Endocrine Functions of Adipose Tissue in Disease
Visceral and subcutaneous tissues to adipokine secretion have various variations. In this context, the accumulation of subcutaneous adipose tissue characterizes peripheral obesity and is more common for women. The increased risk of associated pathologies does not suggest this form of obesity (Rittig et al., 2012). Yet central and abdominal obesity in men is more common and requires a buildup of visceral adipose tissue. In epidemiological research, these kinds of obesity were associated with an increased risk of diseases including resistance to insulin, type 2 diabetes, and hypertension, and the cardiovascular risk was dramatically increased.
Under obesity, dietary excess and obesity itself, lipids accumulation is causing cell tension, and JNK and NF-SB pathways are activated. Inflammatory signals control protein phosphorylation and various transcriptional effects that lead to the growth of pro-inflammatory molecules, including TNF-α, IL-6, leptin and resistance, hemocytes including monocyte protein 1 (MCP-1), and other proatherogenic mediators such as PAI-1. The tissue of white adipose is also a secretory organ of certain molecules with endocrine, paracrine and autocrine behavior, not only an energy reservoir (Wu et al., 2012). Some of those molécules, which are secreted by adipocytes, are involved in body weight regulation (leptin, adiponectin), in local inflammation of the body caused by obesity (TM-α, IL-6and IL-1β).
Leptin is the mainly adipocytic hormone that plays an important role in body weight control through its central appetite and peripheral consequences on energy expenditure regulation (Marti et al., 2001). The vast majority of obese patients have high levels of leptin increased according to adiposity and hyperinsulinemia, often referred to as leptin resistance (Arita, 2012). This is an insulin resistance to hyperleptinemia shown by obese people in changes in the phosphorylation of the insulin receptor. Adiponectin is also an extra hormone that is secreted by adipocytes that regulate food intake. In several trials, obesity, diabetes mellitus, and Coronary Artery Disease are hypoadiponectinemia (Furukawa et al., 2003). It also has an inverse relationship to other risk factors such as blood pressure, total cholesterol and low-density lipoproteins (LDL). In addition to its anti-diabetogenic and antiatherogenic influence. Low concentrations or high levels of leptin were associated with an increase in metabolic and cardiovascular risk in cross-cutting population studies.
Several proinflammatory cytokines are secreted by different cell types, including adipocytes. They conduct paracrine or autocrine activities and they are involved in a local inflammatory response in obese patients ‘ adipocytes. TNF-α levels have been described as having a positive relationship to adipose depot size in the adipocyte (Rodríguez et al., 2015). Also, mRNA levels of TNF-α are increasingly associated with insulin resistance in the fat-treated tissue of several murine models of obesity and diabetes and obese patients. TNF-α stimulates, on the one hand, lipolysis and inhibits LPL and GLUT-4 expression as a pathway to reduce fat depot excesses. Nevertheless, elevated TNF-α levels in adiposity could be responsible for any metabolism of obesity-related modification such as resistance to insulin. TNF-α thus increases free fatty acids to minimize insulin sensitivity and has an inhibitory effect in the liver on insulin action to increase the production of hepatic glucose.
Therefore, TNF-α neutralization with monoclonal antibodies decreases the amount of glucose in the KKAy diabetic murine (Winkler et al., 2003) and boost glycemic control in subjects immune to insulin (Gómez-Hernández et al., 2012). Similarly, six weeks of anti-TNF-α treatment reduced fasting glycemia and glucose intolerance in the visceral white adipose tissue and improved insulin sensitivity, particularly in the 52-week-old BATIRKO depot with serious brown fat lipoatrophy.
In both adipose and protein expression regulated by this transcript factor, the anti-TNF-α treatment decreased activation for NF–μB in both gonadal white adiposity and brown adipose tissue as well as in aorta (Gómez-Hernández et al., 2012). This mouse model is based on anti-TNF-α antibodies. However, therapy with anti-TNF-α antibodies was used to reverse vascular insulin resistance and functional dysfunction (Gómez-Hernández et al., 2012). Inhibitor 1 (PAI-1) of angiotensin and plasminogen activators are also molecules secreted by adipocytes with increased gene expression in obesity.
Displaying a vascular role deleterious effect. Also, another element of the adipocytic renin-angiotensin system is angiotensin II that has a positive impact on adipose tissue differentiation and regulates adiposities by its lipogenic actions. In addition to subcutaneous fat, increased production of visceral fat to PAI-1 secretion by adipose tissue has been found. PAI-1 levels in central obesity along with related vascular changes have been increased.
Brown fatty adipose is also a wet organ and includes many cytokines, adiponectin, and leptin as well as various hormones and influences, such as TNF-α. There are, however, a large number of molecules secreted by BAT, too. Many are needed to adapt to cold conditions and to stimulate adrenergic, including the fibroblast growth factor type 21 (FGF 21). The brown adipose activation decreases adiposity in mice and protects against high-fat obesity from the diet (Ghorbani, Claus and Himms-Hagen, 1997, P121). Over the past few years, the amount of BAT has been identified as a reverse correlation with the human body mass index, especially in older people (Cypess et al., 2009, P150). Moreover, it has been recently shown that BAT can be protected from several aging diseases. Thus, people with smaller BAT depots are more vulnerable to WAT accumulation and an increased risk of metabolic and vascular alterations than thermogenic, recent studies have shown that BAT can play an important part in the metabolism of lipids and carbohydrates (Giralt and Villarroya, 2013, P299). First, brown adipose tissue can contribute to a decrease of high triglyceride levels and thus reduce obesity in humans (Cereijo, Giralt and Villarroya, 2014). Thus, lipoprotein-rich triglycerides (TRLs), which can release a portion of fatty acids by LPL, bring lipids into circulation. Fatty acids are processed by other secondary organs such as white adipose tissue and skeletal muscle, while excess cholesterol-rich particles are eliminated in the liver. High rates of remnants, such as diabetic dyslipidemia, of triglycerides and cholesterol-rich, also pose a risk for the development of cardiovascular disorders (Ouellet et al., 2012). Increased BAT activity with short cold exposures has been identified as a way of controlling the metabolism of the TRLs in mice by controlling the elimination and excess of lipoproteins (Bartelt et al., 2011, p200), thereby reducing triglyceride levels and slightly raising the levels of HDL. Therefore, a metabolic system that pushes TRLs to highly successful intake of fatty acids effectively integrates fatty acids into the brown adipose tissue. This process linked to an increase in VEGF expression (Bartelt et al., 2011, p200) leads to increased lipoprotein permeability and the emergence of triglycerides from capillaries. The norepinephrine activated BAT not only stimulates triglyceride fatty acid release and higher VEGF output but also increases the LPL expression. LPL is, therefore, able to degrade triglycerides and to provide plasma membrane transporters for fatty acids like CD36. In human beings, the activation by cold exposure of BAT has also been shown to increase its oxidative metabolism and to decrease the content of triglyceride and make a significant difference to the energy consumption (Fitzgibbons et al., 2011). Therefore, activation of BAT would help correct hyperlipidemia, which would boost deleterious effects such as insular-resistance or atherogenic processes of obesity and dyslipidemia. This year’s BAT activation has thus been identified as reducing plasma triglyceride and cholesterol rates and diminishing the production of diet-induced atherosclerosis in an experimental model. Initial studies have indicated that human BAT activation could also reduce triglyceride and cholesterol, but future research should consider possible anti-atherogenic effects. On the other hand, BAT could regulate the metabolism of carbohydrates (Bartelt et al., 2011, p200). It has also been defined. When UCP-1 is activated by fatty acids, mitochondria of BAT use pyruvate for combustion. Also, GLUT-1 and GLUT-4 glucose transporter may be associated with BAT glucose uptake as both cold and norepinephrine increase the activity and expression of both transporters. Therefore, concerning the high-fat diet-induced obesity of the white adipetic tissue, which is easily infiltrated by inflammatory cells, brown adipetic tissue does not seem to accumulate the macrophage infiltration. The large number of BAT mitochondria that allow metabolism of the fatty acids by β-oxidation can be attributed to this. In WAT, the capacity to metabolize lipids would, however, be surpassed with lipotoxic effects and inflammatory reactions, and macrophages and immune cell infiltrations facilitated (Teresa Ortega et al., 2011).
Perivascular adipose tissue extending from the adventitious layer is a central modulator of vascular function for both the models and subjects of the thin species. However, the beneficial effects of PVAT on vascular functions are impaired (PVAT dysfunction) and transformed into harmful roles under pathological conditions, particularly obesity-related cardiovascular diseases (Ozen et al., 2015, p 162). It increases the size of the perivascular tissue and produces a hypoxia condition that can minimize the development of adiponectin and protect it against atherogenesis and other vascular complications. PVAT also secretes other biologically active compounds, which can be autocrine as well as paracrine. In vascular inflammation, too, PVAT has a proven function (Ozen et al., 2015, p 162). On the other hand, a diet-induced weight loss has been identified to reverse PVAT dysfunction by a mechanism involving reduced inflammation and increased activity within PVAT nitric oxide synthase. PVAT also loses its vasoregulation ability with obesity and metabolic syndrome as a result of decreased releases of adipokines of vasodilator and a reciprocal increase in the release of vasoconstrictor factors (Aghamohammadzadeh et al., 2015, p299). Therefore, anti-contractile properties of the perivascular adipose tissue are impaired in obesity (Aghamohammadzadeh et al., 2015, p299). An increased PVAT may also correlate positively with the amount of intra-abdominal adipose tissue. It was also identified. Thus PVAT can be infiltrated by immune cells including macrophages and T lymphocytes in obesity and atherosclerosis in addition to increasing their size (Fitzgibbons et al., 2011). The accumulation of T lymphocytes may support the growth of adipose tissue by an increase in the development of 15d-PGJ2 and PPAR-activation due to adipose genesis. Macrophages, however, don’t impact PVAT growth but produce cytokines that alter the secretion of adipocyte. The PVAT has therefore been identified with models of obesity, lower levels of adiponectin and increased levels of leptin (Takaoka et al., 2010), pro-inflammatory cytogenic and chemokine, and reactive oxygen species [ROS] (Meijer et al., 2011, p211) and esterified fatty acids (Ghorbani, Claus and Himms-Hagen, 1997). The inflammatory characteristics of the epicardial adipose tissue were nevertheless defined as independent of obesity (Meijer et al., 2011, p211). In this relation, recent mice studies have also shown that the morphological and gene-expression profiles of PVAT surrounding the thoracic aorta artery are very similar to BAT (Fitzgibbons et al., 2011). Also, the thoracic aorta of perivascular adipose tissue and BAT are more resistant to high-fat dietary inflammation (Fitzgibbons et al., 2011). Also, the production of atherosclerosis can be prevented by PVAT which has thermogenic characteristics like BAT in rodents and beige fat in humans along with the clearance of triglycerides (Trayhurn, 2013). It would be worthwhile investigating whether perivascular adipose tissue has similar morphology and gene expression to BAT in the studied murine trends in obese patients with and without cardiovascular disease. Therefore, triggering PVAT, the BAT phenotype may be useful for the prevention of obesity-related vascular diseases such as high blood pressure and atherogenesis.
A variety of adipokines have been shown to improve obesity and overweight. These pro-inflammatory ones, in particular, are unregulated: TNFα, resistance, fatty acid-binding protein adipocytes (A-FABP), Retinol-binding protein 4, Monocyte chemo-attracting protein (MCP1) and Interleukin 6 and so on (Ouchi et al., 2011).
2.4.1 A- FABP; more than just a lipid chaperon
Intracellular lipid chaperones, which contain molecular weight molecules of 14–15 kDa are intracellular fatty acid-binding proteins . In their inner cavity with a high affinity to organize lipid responses in different cells, they reversibly bind to hydrophobic ligand including saturated and unsaturated long-chain fatty acids, eicosanoids and other associated compounds (bile acids or retinoids). The reality of the A-FABP expression is highly regulated during the differentiation of the adipogenesis, and its mRNA transcription is regulated with fatty acids, peroxisome proliferator gamma (PPAR-α), and also insulin (Unamuno et al., 2018), as its name indicates. The expression of a-FABP is most abundant in mature adipocytes. Because of the striking phenotype found in A-FABP knockout mice, A-FABP is best represented in the FABP family. Mice with no mutation in aP2 are morbidly obese, the gene encoding A-FABP (Unamuno et al., 2018). Besides, small molecules targeting A-FABP have proved effective in the prevention of some diseases, including atherosclerosis (Hoo et al., 2013), acute liver injury and non-alcoholic liver fatty disease (Hoo et al., 2013), endothelium dysfunction and so on. While cloned in 1983, it was just one decade ago that A-FABP was identified as a secretory protein. Xu et al. found that A-FABP is present to a high level in a culture medium from differentiated 3T3L1-adipocytes during the detection of adipocyte proteins by tandem mass spectrometry-based proteomic analysis (Hui and Feng, 2018). More studies were performed on the presence of A-FABP in people (121 men and 108 women, age 33-72). More analyzes showed a positive association between age and gender-specific serum A-FABP (P < 0.005) levels with waist circumference, blood pressure, dyslipidemia, rapid insulin, and insulin inspection resistance rates of homeostasis.
2.4.2 Hypoadiponectinemia and metabolic syndromes
In 1996, obesity has cloned in three separate groups (Hui and Feng, 2018) and is one of the most concentrated adipokine (0.01% of the total serum protein) in the circulation. After its discovery, its negative relation with obesity is in direct contrast to the majority of the known adipokines. it has generated strong interest. Adiponectin monomeric is a 30 kDa protein with a global domain C-terminal and N-terminal domain-like collagen (Hui and Feng, 2018). Adiponectin monomer has never been detected under physiological conditions, however. Instead, the primary type, known as the low-molecular, medium-and high-molecular-weight form of adiponectin are the cutter, hexamer, and oligomers (18 meters or higher). At through step of transcriptions, translations and multimers and finally secretion, circulating adiponectin levels are tightly regulated (Hui and Feng, 2018). It is also no surprise that adiponectin often has varying blood rates and multimer ratios in the bloodstream. Adiponectin decrease has been observed in both animal and clinical models in obese adipose tissue and circulation at a transcriptional level. Nevertheless, the serum HMW adiponectin values are much more important to the prevalence and extent of metabolic syndromes relative to the total serum level of adiponectin. Inverted associations have been identified by numerous clinical trials between high molecular adiponectin weight, (HMW) and triglycerides, blood pressure, obesity, and rapid glucose, whereas cholesterol labeled’ good-cholesterol’ is positively correlated with high-density lipoprotein (HDL) (Hui and Feng, 2018).