As chronic inflammation is a hallmark of obesity, pathways that integrate nutrient and pathogen sensing pathways are of great interest in understanding the mechanisms of insulin resistance, type 2 diabetes, and other chronic metabolic pathologies. Here, we provide evidence that double-stranded RNA dependent protein kinase (PKR) can respond to nutrient signals as well as endoplasmic reticulum (ER) stress and coordinate the activity of other critical inflammatory kinases such as the c-Jun N-terminal kinase (JNK) to regulate insulin action and metabolism. PKR also directly targets and modifies insulin receptor substrate and hence integrates nutrients and insulin action with a defined pathogen response system. Dietary and genetic obesity features marked activation of PKR in adipose and liver tissues and absence of PKR alleviates metabolic deterioration due to nutrient or energy excess in mice. These findings demonstrate PKR as a critical component of an inflammatory complex that responds to nutrients and organelle dysfunction.
Obesity, long considered a condition characterized by the deposition of inert fat, is now recognized as a chronic and systemic inflammatory disease, where adipose tissue plays a crucial endocrine role through the production of numerous bioactive molecules, collectively known as adipokines. These molecules regulate carbohydrate and lipid metabolism, immune function and blood coagulability, and may serve as blood markers of cardiometabolic risk. Local inflammatory loops operate in adipose tissue as a consequence of nutrient overload, and crosstalk among its cellular constituents-adipocytes, endothelial and immune cells-results in the elaboration of inflammatory mediators. These mediators promote important systemic effects that can result in insulin resistance, dysmetabolism and cardiovascular disease. The understanding that inflammation plays a critical role in the pathogenesis of obesity-derived disorders has led to therapeutic approaches that target different points of the inflammatory network induced by obesity.
Adipose tissue plays an important role in storing excess nutrients and preventing ectopic lipid accumulation in other organs. Obesity leads to excess lipid storage in adipocytes, resulting in the generation of stress signals and the derangement of metabolic functions. SIRT1 is an important regulatory sensor of nutrient availability in many metabolic tissues. Here we report that SIRT1 functions in adipose tissue to protect from inflammation and obesity under normal feeding conditions, and to forestall the progression to metabolic dysfunction under dietary stress and aging. Genetic ablation of SIRT1 in adipose tissue leads to gene expression changes that highly overlap with changes induced by high-fat diet in wild-type mice, suggesting that dietary stress signals inhibit the activity of SIRT1. Indeed, we show that high-fat diet induces the cleavage of SIRT1 protein in adipose tissue by the inflammation-activated caspase-1, providing a link between dietary stress and predisposition to metabolic dysfunction.
Obesity is characterized by the development of a low-grade chronic inflammatory state in different metabolic tissues including adipose tissue and liver. This inflammation develops in response to an excess of nutrient flux and is now recognized as an important link between obesity and insulin resistance. Several dietary factors like saturated fatty acids and glucose as well as changes in gut microbiota have been proposed as triggers of this metabolic inflammation through the activation of pattern-recognition receptors (PRRs), including Toll-like receptors (TLR), inflammasome, and nucleotide oligomerization domain (NOD). The consequences are the production of pro-inflammatory cytokines and the recruitment of immune cells such as macrophages and T lymphocytes in metabolic tissues. Inflammatory cytokines activate several kinases like IKKβ, mTOR/S6 kinase, and MAP kinases as well as SOCS proteins that interfere with insulin signaling and action in adipocytes and hepatocytes. In this review, we summarize recent studies demonstrating that PRRs and stress kinases are important integrators of metabolic and inflammatory stress signals in metabolic tissues leading to peripheral and central insulin resistance and metabolic dysfunction. We discuss recent data obtained with genetically modified mice and pharmacological approaches suggesting that these inflammatory pathways are potential novel pharmacological targets for the management of obesity-associated insulin resistance.
obesity; insulin resistance; inflammation; adipose tissue; pattern-recognition receptors; stress kinases; macrophages
Insulin resistance is a major metabolic feature of obesity and is a key factor in the etiology of a number of diseases, including type 2 diabetes. In this review, we discuss potential mechanisms by which brief nutrient excess and obesity lead to insulin resistance and propose that these mechanisms of action are different but interrelated. We discuss how pathways that “sense” nutrients within skeletal muscle are readily able to regulate insulin action. We then discuss how obesity leads to insulin resistance via a complex interplay among systemic fatty acid excess, microhypoxia in adipose tissue, ER stress, and inflammation. In particular, we focus on the hypothesis that the macrophage is an important cell type in the propagation of inflammation and induction of insulin resistance in obesity. Overall, we provide our integrative perspective regarding how nutrients and obesity interact to regulate insulin sensitivity.
The increasing incidence of obesity and the metabolic syndrome is disturbing. The activation of inflammatory pathways, used normally as host defence, reminds the seriousness of this condition. There is probably more than one cause for activation of inflammation. Apparently, metabolic overload evokes stress reactions, such as oxidative, inflammatory, organelle and cell hypertrophy, generating vicious cycles. Adipocyte hypertrophy, through physical reasons, facilitates cell rupture, what will evoke an inflammatory reaction. Inability of adipose tissue development to engulf incoming fat leads to deposition in other organs, mainly in the liver, with consequences on insulin resistance. The oxidative stress which accompanies feeding, particularly when there is excessive ingestion of fat and/or other macronutrients without concomitant ingestion of antioxidant-rich foods/beverages, may contribute to inflammation attributed to obesity. Moreover, data on the interaction of microbiota with food and obesity brought new hypothesis for the obesity/fat diet relationship with inflammation. Beyond these, other phenomena, for instance psychological and/or circadian rhythm disturbances, may likewise contribute to oxidative/inflammatory status. The difficulty in the management of obesity/metabolic syndrome is linked to their multifactorial nature where environmental, genetic and psychosocial factors interact through complex networks.
Women have more body fat than men, but in contrast to the deleterious metabolic consequences of the central obesity typical of men, the pear-shaped body fat distribution of many women is associated with lower cardiometabolic risk. To understand the mechanisms regulating adiposity and adipose tissue distribution in men and women, significant research attention has focused on comparing adipocyte morphological and metabolic properties, as well as the capacity of preadipocytes derived from different depots for proliferation and differentiation. Available evidence points to possible intrinsic, cell autonomous differences in preadipocytes and adipocytes, as well as modulatory roles for sex steroids, the microenvironment within each adipose tissue, and developmental factors. Gluteal-femoral adipose tissues of women may simply provide a safe lipid reservoir for excess energy, or they may directly regulate systemic metabolism via release of metabolic products or adipokines. We provide a brief overview of the relationship of fat distribution to metabolic health in men and women, and then focus on mechanisms underlying sex differences in adipose tissue biology.
Adipocyte; Fat distribution; Lipolysis; Fatty acid uptake
Metabolic and inflammatory pathways crosstalk at many levels and while required for homeostasis, interaction between these pathways can also lead to metabolic dysregulation under conditions of chronic stress. Thus, we hypothesized that mechanisms might exist to prevent overt inflammatory responses during physiological fluctuations in nutrients or under nutrient-rich conditions, and identified the six-transmembrane protein STAMP2 as a critical modulator of this integrated response system of inflammation and metabolism in adipocytes. Lack of STAMP2 in adipocytes results in aberrant inflammatory responses to both nutrients and acute inflammatory stimuli. Similarly, in whole animals, visceral adipose tissue of STAMP2-/- mice exhibits overt inflammation, and these mice develop spontaneous metabolic disease on a regular diet, manifesting insulin resistance, glucose intolerance, mild hyperglycemia, dyslipidemia, and fatty liver disease. We conclude that STAMP2 has a novel role in integrating inflammatory and metabolic responses, and thus plays a key role in systemic metabolic homeostasis.
Obesity is characterized by the abnormal or excessive deposition of fat in the adipose tissue. Its consequences go far beyond adverse metabolic effects on health, causing an increase in oxidative stress, which leads not only to endothelial dysfunction but also to negative effects in relation to periodontitis, because of the increase in proinflammatory cytokines. Thus obesity appears to participate in the multifactorial phenomenon of causality of periodontitis through the increased production of reactive oxygen species. The possible causal relationship between obesity and periodontitis and potential underlying biological mechanisms remain to be established; however, the adipose tissue actively secretes a variety of cytokines and hormones that are involved in inflammatory processes, pointing toward similar pathways involved in the pathophysiology of obesity, periodontitis and related inflammatory diseases. So the aim of this article is to get an overview of the association between obesity and periodontitis and to review adipose-tissue – derived hormones and cytokines that are involved in inflammatory processes and their relationship to periodontitis.
Adipokines; obesity; periodontal disease
In the United States, obesity is a burgeoning health crisis, with over 30% of adults and nearly 20% of children classified as obese. Insulin resistance, a common metabolic complication associated with obesity, significantly increases the risk of developing metabolic diseases such as hypertension, coronary heart disease, stroke, type 2 diabetes, and certain cancers. With the seminal finding that obese adipose tissue harbors cytokine secreting immune cells, obesity-related research over the past decade has focused on understanding adipocyte–macrophage crosstalk and its impact on systemic insulin sensitivity. Indeed, adipose tissue has emerged as a central mediator of obesity- and diet-induced insulin resistance. In this mini-review, we focus on a potential role of adipose tissue phosphoinositide 3-kinase (PI3K) as a point of convergence of cellular signaling pathways that integrates nutrient sensing and inflammatory signaling to regulate tissue insulin sensitivity.
phosphoinositide 3-kinase; obesity; inflammation; insulin signaling
Adipose tissue plays a central role in maintaining metabolic homeostasis under normal conditions. Metabolic diseases such as obesity and type 2 diabetes are often accompanied by chronic inflammation and adipose tissue dysfunction. In this study, we observed that endoplasmic reticulum (ER) stress and the inflammatory response occurred in adipose tissue of mice fed a high-fat diet for a period of 16 weeks. After 16 weeks of feeding, ER stress markers increased and chronic inflammation occurred in adipose tissue. We found that ER stress is induced by free fatty acid (FFA)-mediated reactive oxygen species (ROS) generation and up-regulated gene expression of inflammatory cytokines in 3T3-L1 adipocytes. Oral administration to obese mice of chemical chaperons, which alleviate ER stress, improved chronic inflammation in adipose tissue, followed by the suppression of increased body weight and improved insulin signaling. These results indicate that ER stress plays important pathophysiological roles in obesity-induced adipose tissue dysfunction.
Obesity and type-2 diabetes (T2D) have increased dramatically over the past several decades, in parallel. One of the major links between these two disorders is chronic, low-grade inflammation 1. Prolonged nutrient excess promotes the accumulation and activation of leukocytes in visceral adipose tissue (VAT) and ultimately other tissues, which provokes metabolic abnormalities such as insulin resistance, T2D and fatty-liver disease. While invasion of VAT by pro-inflammatory macrophages is considered to be a key event driving adipose-tissue inflammation and insulin resistance, little is known about the roles of other immune-system cell-types in these processes. Recently, a unique population of VAT-resident regulatory T cells (Tregs) was implicated in control of the inflammatory state of adipose tissue and, thereby, insulin sensitivity 2. We have identified peroxisome proliferator-activated receptor gamma (PPARγ), the “master-regulator” of adipocyte differentiation, as a critical molecular orchestrator of VAT Treg accumulation, phenotype and function. Unexpectedly, PPARγ expression by VAT Tregs was necessary for complete restoration of insulin sensitivity in obese mice by the thiazolidinedione (TZD) drug, pioglitazone (Pio). These findings suggest a previously unknown cellular mechanism for this important class of T2D drugs, and provide proof-of-principle that discrete populations of Tregs with unique functions can be precisely targeted to therapeutic ends.
regulatory T cell; adipose tissue; obesity; type-2 diabetes; nuclear receptor; TZD drug
The relative or absolute deficiency of pancreatic β-cell mass function underlies the pathogenesis of diabetes. It is necessary to alleviate the metabolic stress and reduce the demand for insulin to decrease the effects of mutations affecting β-cell expansion. Butyrate is a natural nutrient existed in food and can also be produced physiologically through the intestinal fermentation of fiber. Pregnancy and obesity model would be helpful for understanding how β-cell adapt to insulin resistance and how butyrate alleviate the metabolic impairment and protect pancreatic β cell function in pregnant mice with obesity. C57BL/6J female mice were divided into three groups and fed with high fat food (HF group, 40% energy from fat), high fat with sodium butyrate food (HSF group, 95% HF with 5% butyrate), or control food (CF group, 14% energy from fat), respectively. The feeding would last for 14 weeks before mating and throughout the gestation period. A subset of dams were sacrificed at gestational day (GD) 14.5 to evaluate the changes of metabolism and β-cell function, mass, proliferation and apoptosis, inflammatory reaction of islet from different diet. Pancreases were double immuno-labeled to assess the islet morphology, insulin expression, expression of proliferation gene PCNA and anti-apoptosis gene bcl-2. Moreover, we detected the expression of NF-κB, phosphorylated NF-κB (pNF-κB) to evaluate the islet inflammatory response with immunohistochemistry. Mice fed with HSF showed obviously changes including the decreased values of weight gain, glucose, insulin, triglyceride and total cholesterol level of blood compared with high fat diet group, and the reduced circulating maternal pro-inflammation factors at GD14.5. Mice fed with HF displayed β-cell hyperplasia with a greater β-cell size and β-cell area in pancreas. Furthermore, the higher ratio of apoptosis and inflammatory response were found in HF group compared with HSF and CF group, while the proliferation rates of β-cell increased in HF group, but not in HSF or CF. Butyrate shows an obvious function of anti-obesity, and can alleviate the metabolic stress, maintain the β-cell function and protect them from inflammatory response in pregnant obese mouse without obvious fetus toxicity.
Sodium butyrate; β-cell; pancreatic islet; diabetes; GDM
The role of endoplasmic reticulum (ER) stress is a rapidly emerging field of interest in the pathogenesis of metabolic diseases. Recent studies have shown that chronic activation of ER stress is closely linked to dysregulation of lipid metabolism in several metabolically important cells including hepatocytes, macrophages, β-cells, and adipocytes. Adipocytes are one of the major cell types involved in the pathogenesis of the metabolic syndrome. Recent advances in dissecting the cellular and molecular mechanisms involved in the regulation of adipogenesis and lipid metabolism indicate that activation of ER stress plays a central role in regulating adipocyte function. In this paper, we discuss the current understanding of the potential role of ER stress in lipid metabolism in adipocytes. In addition, we touch upon the interaction of ER stress and autophagy as well as inflammation. Inhibition of ER stress has the potential of decreasing the pathology in adipose tissue that is seen with energy overbalance.
Obesity is the result of an imbalance between energy intake and energy expenditure. Using high-density DNA microarrays and Northern analyses, we demonstrated that the activation of a nutrient-sensing pathway, the hexosamine biosynthesis pathway (HBP), rapidly decreased the expression of a cluster of nuclear-encoded mitochondrial genes involved in skeletal muscle oxidative phosphorylation. Conversely, the expression of uncoupling protein-1 and of the same mitochondrial genes was increased in brown adipose tissue. Most important, these transcriptional changes were accompanied by a marked decrease in whole-body energy expenditure. Short-term overfeeding replicated this transcriptional pattern, suggesting that this adaptation to nutrient abundance occurs under physiological conditions. Thus, the activation of the HBP by nutrients represents a biochemical link between nutrient availability, mitochondrial proteins, and energy expenditure, and it is likely to play an important role in the regulation of energy balance.
Nutrient excess in obesity and diabetes is emerging as a common putative cause for multiple deleterious effects across diverse cell types, responsible for a variety of metabolic dysfunctions. The hypothalamus is acknowledged as an important regulator of whole body energy homeostasis, through both detection of nutrient availability and coordination of effectors that determine nutrient intake and utilization, thus preventing cellular and whole body nutrient excess. However, the mechanisms underlying hypothalamic nutrient detection and its impact on peripheral nutrient utilization remain poorly understood. Recent data suggest a role for thioredoxin-interacting protein (TXNIP) as a molecular nutrient sensor important in the regulation of energy metabolism, but the role of hypothalamic TXNIP in the regulation of energy balance has not been evaluated. Here we show in mice that thioredoxin interacting protein is expressed in nutrient sensing neurons of the mediobasal hypothalamus, responds to hormonal and nutrient signals, and regulates adipose tissue metabolism, fuel partitioning and glucose homeostasis. Hypothalamic expression of thioredoxin-interacting protein is induced by acute nutrient excess and in mouse models of obesity and diabetes, and downregulation of mediobasal hypothalamic thioredoxin-interacting protein expression prevents diet-induced obesity and insulin resistance. Thus, mediobasal hypothalamic thioredoxin-interacting protein plays a critical role in nutrient sensing and the regulation of fuel utilization.
Obesity and related metabolic conditions are of epidemic proportions in most of the world, affecting both adults and children. The accumulation of lipids in the body in the form of white adipose tissue in the abdomen is now known to activate innate immune mechanisms. Lipid accumulation causes adipocytes to directly secrete the cytokines interleukin (IL) 6 and tumor necrosis factor α (TNFα), but also monocyte chemoattractant protein 1 (MCP-1), which results in the accumulation of leukocytes in fat tissue. This sets up a chronic inflammatory state which is known to mediate the association between obesity and conditions such as cardiovascular disease, type 2 diabetes, and cancer. There is also a substantial literature linking inflammation with risk for depression. This includes the observations that: 1. People with inflammatory diseases such as multiple sclerosis, cardiovascular disease, and psoriasis have elevated rates of depression; 2. Many people administered inflammatory cytokines such as interferon α develop depression that is indistinguishable from depression in non-medically ill populations; 3. A significant proportion of depressed persons show upregulation of inflammatory factors such as IL-6, C-reactive protein, and TNFα; and 4) Inflammatory cytokines can interact with virtually every pathophysiologic domain relevant to depression, including neurotransmitter metabolism, neuroendocrine function, and synaptic plasticity. While many factors may contribute to the association between inflammatory mediators and depression, we hypothesize that increased adiposity may be one causal pathway. Mediational analysis suggests a bi-directional association between adiposity and depression, with inflammation possibly playing an intermediary role.
Obesity; inflammation; adiposity; depression; risk factors; cytokines; adipocytokines; fatty acids; lipids
Insulin resistance arises from the inability of insulin to act normally in regulating nutrient metabolism in peripheral tissues. Increasing evidence from human population studies and animal research has established correlative as well as causative links between chronic inflammation and insulin resistance. However, the underlying molecular pathways are largely unknown. In this report, we show that many inflammation and macrophage-specific genes are dramatically upregulated in white adipose tissue (WAT) in mouse models of genetic and high-fat diet-induced obesity (DIO). The upregulation is progressively increased in WAT of mice with DIO and precedes a dramatic increase in circulating-insulin level. Upon treatment with rosiglitazone, an insulin-sensitizing drug, these macrophage-originated genes are downregulated. Histologically, there is evidence of significant infiltration of macrophages, but not neutrophils and lymphocytes, into WAT of obese mice, with signs of adipocyte lipolysis and formation of multinucleate giant cells. These data suggest that macrophages in WAT play an active role in morbid obesity and that macrophage-related inflammatory activities may contribute to the pathogenesis of obesity-induced insulin resistance. We propose that obesity-related insulin resistance is, at least in part, a chronic inflammatory disease initiated in adipose tissue.
Metabolic homeostasis in metazoans is regulated by endocrine control of insulin/IGF signaling (IIS) activity. Stress and inflammatory signaling pathways—such as Jun-N-terminal Kinase (JNK) signaling—repress IIS, curtailing anabolic processes to promote stress tolerance and extend lifespan. While this interaction constitutes an adaptive response that allows managing energy resources under stress conditions, excessive JNK activity in adipose tissue of vertebrates has been found to cause insulin resistance, promoting type II diabetes. Thus, the interaction between JNK and IIS has to be tightly regulated to ensure proper metabolic adaptation to environmental challenges. Here, we identify a new regulatory mechanism by which JNK influences metabolism systemically. We show that JNK signaling is required for metabolic homeostasis in flies and that this function is mediated by the Drosophila Lipocalin family member Neural Lazarillo (NLaz), a homologue of vertebrate Apolipoprotein D (ApoD) and Retinol Binding Protein 4 (RBP4). Lipocalins are emerging as central regulators of peripheral insulin sensitivity and have been implicated in metabolic diseases. NLaz is transcriptionally regulated by JNK signaling and is required for JNK-mediated stress and starvation tolerance. Loss of NLaz function reduces stress resistance and lifespan, while its over-expression represses growth, promotes stress tolerance and extends lifespan—phenotypes that are consistent with reduced IIS activity. Accordingly, we find that NLaz represses IIS activity in larvae and adult flies. Our results show that JNK-NLaz signaling antagonizes IIS and is critical for metabolic adaptation of the organism to environmental challenges. The JNK pathway and Lipocalins are structurally and functionally conserved, suggesting that similar interactions represent an evolutionarily conserved system for the control of metabolic homeostasis.
Metabolism of multicellular organisms has to adjust to environmental changes. Insulin signaling plays an important role in this regulation. Stress signals can repress Insulin signaling, curtailing growth to promote stress tolerance and extend lifespan. While this interaction allows managing energy resources under stress conditions, excessive JNK activity in adipose tissue of vertebrates has been found to promote type II diabetes. Thus, the interaction between stress and Insulin signaling has to be carefully regulated to ensure proper metabolic adaptation. Here, we identify a new regulatory mechanism by which stress signaling influences metabolism in fruitflies. We show that an evolutionarily conserved secreted protein, Neural Lazarillo (NLaz), is induced in response to stress signals, and that it is required for metabolic regulation. NLaz mutant animals are more sensitive to stress and show significant metabolic deficiencies. Similarly, increased expression of NLaz inhibits growth, but increases stress and starvation tolerance. We show that these functions are mediated by an interaction with the Insulin signaling pathway. Our results show that the regulation of NLaz by stress signals is critical for metabolic adaptation of the organism to environmental challenges. Both the Insulin and JNK signaling mechanisms analyzed here are evolutionarily conserved, suggesting that similar interactions control metabolic adaptation in vertebrates.
Recent studies consistently support a hypoxia response in the adipose tissue in obese animals. The observations have led to formation of an exciting concept, adipose tissue hypoxia (ATH), in the understanding of major disorders associated with obesity. ATH may provide cellular mechanisms for chronic inflammation, macrophage infiltration, adiponectin reduction, leptin elevation, adipocyte death, ER stress and mitochondrial dysfunction in white adipose tissue in obesity. The concept suggests that inhibition of adipogenesis and triglyceride synthesis by hypoxia may be a new mechanism for elevated free fatty acids in the circulation in obesity. ATH may represent a unified cellular mechanism for variety of metabolic disorders, and insulin resistance in patients with metabolic syndrome. It suggests a new mechanism of pathogenesis of insulin resistance and inflammation in obstructive sleep apnea. Additionally, it may help us to understand the beneficial effects of caloric restriction, physical exercise, and angiotensin II inhibitors in the improvement of insulin sensitivity. In this review article, literatures are reviewed to summarize the evidence and possible cellular mechanisms of ATH. The directions and road blocks in the future studies are analyzed.
Inflammation and altered immune response are important components of obesity and contribute greatly to the promotion of obesity-related metabolic complications, especially cancer development. Adipose tissue expansion is associated with increased infiltration of various types of immune cells from both the innate and adaptive immune systems. Thus, adipocytes and infiltrating immune cells secrete pro-inflammatory adipokines and cytokines providing a microenvironment favorable for tumor growth. Accumulation of B and T cells in adipose tissue precedes macrophage infiltration causing a chronic low-grade inflammation. Phenotypic switching toward M1 macrophages and Th1 T cells constitutes an important mechanism described in the obese state correlating with increased tumor growth risk. Other possible synergic mechanisms causing a dysfunctional adipose tissue include fatty acid-induced inflammation, oxidative stress, endoplasmic reticulum stress, and hypoxia. Recent investigations have started to unravel the intricacy of the cross-talk between tumor cell/immune cell/adipocyte. In this sense, future therapies should take into account the combination of anti-inflammatory approaches that target the tumor microenvironment with more sophisticated and selective anti-tumoral drugs.
adipose tissue; inflammation; immune cells; adipokines; angiogenesis; hypoxia; macrophages; tumor growth
Adipocytes are highly specialized cells that play a major role in energy homeostasis in vertebrate organisms. Excess adipocyte size or number is a hallmark of obesity, which is currently a global epidemic. Obesity is a major risk factor for the development of type II diabetes (T2DM), cardiovascular disease, and hypertension. Obesity and its related disorders result in dysregulation of the mechanisms that control the expression of metabolic and endocrine related genes in adipocytes. Therefore, understanding adipocyte differentiation is relevant not only for gaining insight into the pathogenesis of metabolic diseases, but also for identifying proteins or pathways which might be appropriate targets for pharmacological interventions. Significant advances towards an understanding of the regulatory processes involved in adipocyte differentiation have largely been made by the identification of transcription factors that contribute to the adipogenic process. It is important to note that the developmental origin of white and brown fat is distinct and different precursor cells are involved in the generation of these different types of adipose tissue (reviewed in Lefterova and Lazar, 2009; Seale et al., 2009). Several transcription factors, notably PPARγ, several members of the C/EBP and KLF families, STAT5, and SREBP-1c, have been shown to have significant roles in promoting adipogenesis. More comprehensive reviews on negative and positive regulators of adipogenesis have been published in the past year (reviewed in Christodoulides et al., 2009; Lefterova and Lazar, 2009). Though many proteins are known to negatively regulate adipogenesis, including Wnts, KLFs, the E2F family of transcription factors, CHOP, Delta-interacting protein A, ETO/MTG8, and members of the GATA and forkhead transcription factor families, this review will focus on transcription factors that positively impact the development of white adipose tissue.
Adipocyte; PPAR; C/EBP; STAT5; KLF; SREBP
Stress of endoplasmic reticulum (ERS) is one of the molecular triggers of adipocyte dysfunction and chronic low inflammation accompanying obesity. ERS can be alleviated by chemical chaperones from the family of bile acids (BAs). Thus, two BAs currently used to treat cholestasis, ursodeoxycholic and tauroursodeoxycholic acid (UDCA and TUDCA), could potentially lessen adverse metabolic effects of obesity. Nevertheless, BAs effects on human adipose cells are mostly unknown. They could regulate gene expression through pathways different from their chaperone function, namely through activation of farnesoid X receptor (FXR) and TGR5, G-coupled receptor. Therefore, this study aimed to analyze effects of UDCA and TUDCA on human preadipocytes and differentiated adipocytes derived from paired samples of two distinct subcutaneous adipose tissue depots, abdominal and gluteal. While TUDCA did not alter proliferation of cells from either depot, UDCA exerted strong anti-proliferative effect. In differentiated adipocytes, acute exposition to neither TUDCA nor UDCA was able to reduce effect of ERS stressor tunicamycin. However, exposure of cells to UDCA during whole differentiation process decreased expression of ERS markers. At the same time however, UDCA profoundly inhibited adipogenic conversion of cells. UDCA abolished expression of PPARγ and lipogenic enzymes already in the early phases of adipogenesis. This anti-adipogenic effect of UDCA was not dependent on FXR or TGR5 activation, but could be related to ability of UDCA to sustain the activation of ERK1/2 previously linked with PPARγ inactivation. Finally, neither BAs did lower expression of chemokines inducible by TLR4 pathway, when UDCA enhanced their expression in gluteal adipocytes. Therefore while TUDCA has neutral effect on human preadipocytes and adipocytes, the therapeutic use of UDCA different from treating cholestatic diseases should be considered with caution because UDCA alters functions of human adipose cells.
Chronic periodontitis is an inflammatory disease with an aberrant response characterized by exaggerated inflammation, involving the release of excess proteolytic enzymes and reactive oxygen species (ROS). Diabetes mellitus is a group of complex multisystem metabolic disorders characterized by a relative or absolute insufficiency of insulin secretion and or concomitant resistance to the metabolic action of insulin on target tissues. Increased production of ROS necessitates elevated requirements for the nutrients involved in antioxidant defenses: Selenium, zinc, and copper. Inflammatory states promote a decrease in the amount of systemic glutathione levels. Catalase is a central antioxidant enzyme constituting the primary defense against oxidative stress.
This study has been designed to evaluate the comparison of glutathione, catalase, and selenium levels in the serum of diabetes mellitus type 2 patients and healthy individuals with and without periodontal disease.
Settings and Design:
This study is a case control study.
Materials and Methods:
The study was designed as a case - control study comprising of 150 subjects, inclusive of both sexes and were divided into three groups of 50 patients each. Group I: 50 subjects with type 2 diabetes mellitus and chronic periodontitis. Group II: 50 subjects who are systemically healthy with the chronic periodontitis. Group III: 50 subjects who are systemically healthy and not suffering from
Serum samples were taken for estimation of glutathione, catalase, and selenium from all groups, and Subjected to biochemical analysis after which atomic absorption spectrophotometry method was used to obtain their levels in serum.
Statistical Analysis Used:
ANOVA and Tukey HSD.
The serum levels of glutathione in diabetic patients with periodontitis were significantly lower with a mean of 61.36 + 8.054 when compared to healthy individuals with and without periodontitis with a mean of 56.93 + 6.874 and 90.36 + 6.564 respectively (P ≤ 0.005). The serum levels of catalase were significantly lower in diabetic patients with periodontitis with a mean of 19.30 + 7.355 when compared to healthy individuals with and without periodontitis with a mean of 20.71 + 6.472 and 36.09 + 5.108 respectively (P ≤ 0.005). The serum levels of selenium were significantly lower in diabetic patients with periodontitis with a mean of 81.41 + 55.419 when compared to healthy individuals with and without periodontitis with a mean of 161.44 + 84.787 and 193.84 + 66.713 respectively (P ≤ 0.005).
The findings from the study suggest that the levels of glutathione, catalase, and selenium are significantly lower in diabetic patients with periodontitis and also in healthy individuals with periodontitis, but are highest in healthy controls, showing that the serum levels are inversely proportional to inflammation and tissue destruction.
Catalase; diabetes mellitus type 2; glutathione; periodontitis; selenium
Obesity is a condition characterized by excess adipose tissue that results from positive energy balance and is the most common metabolic disorder in the industrialized world. The obesity epidemic shows no sign of slowing, and it is increasingly a global problem. Serious clinical problems associated with obesity include an increased risk for type 2 diabetes, atherosclerosis, and cancer. Hence, understanding the origin and development of adipocytes and adipose tissue will be critical to the analysis and treatment of metabolic diseases. Historically, albeit incorrectly, adipocytes were thought to be inert cells whose singular function was lipid storage. It is now known that adipocytes have other critical functions; the most important include sensitivity to insulin and the ability to produce and secrete adipocyte-specific endocrine hormones that regulate energy homeostasis in other tissues. Today, adipocytes are recognized as critical regulators of whole-body metabolism and known to be involved in the pathogenesis of a variety of metabolic diseases. All cells come from other cells and many cells arise from precursor cells. Adipocytes are not created from other adipocytes, but they arise from precursor cells. In the last two decades, scientists have discovered the function of many proteins that influence the ability of precursor cells to become adipocytes. If the expansion of the adipose tissue is the problem, it seems logical that adipocyte development inhibitors could be a viable anti-obesity therapeutic. However, factors that block adipocyte development and limit adipocyte expansion also impair metabolic health. This notion may be counterintuitive, but several lines of evidence support the idea that blocking adipocyte development is unhealthy. For this reason it is clear that we need a better understanding of adipocyte development.