Adipocyte insensitivity syndromes – novel approach to nutritional metabolic problems including obesity and obesity related disorders

Medical Hypotheses (2005) 64, 826–832

http://intl.elsevierhealth.com/journals/mehy

Adipocyte insensitivity syndromes – novel approach to nutritional metabolic problems including obesity and obesity related disorders Adnan Erol* Department of Internal Medicine, Silivri City Hospital, Ali Cetinkaya Cad, 34930 Silivri, Istanbul, Turkey Received 20 August 2004; accepted 13 September 2004

Summary Progresses in molecular biology have highlighted the central role of adipocytes in the development of obesity and other nutrition based disorders. Adipocytes, by virtue of their excellent and sensitive molecular machinery, seem to reflect nutritional alterations very precisely. Adipocyte determination and differentiation factor 1 (ADD1)/ sterol regulatory element binding protein-1c (SREBP-1c), which is the main transcription factor, regulates the characteristic features of adipocyte, senses the glucose and fat excess and draws the excess into the adipocyte to preserve energy, and maintains the blood biochemistry within physiological ranges. ADD1/SREBP-1c has regulatory functions via transactivation over the other important mature adipocyte markers such as leptin, peroxisome proliferator-activated receptor c (PPARc) and lipogenic enzymes. In this paper, considering to the role of ADD1/SREBP1c on adipogenic markers, two new concepts have been defined: the first is sensitive adipocyte, implying a fat cell that functions perfectly at molecular level; and the second is adipocyte insensitivity syndrome (AIS), in which deviations from the optimal function of adipocyte leads to various metabolic abnormalities. The two extreme ends for adipocyte function; obesity and lipodystrophy, and intermediate spectrums between these are categorized into four subgroups. According to this categorization, responses of adipogenic markers to the stimulation of the master transcription factor, ADD1/SREBP-1c might be different in adipocytes: higher lipogenic enzymes activities in type I AIS, insufficient transactivation of leptin in type II AIS, failure in the expression of PPARc in type III AIS, and insufficient increases of lipogenic enzymes in type IV AIS. The novel AIS classification, which asserts that the adipocyte has a central importance for the development of metabolic devastating diseases like obesity, metabolic syndrome, type 2 diabetes and atherosclerosis, provides simpler but effective answers for the puzzle by unifying the recent, good quality studies and points out to new therapeutic approaches, highlighting the possible molecular defects. c 2004 Elsevier Ltd. All rights reserved.



Introduction As a result of the advances in molecular biology, adipocyte has come into prominence with its al*

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most central importance in the development of obesity and other nutrition based disorders. Adipocytes are very vulnerable to nutritional alterations due to their excellent and sensitive molecular machinery. In this article, two new concepts have been defined: the first is the sensitive adipocyte, implying that a fat cell functioning perfectly at

0306-9877/$ - see front matter c 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2004.09.017

Adipocyte insensitivity syndromes molecular level; and the second is adipocyte insensitivity syndrome, in which deviations from the optimal function of adipocyte leads to various metabolic abnormalities. Also, pathophysiological principles supporting these novel syndromes will be pointed out to emphasize potential new therapeutic approaches.

The importance of adipocyte sensitivity Adipocyte is the most insulin sensitive cell that plays crucial roles in the regulation of energy homeostasis [1,2]. In conditions with a decrease or lack of fat tissue, such as lipodystrophic [3] and lipoatrophic animal models [4] or congenital generalized lipodystrophy in humans [5], insulin resistance with hyperinsulinemia, variable degree of glucose intolerance or overt diabetes, dyslipidemia, and hepatic steatosis are characteristic findings. Transplantation of fat tissue to lipoatrophic mice has caused improvement in insulin resistance [6]. Furthermore, protease inhibitors for the treatment of AIDS result in clinical and laboratory findings of insulin resistance with characteristic lipodystrophic changes [7]. As a general consensus, insulin resistance has been defined as a spectrum of metabolic disorders, which are caused by resistance to the effects of insulin on glucose uptake, metabolism or storage [8]. Recent studies, particularly those by Kahn and colleagues [2,9–11], have also demonstrated the major role of fat tissue in insulin resistance from a different perspective. GLUT4 is the main glucose transporter of adipocyte [9,10]. The blockage of glucose transport to adipocyte in GLUT4 knockout mice results in insulin resistance in both muscle and liver without any significant decrease in the fat mass [11]. This stimulating study has directly emphasized the importance of fat tissue in glucose metabolism, which may cause systemic alterations [12]. In addition to those studies with clear results, current advances in the field have also demonstrated the significance of the fat organ in actively contributing to the regulations against the chronic energy load in order to prevent the development of serious degenerative metabolic disorders [2,12,13]. Thus, the fat cell: (1) draws glucose and fat from the bloodstream that exceed the requirements of other systems [7,9], (2) stores them as triglyceride [14], (3) releases depot fat to non-adipocytes as free fatty acids (FFAs) and glycerol, when needed [15,16] (4) can increase fatty acid oxidation in itself and in non-adipocytes

827 for the maintenance of fat homeostasis and cellular integrity [15]. Adipocyte, as a multi-potential endocrine cell, while responding specifically and sensitively to systemic influences, affects important target cells with its powerful secretions. Therefore, the adipocyte is considered healthy if it can sense the changes in energy equilibrium of the organism and respond by adequately performing the four features described above. In other words, it might be considered as the sensitive adipocyte, meaning that it has optimal functioning capacity.

Adipocyte physiology: an outline The main transcription factor designating the characteristics of adipocyte is most likely the adipocyte determination and differentiation factor 1 (ADD1)/ sterol regulatory element binding protein-1c (SREBP-1c), which has regulatory functions over the other important adipocyte specific factors [17]. It senses the glucose and fat excess and draws them into the adipocyte in order to preserve energy and maintain the blood biochemistry within physiologic ranges. Otherwise, fat accumulation in non-adipocytes could be deleterious for their functions [2,16,17]. In contrast to inverse relation between cytosolic cholesterol level and ADD1/ SREBP-1c, blood insulin and glucose levels positively affect ADD1/SREBP-1c [18]. Insulin is a critical regulator of virtually all aspects of adipocyte biology, and adipocytes are the most responsive cells to insulin [16–18]. Almost all anabolic effects of insulin in the adipocyte are carried out by this transcription factor (Fig. 1). ADD1/SREBP-1c also controls other mature adipocyte markers via transactivation of peroxisome proliferator activated receptor c (PPARc) and leptin [19]. PPARc has major influences on various aspects of adipogenesis process, such as adipocyte differentiation from preadipocytes and differentiation of fibroblasts to mature adipocytes [20]. ADD1/SREBP-1c and PPARc also regulate the genetic expressions of the enzymes for de novo lipogenesis (DNL) and the glucose transporter GLUT4 [2,20,21]. Leptin, which has autocrine, paracrine, and endocrine effects, probably is the most important substance secreted by the fat cell [22]. It has very important peripheral metabolic influences. Particularly, studies of Unger and colleagues [16,23] have shed light on the effects of leptin on peripheral fatty acid oxidation via PPARa stimulation, and these studies have pointed out the significant

828

Erol GLUCOSE Triglyceride INSULIN LPL

V es s el

TNFα TNFα

l oo tp Fa

ACC FAS GPAT

Leptin

genesis

Adiponectin

ADD1/ SREBP1c de novo lipogenes is

Ad ip oc yt e

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Appetite suppression and food intake ↑ Fatty acid oxidation in nonadipocytes and adipocytes ↑ UCPs ↑

INSULIN

Adipogenesis

PPARγ PPARγ

Triglyceride Resistin

Antiatherogenic and AntiAnti-inflammatory effects on vasculature

Systemic insulin resistance Vessel

Figure 1 In this figure important molecules secreted from the adipocyte and their interactions and systemic influences are outlined. ACC, FAS, GPAT: lipogenic enzymes; ADD1/SREBPc: adipocyte determination and differentiation factor 1/sterol regulatory element binding protein-1c; IR, insulin receptor; LPL, lipoprotein lipase; PPARc, peroxisome proliferator activated receptor c; TNFa, tumor necrosis factor a; UCP, uncoupling protein.

metabolic regulatory role of fat tissue over muscle, liver and pancreas b-cell. The fat organ, which increases lipogenic activity by sensing the fuel excess, also secretes leptin in order to prevent cytosolic fat accumulation that would compromise functions of non-adipocytes [24]. Leptin limits the lipid increase by its autocrine effect in adipocytes; thus, it maintains cellular fat balance [16,24]. Its fatty acid oxidative effects are also enhanced by the up-regulation of mRNA of uncoupling protein-2 (UCP-2) in adipocytes and in some non-adipocytes, such as muscle and b-cell [23]. UCPs result in chemical energy loses by converting the energy coming from Kreb’s cycle to thermogenic heat dissipation in mitochondrial electron transport chain [25]. Adiponectin is a novel adipose-specific molecule that possesses possible anti-atherogenic and anti-inflammatory properties. The plasma levels of adiponectin were lower in obese subjects and in patients with type 2 diabetes, contributing to the development of atherosclerotic complications [26,27]. It is demonstrated that the secretion of adiponectin from adipocytes was stimulated by insulin [28]. Thus, it could be speculated that ADD1/SREBP-1c might also be responsible for the control of adiponectin at transcription level. Adipocytes do not have unlimited capacity for expansion by storing fat as triglyceride. When adipocyte reaches a critical fat cell size, adipogenesis

is triggered resulting in increase in the number of fat cells [29]. ADD1/SREBP-1c, and in particular PPARc, very efficiently cause the differentiation of preadipocytes and even fibroblasts or myoblasts to mature adipocytes [17,21]. Thus, relatively older mature adipocytes are protected by diverting the fuel excess to more competent (in terms of lipogenesis) small and younger adipocytes. When the adipogenesis cannot occur, fat cell produces powerful secretions to close the doors against the anabolic actions of insulin. One of those is tumor necrosis factora (TNFa) [2,30], and the next one is the recently recognized hormone, resistin [31]. These adipocyte products may result in the development of metabolic syndrome by creating insensitivity to insulin action, mainly in the fat tissue, and partly in liver and muscle (Fig. 1) [2,30,31]. In brief, physiologically competent or sensitive adipocytes, while utilizing glucose and fat excess during nutritional affluence and storing them as triglyceride, release energy as FFA and glycerol by lipolysis. These FFAs do not produce significant metabolic problems as long as they are oxidized in target tissues by endocrine secretions, in particular by the leptin of adipocyte. Long chain fatty acids (LCFAs) in non-adipocytes, which cannot undergo mitochondrial b-oxidation, whether cause signal transduction defects [32] or result in pathologic impairments leading to even apoptotic cell losses via accumulating as cytosolic triglyceride. Besides, sensitive adipocyte could also prevent

Adipocyte insensitivity syndromes atherosclerotic damages on vasculature by its product adiponectin [27,28].

The effects of glucose in adipocyte Glucose, (1) determines the fate of nutritional energy (whether it is oxidized or stored as triglyceride by controlling genetic and metabolic regulations) [18,34,35]; (2) inhibits the oxidation of LCFA, causing the accumulation of LCFA and its metabolites in cytosol resulting in an impairment of signal transduction [32,34,35]; (3) stimulates apoptotic cell losses, when unoxidized LCFA metabolites continue to accumulate in the long term (=glucolipotoxicity) [33,35]. ADD1/SREBP-1c, which is mostly dependent on insulin as outlined above, bears a central importance in the fat tissue for the regulation of energy metabolism [16,17,19]. The amount and type of fat and associated cholesterol contents of food generally inhibit ADD1/SREBP-1c expression via affecting cytosolic cholesterol level [36]. Although, the activation of this transcription factor changes mainly according to cytosolic cholesterol level [37], glucose component of the nutritional excess and glucose dependent hormone, insulin, are the predominant stimulator for the genetic expression of ADD1/SREBP-1c in the fat tissue [18]. Thus, we can propose that the amount and quality of nutritional carbohydrate, which determines the glycemic index and the responding insulin level, control the activation of ADD1/SREBP-1c, underscoring two facts: (1) extracellular glucose level is not only the operating lipogenic machinery of fat cell, but also controls the adipocyte secretions that will be effective in non-adipocytes and its own energy regulation, (2) glucose determines the fuel partitioning, oxidation or storage in cells, including the fat tissue. Briefly, chronic energy dense nutrition, particularly rich in carbohydrates, would cause impairment in transcriptional regulatory effects of ADD1/SREBP-1c, leading to the development of a variety of metabolic disorders.

Adipocyte insensitivity syndrome(s) Individuals exhibit different metabolic responses and body mass indexes to ingested nutritional energy, even with the assumption that their expenditures are equal. In other words, we have met people who take plenty of calories with their voracious appetites but maintaining their weights in

829 normal ranges, and others putting extra pounds progressively despite of their comparably less caloric intake. Alterations in transcriptional mechanisms involved in the adaptation of cells to environmental changes may participate in the pathogenesis of the disease [38]. In keeping with this statement, the expression of some important genes involved in metabolic regulations have been found to be altered in adipose tissue. It is obvious that total unresponsiveness of adipocyte would develop with congenital or most frequently acquired defects in ADD1/SREBP-1c, as it happens in the treatment of HIV with protease inhibitors [7]. Interestingly, overexpression of ADD1/SREBP-1c in adipose tissue of mice is associated with insulin resistance, diabetes, and lipodystrophy [39]. Moreover, alterations in expressions of SREBP-1c and PPARc in humans are present in some obese and metabolic syndrome cases [38,40,41]. Therefore, three main pathways, which are the activations of lipogenic enzymes, PPARc, and leptin by ADD1/SREBP-1c stimulation, occur in optimal equilibrium in adipocytes of the people demonstrating appropriate fat tissue distribution and energy metabolism (Fig. 1). Here, I would like to suggest the classification of AISs into four categories with the assumption that adipocyte might give different responses to ADD1/SREBP-1c activation.

Type I AIS Lipogenic enzymes give stronger responses to ADD1/SREBP-1c activation than to PPARc and leptin. Adipocyte increases its fat storage due to the augmentation in DNL and by extracting triglyceride into the fat cell by the enzyme lipoprotein lipase. ADD1/SREBP-1c, directly and/or indirectly through PPARc, causes the hyperplasia of fat tissue or adipogenesis, which diverts ongoing energy load to new adipocyte reserves. Therefore, the magnitude of adipocyte hypertrophy does not exceed the threshold for triggering the secretion of TNFa or resistin, and insulin resistance would not develop despite a progressive increase in obesity. Leptin provides the maintenance of normal physiologic functions in these target systems via increasing fatty acid oxidation and inhibition of the cytosolic fat accumulation. We can categorize most of the overweight and obese people with metabolic parameters within normal ranges in this group. Target organ damages may develop because of leptin insensitivity through down-regulation of leptin receptors due to chronic stimulation following long term energy dense nutrition. Abundance of energy dense food

830 and progressive sedentary life after industrial revolution have caused genetic re-regulations in lipogenic capabilities of adipose tissue in order to preserve the biochemistry of blood within physiologic ranges, leading to an increase in the prevalence of type I AIS in the world at the expense of the obesity epidemic [35].

Type II AIS While lipogenic and PPARc pathways are working effectively, transactivation of leptin by the stimulated ADD1/SREBP-1c lacks or is insufficient. These kinds of mutations have been shown in animals. Here, in this syndrome, hypertrophic and hyperplastic obesity develop by mechanisms as described above for type I. However, the lack of leptin production causes defects in non-adipocytes leading to arrhythmias, type 2 diabetes, and heart failure due to impairment in intracellular signal transduction or via the apoptotic cell losses by the decrease in fatty acid oxidation and the cytosolic triglyceride accumulation. We can include obese patients with early-onset obesity associated target organ failures in this category.

Type III AIS In this group of patients, although lipogenic pathway and the transactivation of leptin work appropriately, PPARc is not sufficiently activated by the stimulated ADD1/SREBP-1c. Therefore, significant hypertrophy but limited hyperplasia would occur in adipocytes in fuel abundances. Leptin decreases the hypertrophy in peripheral subcutaneous fat by increasing the fatty acid oxidation; however, the tendency to develop central obesity due to visceral fat tissue hypertrophy would be increased, because leptin production is higher in subcutaneous than in visceral fat depots [29]. Lipotoxicity does not occur since the fatty acid metabolism in target organs works efficiently by the effects of the leptin, at least in the early stages. However, the findings of insulin resistance develop quite early by TNFa and resistin, which are secreted from hypertrophic, in particular, visceral adipocytes. Patients, who have insulin resistance with or without obesity, may be included in this category.

Type IV AIS In this group of patients, lipogenic response to ADD1/SREBP-1c activation is insufficient leading

Erol to fat tissue involution. There is close correlation between lipogenesis, particularly DNL and leptin production. Therefore, the decrease in triglyceride in adipocytes due to insufficient expression of lipogenic enzymes might lead to the reduction in leptin synthesis and secretion. Organ dysfunctions might occur in the long term due to fat accumulation in non-adipocytes such as pancreatic b-cell, hepatocyte, and myocyte. Lipodystrophic patients and anorexia nervosa, in which there might be a specific decrease in the expression of fatty acid synthase may be included in this category.

New therapeutic challenges This new and original classification has the potential to explain why diets and conservative drugs do not work in some forms of obesity and obesity related complications. The presence of effectively functioning fat cell is mandatory for the management of nutritional energy regulation of the organism. Thus, we must explore the specific defect(s) in adipocytes and appropriate agents to correct this defect leading to obesity or nutritional metabolic disorders. Chronic energy dense nutrition beginning from the early childhood, even in intrauterine period, is an important factor for the development of AIS; therefore, it is crucial to make proper dietetic arrangements as a prophylactic measure, at least following the lactation period. In the case of persisting defects in molecular functions of adipocyte, every effort should be made for the detection and the correction of this problem. Thiazolidinediones, with a clear mechanism of action, have been used for the treatment of insulin resistance and type 2 diabetes with favourable results since 1997 [1]. However, in view of this novel classification, these agents particularly seem to be specific and effective for type III AIS. When thiazolidinediones, or PPARc agonists, are used for the treatment of insulin resistance long before the establishment of organ failure – as in type 2 diabetes – they may provide an opportunity to correct the specific molecular defect in the adipocyte. Thiazolidinediones are thought to increase the obesity by fat tissue hyperplasia; however, the increase in fatty acid oxidation in adipose tissue and the suppression of appetite via leptin will compensate such an increase in this group of patients. Otherwise, if used non-specifically as an insulin sensitizer for type 2 diabetes associated with type II AIS, thiazolidined-

Adipocyte insensitivity syndromes iones might worsen the prognosis through increase in the body mass. It seems possible to control the activation of de novo lipogenic enzymes in type I AIS by chemical agents or by the suppression of their genetic expression with diet modifications. It is reasonable to assume that the pharmacological analogues of the acetyl CoA carboxylase inhibitors, such as 5(tetradecyloxy)-2-furancarboxylic acid (TOFA) [42] or 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) [43] and the FAS inhibitors, cerulenin [44] or C75 [45] may be beneficial in humans. Polyunsaturated fats inhibit the genetic expression of these lipogenic enzymes. A dramatic regression in obesity was shown with the use of high fat (particularly polyunsaturated) and low carbohydrate diet in our clinical study [46]. The early diagnosis of type II AIS before irreversible organ damage occurs is crucial, but usually challenging. Type 2 diabetes and the other most probable organ dysfunctions could be controlled by leptin replacements. The treatment with adiponectin or adiponectin analogues in the future potentially attenuate the ongoing insulin resistance and provide significant protection against atherosclerotic cardiovascular diseases in type I, II, and type III AISs [47].

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