endocrinology and Metabolism

Insulin

(a)

139

Vol.14 No.3 April 2003

Insulin

(b)

Insulin receptor Insulin receptor

TNF-α

Adipocyte IRS proteins

Adipocyte IRS proteins

TNF-α/FFA

PI 3-kinase

Activation of protein kinases (e.g. Akt/PKB)

Increased translocation of GLUT4 glucose transporters to the cell surface

PI 3-kinase

TNF-α/FFA

Ceramide

Activation of protein kinases (e.g. Akt/PKB)

Decreased translocation of GLUT4 glucose transporters to the cell surface

TNF-α Increased glucose uptake into the adipocyte via GLUT4

Decreased glucose uptake into the adipocyte via GLUT4 TRENDS in Endocrinology & Metabolism

Fig. 1. Insulin signalling in the adipocyte. (a) In insulin-sensitive adipocytes, insulin binds to its receptor and activates the insulin receptor tyrosine kinase, leading to phosphorylation/activation of insulin receptor substrate (IRS) proteins and stimulation of phosphatidylinositol 3-kinase (PI 3-kinase). Although PI 3-kinase activation is required for insulin-mediated stimulation of glucose transport, other pathways might also be necessary [17]. In turn, PI 3-kinase activates downstream protein kinases, including Akt/PKB [17,18]. Other pathways that operate downstream of PI 3-kinase and are implicated in adipocyte insulin signalling include protein kinase C l/j, p70 S6-kinase, 4EBP1/PHAS1 and the ras –mitogen-activated protein kinase pathway (not shown) [17,18]. Ultimately, these signalling events lead to stimulation of insulin-mediated glucose uptake into adipocytes via enhanced translocation of glucose transporter 4 (GLUT4) molecules to the cell membrane, leading to an increase in adipocyte glucose uptake [18]. In addition, the transcription factor, adipocyte determination and differentiation factor-1/sterol regulatory element-binding protein-1c, appears to play a crucial role in mediating the effects of insulin on adipocyte differentiation, inducing genes involved in lipogenesis and repressing those involved in fatty acid oxidation (not shown) [17]. As regards the antilipolytic effect of insulin [18,19], the activation of PI 3-kinase stimulates phosphodiesterase-3 so that more cAMP is metabolized in fat cells. This decreases phosphorylation of hormone-sensitive lipase, which in turn makes the triglyceride hydrolysing enzyme less active, so that the lipolytic activity in fat cells decreases. (b) In insulin-resistant adipocytes, the insulin signal is reduced at several stages, including insulin receptor binding, phosphorylation and tyrosine kinase activity, phosphorylation of IRS proteins, activation of downstream insulin-sensitive protein kinases (e.g. Akt/PKB) by PI 3-kinase, and the synthesis/translocation of GLUT4 glucose transporters to the adipocyte plasma membrane [17]. The resistance to glucose metabolism is more marked than resistance to lipolysis in human fat cells. Furthermore, in human fat cells, it appears that a decrease in the activity of IRS-1 is of particular importance for the insulin resistance seen in type 2 diabetes and obesity [23,65]. Circulating factors released from the adipocyte [e.g. tumour necrosis factor a (TNF-a) and free fatty acids (FFAs)] appear to play a role in the development of adipocyte insulin resistance by inhibiting insulin signalling.

adipocyte fatty acid-binding protein (aP2) and glucose transporter 4 (GLUT4), and might have a role in regulating the synthesis of Gi proteins and perilipin, although further confirmation is awaited [20]. TNF-a is a major contributor to the development of adipose tissue insulin resistance [20]. In obese individuals and subjects with T2DM, TNF-a levels are raised and correlate with high plasma insulin levels and decreased insulin sensitivity. In adipose tissue of obese humans, there is a strong inverse correlation between secretion of TNF-a and insulin-stimulated glucose metabolism [21]. Further support comes from studies of obese rats, where neutralization of TNF-a improved insulin sensitivity, and of humans, where weight loss correlated with decreased plasma TNF-a levels and increased insulin sensitivity, although administration of TNF-a antibody did not improve http://tem.trends.com

insulin sensitivity in obese T2DM patients [20]. One mechanism by which raised TNF-a concentrations might induce insulin resistance is via changes in the insulin signalling pathway (Fig. 1b). Chronic administration of TNF-a has been shown to downregulate several steps in the adipocyte insulin signalling cascade, leading to decreases in insulin receptor tyrosine kinase activity, insulin receptor substrate 1 (IRS-1) phosphorylation and GLUT4 synthesis/translocation [22]. In addition to its direct effects in adipose tissue, TNF-a secreted from adipose tissue might also have a role in the development of muscle and liver insulin resistance, although such effects are not clearly established in humans as opposed to animal models [22]. However, although TNF-a is a major contributor to the development of insulin resistance in fat cells, other indirect factors are also involved. For example,

Review

140

TRENDS in Endocrinology and Metabolism

(a)

(b)

+

TG

Vol.14 No.3 April 2003

FFA

–

TG

FFA –

+ LPL Nucleus PPARγ + Gene transcription +

LPL Nucleus

FATP

+

Protein synthesis

+

+

ACS

Gene transcription +

Adipocyte

FFA

–

Protein synthesis –

TG Adipocyte

FATP

–

PPARγ +

FFA

+

–

ACS

–

TG

TNF-α

TRENDS in Endocrinology & Metabolism

Fig. 2. Lipid metabolism/uptake in the adipocyte. (a) Normal regulation. Peroxisome proliferator-activated receptor g (PPARg) enhances the storage of free fatty acids (FFAs) as triglycerides (TGs) in adipocytes by activating the production of proteins involved in lipid metabolism/uptake, including lipoprotein lipase (LPL), fatty acid transport protein (FATP) and acetyl CoA-synthase (ACS). LPL acts on plasma TGs to release FFAs, which are transported into adipocytes by FATP and converted to TGs by ACS. Adapted, with permission, from [15]. (b) Effect of increased tumour necrosis factor a (TNF-a) production. In insulin resistance, TNF-a antagonizes the production of LPL, FATP and ACS, leading to decreased FFA uptake/TG metabolism.

TNF-a stimulates the expression of mediators, such as FFAs and leptin, which might induce insulin resistance in other organs [20]. In particular, the ability of TNF-a to stimulate adipocyte lipolysis and thereby increase the mobilization of FFAs from adipose tissue could be an important indirect mechanism of TNF-a-mediated insulin resistance. FFAs and intracellular lipid accumulation Chronically raised FFA levels are associated with obesity and T2DM. It has been proposed that FFAs might provide

TNF-α FFA

Fat cell TNFR1 Gi Nucleus

+

+

– MAPK

–

Gene – transcription

mRNA

+

+

Protein synthesis –

+

TG

Perilipin

TRENDS in Endocrinology & Metabolism

Fig. 3. Tumour necrosis factor a (TNF-a) stimulation of lipolysis in human fat cells. TNF-a binds to one of its two receptors (TNFR1). This activates mitogen-activated protein kinases (MAPKs) which, in turn, decreases the production of both the antilipolytic Gi protein and perilipin (a chaperone-like protein that protects hormone-sensitive lipase from being phosphorylated and activated). The Gi effect increases cAMP levels, so that more hormone-sensitive lipase becomes phosphorylated. Both of these effects of TNF-a promote lipolysis. Filled arrows, stimulation; broken arrows, inhibition. Abbreviations: FFA, free fatty acid; TG, triglyceride. http://tem.trends.com

the link between these conditions [23– 25], highlighting the central role of the adipocyte in the development of insulin resistance. In individuals with visceral obesity, there is a decrease in the insulin-mediated suppression of lipolysis, leading to increases in circulating FFA concentrations that contribute to both peripheral and hepatic insulin resistance by impairing insulin signalling pathways (Fig. 1b). For example, in muscle, raised FFA concentrations appear to decrease insulin-mediated glucose transport by modifying upstream signalling events, leading to reduced translocation of GLUT4 [25]. Potential targets for FFA-mediated inhibition of glucose transport include IRS-1 and protein kinase C u, a key molecule involved in insulin signalling in skeletal muscle [25,26]. In addition, raised FFAs contribute to insulin resistance by impairing muscle glucose uptake via competitive inhibition. In liver, raised FFAs can stimulate endogenous glucose production, thus contributing to hepatic insulin resistance, although the mechanism is not yet clearly understood [25]. FFAs might also inhibit insulin action in muscle and liver by altering insulin receptor signalling [15,24,25]. Intracellular lipid accumulation has also been shown to inhibit insulin signalling. In vivo studies suggest that accumulation of intramyocellular triglycerides is strongly associated with insulin resistance in human muscle [27]. In transgenic mice in which the normal development of adipose tissue is prevented, leading to abnormal fat deposition or lipodystrophy, severe insulin resistance develops [25]. These mice have increased intracellular lipid content in both muscle and liver, accompanied by a reduced response to IRS-1 and phosphatidylinositol 3-kinase (PI 3-kinase) activity. Transplantation of normal adipose tissue also leads to restoration of insulin signalling and intracellular lipid content to normal levels, supporting the proposal that intracellular lipid accumulation leads to abnormal insulin signalling and insulin resistance [25].

Review

TRENDS in Endocrinology and Metabolism

Further evidence comes from studies of transgenic mice that overexpress the gene encoding LPL in muscle. In these animals, a threefold increase in intramyocellular triglyceride concentrations was associated with insulin resistance, caused by decreases in insulin-stimulated glucose transport and insulin activation of IRS-1-associated PI 3-kinase activity [25]. Emerging factors: adiponectin and resistin More recently, additional factors – adiponectin and resistin – have become of great interest because of their potential roles in both obesity and T2DM [28]. Adiponectin is a circulating protein produced by adipose tissue that has anti-inflammatory and anti-atherogenic properties. Serum levels of adiponectin are decreased in obesity and T2DM, and weight loss leads to increased adiponectin levels in humans [28]. Although the regulatory processes affecting adiponectin production have not yet been fully characterized, TNF-a has been reported to repress its synthesis [28]. Adiponectin appears to increase insulin sensitivity by improving glucose and lipid metabolism. In animal models of obesity and diabetes, adiponectin affected both skeletal muscle and liver, promoting fatty acid oxidation in muscle and inhibiting glucose production from the liver, thereby leading to decreases in circulating FFA, triglyceride and glucose levels [28]. Plasma adiponectin levels are also reduced in patients with coronary heart disease, and adiponectin decreases the synthesis of endothelial adhesion molecules and inhibits inflammatory responses [28]. These effects suggest a potential role for adiponectin in preventing atherosclerosis, in addition to its beneficial impact on glucose and lipid homeostasis, although the specific receptor mediating the biological activities of adiponectin remains unidentified. Another recently identified circulating factor that is specifically found in adipose tissue, resistin, has been reported to induce insulin resistance and impair glucose tolerance [29]. Although its precise function is not yet known, animal studies suggest that resistin is involved in the regulation of adipocyte differentiation and is a key signal in the induction of insulin resistance. The nature of the resistin receptor is still unknown. Leptin Leptin has been proposed to play a major role in obesity and insulin resistance [30]. Leptin is secreted principally, but not exclusively, by adipocytes and acts both centrally and peripherally, with a major role in the regulation of food uptake, body weight and energy balance (for a detailed review, see [31]). Leptin also acts as a signal for reproduction, angiogenesis and the immune system, and has been reported to affect processes ranging from inhibition of b-cell insulin secretion to stimulation of sugar transport and platelet aggregation. Several suggestions have been made for a unifying function for leptin, including a primary role as a starvation signal or a regulator of FFA homeostasis. In terms of the link with insulin resistance, recent data indicate that circulating leptin levels correlate with subcutaneous, rather than intra-abdominal, fat deposition, whereas intra-abdominal fat accumulation correlates with insulin resistance [32]. http://tem.trends.com

Vol.14 No.3 April 2003

141

Lipotoxicity and b-cell dysfunction b-Cell dysfunction is a major factor in the development and progression of T2DM. Factors released from adipose tissue that contribute to insulin resistance, such as FFAs and TNF-a, might also play a role in the characteristic decline in b-cell function. For example, there is a growing body of evidence to support the proposal that chronically raised FFAs have a lipotoxic effect on the pancreas [25]. One mechanism by which FFAs might cause b-cell dysfunction is via increased production of nitric oxide (NO), leading to b-cell apoptosis [25]. In addition, lipid accumulation in b cells might lead to reductions in insulin secretion [25]. There is also evidence that TNF-a contributes to b-cell dysfunction and increases sensitivity to b-cell toxicity. As with FFAs, these effects might be mediated, at least in part, by increasing NO formation [22]. Furthermore, TNF-a has been implicated in the development of insulin resistance in the pancreas. The mechanisms by which TNF-a appears to decrease b-cell insulin signalling are currently under investigation [22]. Given that these factors could provide a common link between insulin resistance and b-cell dysfunction, it has been proposed that reductions in FFA and TNF-a levels should be a therapeutic target in patients with T2DM [22,25]. Species differences in adipocyte function Most of our knowledge about fat cell function is derived from animal studies, in particular studies on rodents. However, some caution should be exercised when extrapolating these data to human fat cells because there are several species differences, the most important of which are described in Table 2. Impact of thiazolidinediones on the adipocyte Role of peroxisome proliferator-activated receptor g Peroxisome proliferator-activated receptor g (PPARg) is a nuclear receptor with a major role in the regulation of adipocyte differentiation and lipid metabolism [33,34]. Most abundant in adipose tissue, PPARg is also found at low levels in liver, muscle, pancreas, breast, colon, prostate and in vascular cells, including smooth muscle cells, endothelial cells, monocytes, macrophages and foam cells [33 –35]. Together with the retinoid X receptor, PPARg binds to DNA as a heterodimer, acting as a transcription factor to regulate the production of proteins involved in lipid and glucose metabolism. To date, several genes have been identified as being direct targets for PPARg; for example, genes encoding LPL, FATP, ACS (Fig. 2), aP2, adipophilin, phosphoenolpyruvate carboxykinase and liver X receptor a [34]. Furthermore, numerous genes are currently under investigation as potential targets for PPARg, including those encoding resistin and IRS-2 [34]. As a central regulator of adipogenesis, PPARg regulates the differentiation of pre-adipocytes to adipocytes in cooperation with other transcription factors. In addition, it is involved in modulating insulin sensitivity and regulating the endocrine functions of adipose tissue, and activation of PPARg might even have a role in reversing atherogenicity [34].

142

Review

TRENDS in Endocrinology and Metabolism

Vol.14 No.3 April 2003

Table 2. Species differences in adipocyte functiona Factor

Humans

Rodents

Refs

De novo fatty acid synthesis from glucose Adrenoceptors involved in lipolysis regulation

Small or absent Utilize lipolytic b1-, b2- and (to some extent) b3-adrenoceptors in addition to the antilipolytic a2A-adrenoceptors IRS-1, IRS-2 (lack IRS-3)

Prominent Usually lack the a2A-receptor and predominantly use the lipolytic b3-receptor

[56] [57]

At least three IRS molecules are functional (IRS-1, IRS-2, IRS-3) Autocrine and peripheral (endocrine) effects

[16,58]

Utilizes different pathways from humans Major role One form of HSL

[60] [55] [61,62]

Important for thermogenesis in adult life

[63]

Less marked regional variations

[64]

IRS molecules involved in insulin action TNF-a secretion

TNF-a signalling Resistin HSL

Brown fat cells Regional variations

a

Little in vivo release of TNF-a from adipose tissue. Most of the cytokine seems to be used locally, providing autocrine effects Through MAPK No or minor role Two isoforms of HSL, one of which is unique to humans and might be of pathophysiological importance in insulinresistant conditions Less important in adults but abundant at onset of life Marked differences between subcutaneous and visceral depots in metabolic and endocrine activities

[59]

Abbreviations: HSL, hormone-sensitive lipase; IRS, insulin receptor substrate; MAPK, mitogen-activated protein kinase; TNF-a, tumour necrosis factor a.

Impact of PPARg agonists on adipose tissue Given the roles played by PPARg in adipose tissue and other organs, it is logical to assume that agonists of PPARg will have a beneficial action in insulin resistant individuals affected by, or at high risk of, T2DM and/or CVD. One group of PPARg agonists, the thiazolidinediones (TZDs), has been shown to decrease insulin resistance and impact on a range of factors associated with adipocyte metabolism. To date, three TZDs (troglitazone, rosiglitazone and pioglitazone) have been approved for the treatment of T2DM. Although troglitazone was withdrawn from the market because of drug-related hepatotoxicity, the last two agents are not associated with adverse effects on the liver [36] and are commonly used in clinical practice. These agents decrease hyperglycaemia by directly reducing insulin resistance, leading to increased glucose uptake into skeletal muscle and adipose tissue, and decreased hepatic glucose output. Furthermore, the TZDs appear to improve b-cell function in the pancreas [37,38]. In adipose tissue, the TZDs promote adipocyte differentiation, leading to the production of smaller, more insulin-sensitive fat cells [15]. Although some data have indicated that the TZDs have depot-specific effects [39], more recent findings suggest that their impact on preadipocyte differentiation is equivalent in subcutaneous and visceral depots [40]. However, in vivo, the TZDs have been shown to increase subcutaneous, but not visceral, adipose tissue. This effect on subcutaneous fat could account for part of the modest weight gain that is observed with TZD therapy, although, importantly, there is no increase in the visceral compartment [41– 43], which is the only fat depot that is strongly associated with insulin resistance and increased cardiovascular risk. In fact, in a study of patients with T2DM, rosiglitazone was shown to decrease visceral fat by , 10%, indicating a reduction in cardiovascular risk [41]. In addition, the TZDs have other important effects in adipose tissue, such as influencing FFA and triglyceride metabolism. By activating PPARg, http://tem.trends.com

TZDs increase the synthesis of LPL, FATP and ACS, which have important roles in triglyceride lipolysis, FFA transport and conversion of FFAs to triglycerides, respectively [15] (Fig. 2). Overall, these effects lead to increases in plasma triglyceride breakdown and adipocyte FFA storage, while the TZDs also reduce triglyceride metabolism in adipocytes via decreases in TNF-a and hormone-sensitive lipase activity (for more details, see [15]). A key question since the discovery of the TZD class of PPARg agonists has been: how does the activation of a receptor found predominantly in adipocytes lead to a wide range of effects impacting on skeletal muscle, liver and pancreas in addition to adipose tissue? One way in which the TZDs achieve this is by altering the endocrine functions of adipose tissue; for example, modulation of factors released from the adipocyte (e.g. TNF-a, FFA, adiponectin, leptin and resistin) might lead to effects in other organs [44]. In addition, TZDs might alter the autocrine effects of these factors within adipocytes [44]. As described above, increases in adipocyte TNF-a levels are seen in obesity and T2DM, resulting in reduced insulin signalling and decreased uptake of glucose and FFAs into adipose tissue. TZDs might interfere with TNF-a activity by three main mechanisms: by decreasing circulating TNF-a levels, by antagonizing TNF-a-mediated inhibition of insulin signalling and by reducing TNF-a stimulation of lipolysis in fat cells. First, experiments carried out in rodents and in human adipocytes indicate a reduction in TNF-a with TZD administration [34,40,45]. For example, rosiglitazone has recently been shown to inhibit the synthesis and secretion of TNF-a in human pre-adipocytes [40]. Second, TZDs appear to affect adipocyte insulin signalling via several mechanisms (e.g. by reducing the inhibitory effect of TNF-a on insulin receptor and IRS-1 signalling, and increasing the synthesis of IRS-2 and the p85 subunit of PI 3-kinase [34]). To date, there is no evidence that the TZDs lower plasma TNF-a levels in humans [46], although local concentrations of TNF-a, such

Review

PBO

RSG (8 mg d–1)

143

Vol.14 No.3 April 2003

∗

∗∗

3 Time (months)

6

25

0 -1 -2 -3 -4 -5

*

*

-6

(b) Mean change from baseline in plasmafree fatty acids (mg dl-1)

RSG (4 mg d–1)

MET + PBO

MET + RSG (4 mg d–1)

MET + RSG (8 mg d–1)

0 -1

Plasma adiponectin (µg ml-1)

Mean change from baseline in plasma free fatty acids (mg dl-1)

(a)

TRENDS in Endocrinology and Metabolism

20

15

10

5

0

0

TRENDS in Endocrinology & Metabolism

-2 Fig. 5. Impact of rosiglitazone on plasma adiponectin in patients with type 2 diabetes mellitus. Mean of plasma adiponectin levels at baseline and after three and six months’ treatment with rosiglitazone. White bars, placebo group; black bars, rosiglitazone group. Error bars: standard error of mean, *P , 0.05, **P , 0.01. Reproduced, with permission, from [51].

-3 -4

**

-5 -6

** TRENDS in Endocrinology & Metabolism

Fig. 4. Impact of rosiglitazone (RSG) on plasma free fatty acids. RSG produced significant reductions from baseline in circulating free fatty acid levels in patients with type 2 diabetes mellitus, either in monotherapy (a) or in combination with metformin (MET) (b), whereas changes in the placebo (PBO) group were not significant. Error bars: standard error of mean, *P , 0.05, **P , 0.001 from baseline. Data taken from [37] and [47], respectively.

as in adipose tissue, might be more important than circulating levels. Furthermore, the impact of the TZDs on TNF-a signalling, in addition to its synthesis and secretion, should also be taken into consideration. The TZDs also produce significant reductions in circulating levels of FFAs, which might play a vital role in their dual effects of improving both insulin sensitivity and b-cell function [25]. For example, rosiglitazone, either in monotherapy or in combination with other agents, decreases plasma FFA levels in patients with T2DM (Fig. 4) [37,47,48]. Importantly, these decreases in plasma FFA levels are sustained for at least 30 months [49]. Recently, it was shown that rosiglitazone therapy improved the antilipolytic effect of insulin in vivo in adipose tissue of patients with T2DM [50]. In parallel with this effect, the TZDs might also induce redistribution of intracellular lipid from skeletal muscle, liver and pancreas to peripheral adipocytes, leading to restoration of insulin signalling in these tissues [25]. The TZDs appear to have a significant influence on the circulating levels of adiponectin and resistin. In a study of patients with T2DM taking rosiglitazone or placebo, plasma adiponectin levels more than doubled from baseline after six months of treatment with rosiglitazone, whereas no difference was seen in those on placebo (Fig. 5) [51]. Because preclinical studies have indicated that http://tem.trends.com

adiponectin has anti-inflammatory and anti-atherogenic effects, this might contribute to the proposed benefits of PPARg agonists in reducing factors associated with inflammation and atherogenicity [52]. In addition, in adipocytes, rosiglitazone downregulates the production of resistin and also blocks its secretion, which is stimulated by insulin in the absence of rosiglitazone [53,54]. No data are currently available to confirm whether the same is true in clinical studies. Furthermore, the role of resistin in human physiology and pathophysiology remains to be established [55]. Finally, it is important to note that most studies of TZD action have been conducted on animal models. Bearing in mind the species differences in adipocyte function discussed above, it is possible that some TZD effects are unique or absent in humans. Conclusions Correlations between the global epidemics of obesity and T2DM have encouraged investigation into potential molecular links between the related impairments in lipid and glucose homeostasis. Key molecules in adipose tissue have been identified that could have far-reaching effects in other insulin-sensitive tissues, such as skeletal muscle, liver and pancreas. For example, PPARg appears to have a central role in regulating adipocyte function and modulating the circulating concentrations and/or intracellular actions of molecules such as FFA and TNF-a, which in turn leads to effects on other organs. Agents that activate PPARg, such as the TZDs, appear to ameliorate insulin resistance by modifying levels of these circulating factors, in particular FFAs, leading to restoration of insulin signalling in the adipocyte and other tissues, and thus maintaining lipid and glucose homeostasis. In addition, the TZDs decrease lipotoxicity, which

144

Review

TRENDS in Endocrinology and Metabolism

might explain, at least in part, their beneficial action on b-cell function. By targeting adipocyte factors to achieve the dual effect of decreasing insulin resistance while improving b-cell function, the TZDs might have the potential to delay disease progression. References 1 Mokdad, A.H. et al. (2001) The continuing epidemics of obesity and diabetes in the United States. J. Am. Med. Assoc. 286, 1195 – 1200 2 Mokdad, A.H. et al. (2000) Diabetes trends in the U.S.: 1990– 1998. Diabetes Care 23, 1278– 1283 3 Dunstan, D.W. et al. (2002) The rising prevalence of diabetes and impaired glucose tolerance: the Australian Diabetes, Obesity and Lifestyle Study. Diabetes Care 25, 829– 834 4 Deckelbaum, R.J. and Williams, C.L. (2001) Childhood obesity: the health issue. Obes. Res. 9, 239S – 243S 5 Rocchini, A.P. (2002) Childhood obesity and a diabetes epidemic. N. Engl. J. Med. 346, 854– 855 6 Sims, E.A. et al. (1973) Endocrine and metabolic effects of experimental obesity in man. Recent Prog. Horm. Res. 29, 457 – 496 7 Beck-Nielsen, H. et al. (1979) Normalization of the insulin sensitivity and the cellular insulin binding during treatment of obese diabetics for one year. Acta Endocrinol. (Copenh.) 90, 103– 112 8 Freidenberg, G.R. et al. (1988) Reversibility of defective adipocyte insulin receptor kinase activity in non-insulin-dependent diabetes mellitus. Effect of weight loss. J. Clin. Invest. 82, 1398– 1406 9 Bak, J.F. et al. (1992) In vivo insulin action and muscle glycogen synthase activity in type 2 (non-insulin-dependent) diabetes mellitus: effects of diet treatment. Diabetologia 35, 777– 784 10 DeFronzo, R.A. et al. (1992) Pathogenesis of NIDDM. A balanced overview. Diabetes Care 15, 318 – 368 11 Hotamisligil, G.S. (2000) Molecular mechanisms of insulin resistance and the role of the adipocyte. Int. J. Obes. Relat. Metab. Disord. 24, S23– S27 12 Bergman, R.N. et al. (2001) Central role of the adipocyte in the metabolic syndrome. J. Investig. Med. 49, 119 – 126 13 Arner, P. (1997) Regional adipocity in man. J. Endocrinol. 155, 191 – 192 14 Trayhurn, P. and Beattie, J.H. (2001) Physiological role of adipose tissue: white adipose tissue as an endocrine and secretory organ. Proc. Nutr. Soc. 60, 329 – 339 15 Arner, P. (2001) Free fatty acids – do they play a central role in type 2 diabetes? Diabetes Obes. Metab. 3, 11 – 19 16 Rhodes, C.J. and White, M.F. (2002) Molecular insights into insulin action and secretion. Eur. J. Clin. Invest. 32, 3 – 13 17 Kahn, B.B. and Flier, J.S. (2000) Obesity and insulin resistance. J. Clin. Invest. 106, 473 – 481 18 Summers, S.A. et al. (2000) Insulin signaling in the adipocyte. Int. J. Obes. Relat. Metab. Disord. 24, S67 – S70 19 Smith, U. et al. (1999) Insulin signaling and action in fat cells: associations with insulin resistance and type 2 diabetes. Ann. New York Acad. Sci. 892, 119 – 126 20 Sethi, J.K. and Hotamisligil, G.S. (1999) The role of TNFa in adipocyte metabolism. Semin. Cell Dev. Biol. 10, 19 – 29 21 Lo¨fgren, P. et al. (2000) Secretion of tumor necrosis factor-a shows a strong relationship to insulin-stimulated glucose transport in human adipose tissue. Diabetes 49, 688 – 692 22 Greenberg, A.S. and McDaniel, M.L. (2002) Identifying the links between obesity, insulin resistance and b-cell function: potential role of adipocyte-derived cytokines in the pathogenesis of type 2 diabetes. Eur. J. Clin. Invest. 32, 24– 34 23 Carvalho, E. et al. (1999) Low cellular IRS 1 gene and protein expression predict insulin resistance and NIDDM. FASEB J. 13, 2173 – 2178 24 Arner, P. (2002) Insulin resistance in type 2 diabetes: role of fatty acids. Diabetes Metab. Res. Rev. 18, S5– S9 25 Boden, G. and Shulman, G.I. (2002) Free fatty acids in obesity and type 2 diabetes: defining their role in the development of insulin resistance and b-cell dysfunction. Eur. J. Clin. Invest. 32, 14 – 23 26 Idris, I. et al. (2002) Insulin action in skeletal muscle: isozyme-specific effects of protein kinase C. Ann. New York Acad. Sci. 967, 176 – 182 27 Kelley, D.E. (2002) Skeletal muscle triglycerides: an aspect of regional http://tem.trends.com

28

29 30 31 32

33 34

35

36

37 38

39

40

41

42

43

44 45

46

47

48

49

50

51

52

Vol.14 No.3 April 2003

adiposity and insulin resistance. Ann. New York Acad. Sci. 967, 135– 145 Holst, D. and Grimaldi, P.A. (2002) New factors in the regulation of adipose differentiation and metabolism. Curr. Opin. Lipidol. 13, 241– 245 Steppan, C.M. et al. (2001) The hormone resistin links obesity to diabetes. Nature 409, 307– 312 Girard, J. (1997) Is leptin the link between obesity and insulin resistance? Diabetes Metab. 23, 16– 24 Trayhurn, P. et al. (1999) Leptin: fundamental aspects. Int. J. Obes. Relat. Metab. Disord. 23, 22 – 28 Cnop, M. et al. (2002) The concurrent accumulation of intra-abdominal and subcutaneous fat explains the association between insulin resistance and plasma leptin concentrations: distinct metabolic effects of two fat compartments. Diabetes 51, 1005 – 1015 Spiegelman, B.M. (1998) PPAR-g: adipogenic regulator and thiazolidinedione receptor. Diabetes 47, 507 – 514 Walczak, R. and Tontonoz, P. (2002) PPARadigms and PPARadoxes. Expanding roles for PPARg in the control of lipid metabolism. J. Lipid Res. 43, 177 – 186 Masamune, A. et al. (2002) Ligands of peroxisome proliferatoractivated receptor-g block activation of pancreatic stellate cells. J. Biol. Chem. 277, 141 – 147 Lebovitz, H.E. (2002) Differentiating members of the thiazolidinedione class: a focus on safety. Diabetes Metab. Res. Rev. 18 (Suppl. 2), S23– S29 Lebovitz, H.E. et al. (2001) Rosiglitazone monotherapy is effective in patients with type 2 diabetes. J. Clin. Endocrinol. Metab. 86, 280 – 288 Miyazaki, Y. et al. (2002) Dose – response effect of pioglitazone on insulin sensitivity and insulin secretion in type 2 diabetes. Diabetes Care 25, 517 – 523 Adams, M. et al. (1997) Activators of peroxisome proliferator-activated receptor g have depot-specific effects on human preadipocyte differentiation. J. Clin. Invest. 100, 3149– 3153 Van Harmelen, V. et al. (2002) Increased lipolysis and decreased leptin production by human omental as compared with subcutaneous preadipocytes. Diabetes 51, 2029 – 2036 Kelley, D.E. et al. (2002) Comparative effects of rosiglitazone and metformin on fatty liver and visceral adiposity in type 2 diabetes mellitus. Diabetes 51, A35 Virtanen, K.A. et al. (2002) Different effects of rosiglitazone and metformin on adipose tissue glucose uptake in type 2 diabetes. Diabetes 51, A145 Banerji, M. et al. (2001) Rosiglitazone selectively increases subcutaneous but not visceral adipose tissue mass in type 2 diabetes mellitus. Diabetes 50, A90 Wagstaff, A.J. and Goa, K.L. (2002) Rosiglitazone: a review of its use in the management of type 2 diabetes mellitus. Drugs 62, 1805 – 1837 McTernan, P.G. et al. (2002) Insulin and rosiglitazone regulation of lipolysis and lipogenesis in human adipose tissue in vitro. Diabetes 51, 1493– 1498 Tan, S.A. et al. (2002) Comparative study of the effects of rosiglitazone and pioglitazone on interferon, tumor necrosis factor, interleukin-1, interleukin-4, interleukin-6 and C-reactive protein in diabetic patients with atherosclerosis. Diabetes 51, A595 Fonseca, V. et al. (2000) Effect of metformin and rosiglitazone combination therapy in patients with type 2 diabetes mellitus: a randomized controlled trial. J. Am. Med. Assoc. 283, 1695 – 1702 Wolffenbuttel, B.H. et al. (2000) Addition of low-dose rosiglitazone to sulphonylurea therapy improves glycaemic control in type 2 diabetic patients. Diabet. Med. 17, 40 – 47 Zinman, B. (2001) PPARg agonists in type 2 diabetes: how far have we come from ‘preventing the inevitable’? A review of the metabolic effects of rosiglitazone. Diabetes Obes. Metab. 3, S34– S43 Mayerson, A.B. et al. (2002) The effects of rosiglitazone on insulin sensitivity, lipolysis, and hepatic and skeletal muscle triglyceride content in patients with type 2 diabetes. Diabetes 51, 797– 802 Yang, W.S. et al. (2002) Synthetic peroxisome proliferator-activated receptor-g agonist, rosiglitazone, increases plasma levels of adiponectin in type 2 diabetic patients. Diabetes Care 25, 376 – 380 Plutzky, J. et al. (2002) Atherosclerosis in type 2 diabetes and insulin resistance: mechanistic links and therapeutic targets. J. Diabetes Comp. 16, 401 – 415

Review

TRENDS in Endocrinology and Metabolism

53 Hartman, H.B. et al. (2002) Mechanisms regulating adipocyte expression of resistin. J. Biol. Chem. 277, 19754 – 19761 54 McTernan, P.G. et al. (2002) The regulation of resistin expression by insulin and rosiglitazone in human abdominal subcutaneous adipocytes. Diabetes 51, A88 55 Smith, U. (2002) Resistin – resistant to defining its role. Obes. Res. 10, 61 – 62 56 Shrago, E. et al. (1971) Comparative aspects of lipogenesis in mammalian tissues. Metabolism 20, 54 – 62 57 Lafontan, M. et al. (1997) Adrenergic regulation of adipocyte metabolism. Hum. Reprod. 12, 6 – 20 58 Bjo¨rnholm, M. et al. (2002) Absence of functional insulin receptor substrate-3 (IRS-3) gene in humans. Diabetologia 45, 1697– 1702 59 Mohamed-Ali, V. et al. (1997) Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-a, in vivo. J. Clin. Endocrinol. Metab. 82, 4196 – 4200

Vol.14 No.3 April 2003

145

60 Ryde´n, M. et al. (2002) Mapping of early signaling events in tumor necrosis factor-a-mediated lipolysis in human fat cells. J. Biol. Chem. 277, 1085– 1091 61 Laurell, H. et al. (1997) Species-specific alternative splicing generates a catalytically inactive form of human hormone-sensitive lipase. Biochem. J. 328, 137 – 143 62 Ek, I. et al. (2002) A unique defect in the regulation of visceral fat cell lipolysis in the polycystic ovary syndrome as an early link to insulin resistance. Diabetes 51, 484– 492 63 Cannon, B. et al. (1998) Brown adipose tissue. More than an effector of thermogenesis? Ann. New York Acad. Sci. 856, 171 – 187 64 Arner, P. (1998) Not all fat is alike. Lancet 351, 1301– 1302 65 Bjo¨rnholm, M. et al. (2002) Insulin signal transduction and glucose transport in human adipocytes: effects of obesity and low calorie diet. Diabetologia 45, 1128– 1135

Managing your references and BioMedNet Reviews Did you know that you can now download selected search results from BioMedNet Reviews directly into your chosen referencemanaging software? After performing a search, simply click to select the articles you are interested in, choose the format required (e.g. EndNote 3.1) and the bibliographic details, abstract and link to the full-text will download into your desktop reference manager database. BioMedNet Reviews is available on institute-wide subscription. If you do not have access to the full-text articles in BioMedNet Reviews, ask your librarian to contact [email protected] http://tem.trends.com