Department of Cell Biology, University Medical Center Groningen, University of Groningen, A Deusinglaan 1, NL-9713 AV Groningen, The Netherlands
Received date: April 26, 2014; Accepted date: July 25, 2014; Published date: August 03, 2014
Citation: Dashty M (2014) Nutrient Signaling in Adipose Tissue and its Consequences for Metabolic Disease. J Diabetes Metab 5: 406. doi: 10.4172/2155-6156.1000406
Copyright: © 2014 Dashty M. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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The LKB1/AMPK/TSC/mTORC1 cassette constitutes a canonical signaling pathway that integrates the metabolic and nutrient status of the cell for regulation of cell growth and survival and would thus be expected to be of critical importance in adipose tissue; the main organ in the body dealing with energy homeostasis. Indeed it has now become clear that changes in AMPK activity, and to a lesser extent in Akt/PKB, guides almost every process in this tissue and that modulation of the activity of the nutrient signaling cassette offers a wide range of option to deal with metabolic diseases. Here I review the current body of biomedical literature on nutrient signaling in adipose tissue and show that although the effects involved are highly cell type specific in general, pharmacological AMPK activation seems the way forward losses in adiposity. It should thus prove exceedingly interesting to watch the results of clinical trial in obese subjects treated with AMPK analogues.
Brown adipose tissue; AMPK pathway; Insulin pathway
AD: Adiponectin; AICAR: 5-Aminoimidazole- 4-carboxamide-1-β-D-ribofuranoside; AKT/PKB: Protein Kinase B; AMP/ATP ratio: Adenosine monophosphate/Adenosine triphosphate ratio; AMPK: AMP-activated Protein Kinase; ATG13: Autophagy Gene 13; BAT: Brown Adipose Tissue; CaMKK2: Calcium/calmodulindependent Protein Kinase Kinase 2; EBP1: ErbB-3 Binding Protein, eLF-4E: Eukaryotic initiation factors-4E; GLUT4: Glucose Transporter Type 4; IR: Insulin Receptor, IRS: Insulin Receptor Substrate; LD: Lipid Droplets; LKB1: Liver Kinase B1; mTORC1: mammalian Target of Rapamycin Complex 1; p38 MAPK: p38 Mitogen-activated Protein Kinase; P70S6K: P70 ribosomal S6 kinase; PDK: Phosphoinositide dependent Kinases; PI3K: Phosphatidylinositol 3 Kinase; RheB: Ras homolog enriched in Brain; SC: Subcutaneous; TSC: Tuberous Sclerosis Complex; T2DM: Type 2 diabetes mellitus; UCP-1: Uncoupling protein 1; ULK1: Unc-51-like kinase 1; Vis: Visceral; WAT: White Adipose Tissue.
Maintaining energy homeostasis is one of the fundamental tasks of the body that has to be performed, and it is largely achieved through the control of blood glucose level. Thus normoglycemia is regulated through proper energy delivery to the energy-demanding tissues or storage in the adipose tissue through the lipoprotein compartment. The processes constitute a multitude of tightly regulated and highly tuned mechanisms, which is only partly understood and involved in all tissues. Nevertheless, the adipose tissue and in particular adipocytes together with the skeletal muscle and liver seems to be the most important organs for dealing with challenges to keep body energy and energy metabolic system in homeostasis. Although through most of mankind’s history, lack of energy was the main challenge in current societies excess intake of calories and especially fats and sugars as well as their main manifestation, and hyperglycemia-related diseases has become a serious problem. The situation is compounded by the increase of sedentary life-styles and the use of high level of tobacco [1,2]. Currently, 65% of the global population lives in countries where obesity kills more people than malnutrition (WHO - Global strategy on diet, physical activity and health, 2010). The metabolic diseases include obesity-induced metabolic syndrome, lipodystrophy, and Type 2 Diabetes Mellitus (T2DM) represent an ever increasing challenge to health care. A guiding principle of this thesis is that many aspects of these diseases can be better understood through insight into the energy metabolism of the adipocytes as well as improved knowledge of the adipocytes and their production. Furthermore, I shall argue that the lipoprotein compartment is not only a mediator between the adipose compartment and the periphery with respect to the transport of energy-rich hydrophobic molecules, but also is an important transport modality for adipocyte-generated endocrine signals.
The energy metabolic system ensures to regulate the energy metabolism in body and is difficult to categorize. It is mainly composed of energy transporting and storing molecules (e.g. lipids and glucose), lipid carriers (lipoproteins), the endocrine system (e.g. pancreas, adipose tissue, hypothalamus, growth hormones, thyroid, and adrenal gland hormones), the metabolically active tissues (e.g. adipose tissue, skeletal muscles, liver, and kidney) and the metabolic pathways (mainly insulin, Adenosine Monophosphate-Activated Protein Kinase (AMPK), inflammatory molecules). Energy metabolism is defined as a finely tuned regulatory system to ensure the balance of the retour of energy in the form of lipids and carbohydrates in the body and is reflected by the level of the glucose in circulation. Circulatory glucose levels depend on four parameters; i: prandial glucose (food-derived) ii: the consumption of glucose in the tissues (mainly skeletal muscles and the brain), iii: the capacity of the body to store excess glucose in the adipose tissue in the form of triglycerides and iv: the endogenous glucose production through gluconeogenesis in the liver and kidney. Among the involved systems, adipose tissue and skeletal muscle are considered as the main energy reservoir and consumer units in the body respectively. Thus, adipose tissue and skeletal muscle play a main role in determination of the quality of the metabolic system function. A disturbance in the function of these two organs can trigger the metabolic diseases including metabolic syndrome and their medical complications including coagulopathy and atherosclerosis. Here we shall argue that especially regulation of energy metabolism in adipose tissue is an underestimated but principal component regulating these processes.
Nutrient- and metabolic- status sensing is highly fundamental to the eukaryotic life; therefore the involved biochemical principles are broadly similar within eukaryotes. To adjust cell metabolism to the intracellular energy status and extracellular environment, the liver kinase B / AMPK / tuberous sclerosis complex / mammalian target of rapamycin complex 1 (LKB1/AMPK/TSC/mTORC1) pathway integrates information regarding the intracellular energy, oxygen status, the presence of growth factors and nutrient availability and translates this into the regulation of cell growth [3,4]. Lower energy status is reflected in an increased adenosine monophosphate / adenosine triphosphate (AMP / ATP) ratio, directly resulting in higher AMPK activity. Although AMPK can directly influence cellular physiology via the stimulation of glucose import and mitochondrial activity, its main action is to influence mTOR activity. AMPK inhibits mTOR, known as the central energy sensor of the cell, via TSC. mTOR activity provides via S6 kinase a protein synthesis-permissive signal, which actively counteracts autophagia [5-9].
Human diseases such as PJS and TSC knockout animal models and in vitro experiments indicate that both the LKB1 kinase and the TSC1:TSC2 complex are essential proteins in regulating cell growth under conditions of metabolic stress . In addition, the system is under control of the PKB/Akt pathway. Anabolic stimuli, like insulin, employ this pathway to increase mTOR activity. The effect of nutrient signaling in adipose tissue is highly cell type-dependent and thus modulation of this pathway may hold great clinical promise through this system.
The notion that the adipocyte compartment is an important component of the normal and aberrant energy balance and its associated disorders comes from the association that has been made between obesity and metabolic disorders. Obesity is the new major risk worldwide. An overload of energy in the form of triglycerides within lipid droplets of adipocytes is the main cause of obesity . Numerous epidemiological studies implicate the hypertrophy of adipocyte compartment to energy metabolic disorders such as insulin resistance and type 2 diabetes mellitus and their afflictions including coagulopathy, atherosclerosis and cardiovascular diseases. The nature of the problem is further compounded by the observation that both the obesity and its associated disorders seem to display even greater prevalence over the world. The factors driving the obesity epidemic are mainly both the changes in diet with a greater dependency on sugars and fats with a concomitant decrease in fibre in combination with a reduced physical activity. Also, failure to develop a good therapy in dealing with metabolic disorders is remained to be an issue here. The development of humanity has undoubtedly included many episodes of extreme starvation and as a result we are highly capable of storing excess energy in the form of lipids in the body for usage at a later time. The subcutaneous fat layers are the physiological place for this storage and would also protect us against cold. During the activity, the stored energy is released allowing better survival. However, in the whole world calorie restriction is not much of an issue anymore, therefore obesity is depressingly common. Efficient breakdown of fat may be further compounded by differences between individuals with respect to threshold levels of lipid storage and release as well as in difference in gut flora components. In turn, obesity provokes systemic chronic inflammation, which is then directly related to metabolic disorders, cardiovascular disease and malignancy [12,13]. Hence, this review is meant to highlight the role of obesity in initiation of inflammation and the energy metabolic system disturbances including metabolic syndrome and atherosclerosis [14,15].
In eukaryotic cells, mitochondria are energy supplier of the cell. Within the cell, the inner membrane of mitochondria is the main site of OXPHOS. The nutrients will be oxidized to ensure the release of energy; Adenosine Triphosphate (ATP). During OXPHOS reaction, the electrons will be delivered from electron donor such as NADH to electron acceptor like oxygen, in a reaction called redox to release energy. After oxidation of NADH in mitochondria, the energy will be available for anabolic pathways. By flowing electron in electron transport chain, energy comes free to be used to move proton across inner membrane of mitochondria. With respect to OXPHOS, two pints must be noted: 1- OXPHOS is used by mitochondria to provide energy for cell, which is vital for cell and cannot be missed, and 2-From the oxidation process used in mitochondria, Reactive Oxygen Spices (ROS) comes free, which is poison for the cell. In brown adipose tissue that mainly present in baby period and slowly replaced by white adipose tissue in adult phase, UCP plays an important role in providing of energy by mitochondria in the form of heat. UCP cause proton leak during proton transport across inner mitochondria membrane via uncoupling of OXPHOS from ATP synthesis, producing energy in the form of heat .
Survival of a species is dependent on two main processes, which are clearly interrelated; proper maintenance of the level of energy in the body and mounting an immune response to pathogens . Nutrient- and pathogen-sensing pathways are both evolutionary highly conserved and interrelated to each other at many points for instance the crucial role of mTOR gene in both nutrient pathways as well as immunity . mTOR inhibitors are among the most available strong immunomodulators that are often used in transplantation medicine . During obesity, adipose tissue develops low grade inflammation, which is primed by adipocytes and followed by a concerted reaction of the other constituting cell types of the adipose tissue [20,21]. Adipose tissue is one of the largest tissues in the body and is composed of different cells such as adipocytes, residual macrophages, mesenchymal stem cells, preadipocytes, endothelial cells, and fibroblasts (Figure 1). This diversity of cells in the adipose tissue represents its vast function and importance in different pathways including metabolic system and immune system and both functionalities are related to the nutrient signalling [20,22,23]. Adipose tissues are categorized based on the type (Brown Adipose Tissues (BAT) and White Adipose Tissues (WAT)) and location (Visceral (Vis) and Subcutaneous (SC)) in the body. These two classes are separate from each other and are important in the evaluation of the metabolic system functionality.
Figure 1: Illustration of the antagonist association between the insulin and AMPK pathways, two main energy metabolic systems of body. LKB1/AMPK/TSC/mTORC1 pathway is the fundamental nutrient and metabolic status sensing in the body that help cells to adjust their metabolism to the intracellular energy status and extracellular environment. The anabolic insulin pathway and catabolic AMPK (in the skeletal muscle) pathways have a negative regulatory effect on each other and both determine the level of the energy status of the cell. AMPK pathway is activated following lower energy status, which increases the level of AMP/ATP ratio in the body. Increase of the level of adiponectin following coloric restriction has a stimulatory effect on the stimulation of AMPK. AMPK decreases inflammation by enhancing FAO in cell. It also has a stimulatory effect on autophagy and TSC, which inhibits insulin pathway. RheB in insulin pathway via positive influence on mTOR/Rictor (TORC1) influences on the central energy sensor of the cell. TORC1 inhibits autophagy and stimulates cell growth and survival.
In mammals there are two types of adipocytes with opposing functions. Brown adipose tissue-adipocytes are characterized by the small lipids droplets containing triglycerides, which are accessible for rapid hydrolysis and oxidation of fatty acids, while white adipose tissue-adipocytes have one huge lipid droplet per adipocyte for the energy storage in the form of triacylglycerol [24,25]. Ultrastructurally, brown adipocytes are characterized by a high number of mitochondria packed with cristae and expressing thermogenic genes such as UCP-1 (uncoupling protein 1), which is used for fatty acid oxidation and for heat generation (Thermogenesis) and warming the body . Even though brown adipose tissue is the major sort of adipose tissue during the development of the fetal bodies, however during the adulthood it converts to the white adipose tissue . The percentage of the brown adipose tissue in visceral fat is higher than that in the subcutaneous fat tissue . The activation of human brown adipose tissue represents an opportunity to increase energy expenditure and weight loss alongside improved lipid and glucose homeostasis. Active brown adipose tissue is able to uptake a large quantities of lipid and glucose from the circulation . Activity of these cells with respect to thermogenesis is largely under the control of innervated-β-adrenergic receptors on brown adipocytes. But pharmacological approaches to stimulate brown adipocyte tissue activity without central nervous system side effects might hold great promise to combat obesity-related disease .
Nutrient signaling plays a pivotal role in brown adipocyte development, quite different from the situation in white adipose tissue adipocytes. Differentiation of brown adipocytes coincides with strong activation of LKB1/AMPK and canonical downregulation of mTORC1, unusually in conjunction with p38MAP kinase activation, which is a kinase normally more associated with pro-inflammatory processes. Stimulation of mTOR prevents brown adipogenesis, whereas forced activation of signaling cassette through 5-Aminoimidazole-4- Carboxamide Ribonucleoside (AICAR)-induced AMPK activation increases UCP-1 expression and induces an accumulation of brown adipocytes in white adipose tissue . Thus in contrast to classical view in which activation of mTOR promotes acquisition of cellular functionality and in which AMPK activation is associated with energy conservation, during brown adipocyte development AMPK activation is associated with the burning of calorie (storage of excessive energy) in a catabolic process [32,33]. It is hoped that further elucidation of the involved processes could further contribute in fight against metabolic disease.
White adipocytes are the dominant cell type in this adipose tissue. This cell type is characterized by a very long half-life and the ability to store increasing amounts of triglycerides in its lipid droplets in mature adipocytes. However, they concomitantly lose their ability to proliferate . Interestingly, the structure of lipid droplets is comparable with that of plasma lipoproteins, containing a hydrophobic core coated with a hydrophilic monolayer membrane; however, there are differences with respect to phospholipids and the type of their protein composition. Many proteins are associated with the LD monolayer membrane [35-38]. Disregulation of the lipid metabolism in adipocytes as found in obese subjects can, to a large extent, be attributed to the increased size and storage capacity of the LD . Even in lean subject lipid droplets may occupy a high percentage of cellular volume of the adipocytes .
In contrast to brown adipocyte genesis, the generation of white adipose tissue adipocytes is negatively regulated by activation of the AMPK pathway. For instance, it has been shown that various natural compounds like methyl cinnamate or mushroom extracts inhibits adipocyte differentiation via activation of the CaMKK2-AMPK pathway (rather as LKB1, which is the more common activator of AMPK). In rats, chronic stimulation of AMPK is reported to decrease adiposity through inhibition of adipogenesis, but whether it is true for human remains unclear as dieting (which activates AMPK in adipocytes) is not reported to reduce adipocyte number in the short or medium term [40-44]. A possible explanation is the differences in leptin effects between humans and rodents. In rats, AMPK stimulation seemed to increase leptin effects on adiposity but in humans such effects of leptin are much weaker. More in general, it is expected that AMPK activation should facilitate triglyceride-loading on plasma lipoproteins in adipocytes and indeed in animals treated with AMPK inhibitors lower circulating levels of plasma triglycerides have been reported, but further research into this issue is called for.
The metabolic disorder in adipose tissue leads to an obesity state, which in turn is resulted in an inflammatory environment. Importantly, obesity and its consequent disorders change the resident macrophages to activated macrophages (also called migrated macrophages) in adipose tissue, which is a hallmark of energy metabolism disorderinduced insulin resistance [20,35]. The resident macrophages of adipose tissue or Adipose Tissue Macrophages (ATM) have attracted substantial attention with respect to metabolic disease as they have been suggested to be the mediators of the low-grade inflammation present in fat tissue of obese people. Indeed, although conclusive evidence is still lacking and until that time other possibilities have to be kept in mind, these resident macrophages spatially seem to have a close interaction with adipocytes in the adipose tissue and this interaction is thought to stimulate cells to secrete the proinflammatory cytokines . However, Meijer et al. suggested that the primary event in the sequence leading to chronic inflammation in adipose tissue is metabolic disorder in adipocytes, followed by production of immunological mediators by these cells, which is then exacerbated by activated adipose tissue macrophages and finally the recruitment of immune cells. During the obesity, the density of macrophages in adipose tissue increases, either due to increased chemokine expression or maybe local proliferation or conversion of mesenchymal stem cells to macrophages [37-41]. Notably, the resident macrophages in adipose tissue and other tissuescontaining macrophages also have a role in tissue repair [42,43].
Macrophage infiltration increases the fat lipolysis, which leads to an increase of the circulatory free fatty acid (FFA) levels and their sedimentation in the other tissues with a plethora of health-related issues as a consequence . AMPK appears to be a key enzyme that counteracts the high-lipid load-induced inflammatory pressure in these macrophages. Animals genetically engineered to be defective in macrophage AMPK activity displayed a highly inflammatory phenotype in their adipose tissue macrophages. Inhibiting fatty acid oxidation (a key effector mechanism of AMPK kinase to improve the cellular energy balance) also was pro-inflammatory in these cells and, conversely pharmacological activation of AMPK counteracted inflammation . If adipose tissue macrophages are indeed of cardinal importance in metabolic disease, pharmacological targeting the associated pathways (e.g. using rapamycin which mimics AMPK activation in its inhibitory effect on mTOR) may prove a viable option in dealing with such diseases .
Adipose tissue is a rich source of Mesenchymal Stem Cells (MSCs), a highly immunomodulatory cell type with the capacity of self-renewal, proliferation, differentiation, plasticity and intimately involved in tissue repair. The concentration of the MSCs in adipose tissue may be hundreds more than bone marrow and thus it is reasonable to assume that this cell type can influence the physiology of fat [47-49]. Although autophagia is in general associated with protection of cells from hypoxic and hyponutrient stress, this functionality of the autophagic response may be stronger in the MSC compartment . Indeed AMPK activation has emerged a major mediator for MSC survival following hypoxia through AMPK-mediated mTOR inhibition-dependent autophagic responses . Mesenchymal stem cells are able to differentiate into preadipocytes and their precursor fibroblasts . The molecular details to govern the transition of fibroblasts to pre-adipocytes are slowly emerging and involve regulation through the prolyl isomerase Pin1, possibly through enhancing mTOR signaling by stabilizing its upstream activator PKB/ Akt. Pre-adipocytes have multilocular lipid droplets (in contrast to mature adipocytes which contain one droplet) and are thought to be immune active cells through phagocytic and antimicrobial properties . Profiling indicates that molecularly they are closer to macrophages than adipocytes and might be able to differentiate into the former cell type. Remarkably, in obese subjects the capacity of preadipocytes to differentiate adipocytes is impaired . In general, preadipocytes act as a link between the metabolism and innate immunity . It must be noted that autophagy is necessary for adipogenesis and regulation of adipose mass. As mentioned earlier AMPK activation inhibits differentiation of pre-adipocytes to white adipocytes but facilitates the transition to the brown adipocyte type . In toto, AMPK activation has a protective role in these components of fat tissue, whereas mTOR activation increases sensitivity of adipose tissue lipid uptake [56,57].
When the details of nutrient pathway signalling started to emerge, it was always assumed that the way forward of employing this information for improved treatment of metabolic disease would lie in negatively regulating of this system not clear. It was reasoned that if this system enhances cellular conservation and increase metabolic efficiency, it would reduce energy requirements and thus increase adiposity. It has now become clear, however, that the situation is quite reverse. AMPK activation increases brown adipocytes, thus enhancing energy metabolism while simultaneously promoting lipolysis in white adipocytes and protecting adipose tissue resident macrophages from inflammatory responses. The combined anti-adiposity profile and antiinflammatory profile resulting from AMPK stimulation is expected to be highly beneficial when managing metabolic disease and thus pharmacological therapy of this disease through manipulation of nutrient signalling pathways appears highly promising.