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Historically adipose tissue has been widely studied and accepted in its role as an energy store and metabolism. It is only in the last 15 years that it has a recognised role in responding to neural, nutrient and hormonal signals and secreting adipokines that control feeding, thermogenisis, immunity and neuroendocrine functions.ref
Endocrine organs have traditionally included the thyroid gland, parathyroid, placenta, pituitary gland, testes, ovaries and pancreas. However due to the discovery of hormone secretion by adipose tissue in the 1990s and its significant distribution throughout the body, it is becoming widely accepted and studied for its role in endocrinology.
In mammals adipose tissue is composed of adipocytes which are the principle cells involved in hormone secretion and constitute the major differences in Brown and White adipose tissue. However, many secreted proteins are also produced by the non-adipocyte components of adipose tissue. Adipose tissue also contains a matrix of conjunctive tissue, nerve fibres, vascular stroma, lymph nodes, immune cells, fibroblasts and undifferentiated adipose cells.1It is the entire functioning unit that is considered to be a true endocrine organ.3
The adipocyte is important to the body in maintaining proper energy balance, storing calories in the form of triglycerides, mobilizing energy sources in response to hormonal stimulation, and commanding changes by signal secretions (adipokines). They have the capacity to synthesize fatty acids and to store triglycerides when energy supply is high and to break them down via lypolysis when energy is low. During the fed state, glucose uptake is controlled by an insulin dependent GLUT 4 receptor and pushes it through glycolysis to make fatty acids and glycerol to form triglycerides. Free fatty acids are also taken up by VLDL and chylomicrons by LPL. During the fasting state adipose tissue releases fatty acids and glycerol by hydrolysis of triglycerides. Fatty acid conversion is stimulated by noradrenaline and a fall in insulin.The sympathetic system controls metabolic mechanisms and the parasympathetic system controls anabolic mechanisms.
Figure 1: Adipocytes with triglycerides stored as large lipid droplet at centre of cell while the nucleus is forced to the side into the cytosol.
Brown adipose tissue (BAT) is a well vascularised tissue, situated around the kidneys, nape of the neck, between the scapulae and in the axillae. It is abundant in infants and is metabolised to generate extra heat by no-shivering thermogenesis. The metabolism of brown fat is stimulated by catecholamines released in response to cold stress.
In adulthood, white adipose tissue (WAT) predominates and contributes to 20% of total body mass in males and 25% in females. The largest WAT depots are found around viscera and in the subcutaneous areas and they can have different function. Visceral fat has been described as near or inside the viscera of the abdomen particularly in the mesentry, retroperitoneal or omentum. Visceral fat contributes directly to the portal system and potentially impacts on the liver, where as the subcutaneous fat just below the skin secretes into the system circulation.3 White adipose tissue has many functions which fall into two broad categories: Secreted proteins that have metabolic effects on distant cells or tissues and enzymes involved in the metabolism of steroid hormones.
Leptin's primary role is to serve as a metabolic signal of energy sufficiency rather than excess.2 Leptin levels rapidly decline with caloric reduction and weight loss. This decline is associated with adaptive physiological responses to starvation including increased appetite and decreased energy expenditure. Blood brain barrier leptin transport falls in parallel with plasma level during fasting and increases in response to feeding.6 Although leptin is produced by other endocrine organs the amount of leptin produced primarily depends on the mass of adipose tissue particularly in the subcutaneous viscera. Secretion also depends on other factors including insulin, glucocorticoids, TNF-Î± and oestrogens which all increase production while Î²3 adrenergic activity, androgens, free fatty acids and growth factor decrease it. The Obese Leptin gene is located on chromosome 7 in humans.3
These adaptations, which may involve lipids or other nutritional factors, enable leptin to function as both a fasting and satiety signal.
The principle role of leptin is in thermoregulation and energy homeostasis through stimulating the expression of neuropeptides which induce inhibition of nutritional intake, increases overall energy consumption and increases sympathetic tone. Conversely it inhibits the expression of neuropeptide Y and agouti peptide which increases nutritional intake and reduces energy consumption.
Leptin is also involved with many other roles including the maturation of the reproductive cycle and puberty. Its effects on the immune system have also been documented and include improved efficiency by increasing cytokine production, phagocytosis and T-cell proliferation. It plays a role in blood pressure regulation by nitrogen oxide synthesis and activation of the sympathetic nervous system. Finally its other roles include oesteogenesis and angiogenesis.
Leptin receptors vs leptin secretion.
Ob/ob mice eg
Adiponectin is exclusively secreted by adipose tissue, more predominant in the subcutaneous fat and is principally involved with glucose regulation and fatty acid metabolism. Levels of the hormone in the blood stream are inversely correlated with mass of body fat, inflammatory states, insulin resistance and cardiovascular disease. Expression of receptors is correlated with insulin levels particularly in adipose tissue and skeletal muscle. It plays a role in the suppression of the metabolic abnormalities that may result in type 2 diabetes, arthrosclerosis, obesity, non-alcoholic fatty liver disease and metabolic syndrome. The effects of adiponectin not only depend on the level in the blood stream but also the expression of appropriate subtype receptors at the tissue level.
Adiponectin also has numerous vascular effects including increased vasodilation, inhibition of monocyte adhesion and scavenger receptors, decreased TNF-Î± and subsequent effects on immunity, increased production of nitrogen oxide, stimulation of angiogenesis, and reduced thickness of vessel walls and reduced migration of endothelial cells.2
It has been proposed that the decline in plasma adiponectin prior to the onset of obesity and insulin resistance could be a contributing factor.3 It has also been observed that the administration of adiponectin can improve the metabolic profile of these patients.
Tissue Necrosis Factor -Î± (TNF-Î±)
Adipocytes and stromovascular cells secrete TNF-Î± which is a cytokine which induces necrosis of tumors.7 It has many roles including immunomodulatory, pro-inflammatory and apoptosis, carbohydrate and lipid metabolism, insulin resistance and production of other cytokines. The amount secreted and expressed increases with the mass of adipose tissue present and body mass index, tending to be more highly associated with subcutaneous adipose tissue than visceral adipose tissue. Chronic exposure to TNF-Î± has been shown to induce insulin resistance. Adipose tissue expresses TNF-Î± receptors in the membrane bound and soluble forms and has principle roles in lipolysis and insulin resistance. It is suggested that in obese patients adipose tissue contains more macrophages which is associated with increase secretion of TNF-Î± and IL-6.
Interleukin -6 (IL-6)
IL-6 is a cytokine involved with insulin resistance, obesity, lipolysis and proinflammation. It is expressed by adipocytes and the adipocyte matrix particularly in visceral adipose tissue and has both central and peripheral effects. While other tissues produce IL-6, adipose tissue is considered to produce one third of all circulating IL-6. Generally reduced secretion is associated with weight loss, however in obese patients this role appears to reverse where IL-6 deficiency has been associated with obesity.3 In addition, IL-6 has also been found to inhibit adipogenesis and decrease adiponectin secretion.3
Plasminogen Activator Inhibitor (PAI-1)3
Plasminogen activator inhibitor has been implicated in angiogenesis, fibrinolysis and atherogenesis. Increased levels of PAI have been observed in obese patients and those with metabolic syndrome, both a causal and reverse causal effect have been found. It is produced by white adipose tissue particularly visceral and has been associated with thrombotic tendencies. Studies have further shown that PAI-1 correlates with increased fibrosis via inflammatory mechanisms and remodelling of vascular architecture resulting in atherosclerosis and cardiovascular disease.
Adipsin is a serine protein secreted by adipose tissue and it has been notable by its absence in obese individuals. It has been implicated in the immune complement system and has the same activity as compliment D. It has effects on red blood cell lysis by activating the alternative compliment pathway. A long with acylation stimulating protein, correlations have been found with decreased levels in obesity, metabolic syndrome, insulin resistance, dyslipidemia and cardiovascular disease.
Resistin as the name suggests has been associated with insulin resistance in obesity and is more readily expressed by visceral adipose tissue than subcutaneous fat.2 The expression of resistin has been found to increase with inflammation, glucocorticoids and lipolysaccharides and decreased by TNF-Î± and Î²-adrenergic.3 However studies have been unable to substantiate the link with obesity and glucose homeostasis. Resistin is also considered to have a pro-inflammatory influence similar to TNF and IL-6.2
Renin Angiotensin System (RAS) proteins.
Adipocytes have been related to the expression of various proteins involved with the renin angiotensin system. RAS regulates blood pressure and studies have suggested a causal association between obesity and hypertension.3
Furthermore, receptors for angiotensin I and II have been found in adipocytes and angiotensin II appears to control development and differentiation of these cells, secretion of immunomodulating agents and RAS proteins.8
It has been implicated in lipogenisis and the accumulation of adipose tissue. Adipocyte RAS (angiotensin-II) has been further implicated in cardiovascular disease due to its ability to increase production of adhesion molecules, macrophages, platelet aggregation, PAI-1 and atherosclerosis.2
Enzymes involved with metabolism of Steroid Hormones.3
Studies have found that various enzymes produced by adipose tissue can contribute to the conversion, activation and inactivation of steroids.10 The steroidogenic enzymes found in adipose tissue can be broadly classified into the cytochrome P450 proteins and the hydroxysteroid dehydrogenases (HSD).13 The enzyme associated with oestrogen activation is aromatase, androgens with 5Î±-reductase 1 and glucocorticoids with 11Î²-HSD1.
Studies have suggested that as much 100% of oestrogen in the post menopausal woman and 50% of testosterone in the premenopausal woman can be attributed to steroid metabolism by adipose tissue. 3,14,15 Furthermore the enzymes found in adipose tissue linked with glucocorticoid metabolism has been associated with central obesity and metabolic syndrome.3
Sex hormone receptors found in adipose tissue have been found to contribute to the control of leptin and lipoprotein lipase production. As explained they have key roles in the amount and distribution of adipose tissue and subsequent consequences in terms of insulin resistance, obesity and metabolic syndrome. 11Specifically this may explain the impact on an aging individual, as less sex hormones are produced and they tend to develop these health problems.
Visfatin has been identified as an adipocytokine and has been associated with an increase with obesity. Its role has been described as insulin mimetic as it binds to and activates the insulin receptor and has an impact on decreasing plasma glucose levels.9 It was also noted however that the plasma concentration of visfatin did not vary considerably in the fasting or fed states in mice compared to insulin; it concluded that plasma concentrations were so low as to not impact significantly on decreasing glucose levels9.
Peroxisome proliferator activated receptor (PPAR-Î³2)
PPAR-Î³2 is found in adipose tissue and is involved with regulation of cellular differentiation, development and metabolism. PPAR-Î³2 expression is stimulated by insulin. It has also been associated with the proinflammatory response and subsequently the development of atherosclerosis and plaque stability.
Table 1 presents a brief overview of the major individual hormones secreted by adipose tissue and their effects.
Table 1: The factors secreted by white adipose tissue.2
Signals to the CNS about the body's energy stocks
Increases sensitivity to insulin, is antiinflammatory & attenuates progression of artherosclerosis
Increases insulin resistance
Lipolytic, increases energy consumption and reduces sensitivity to insulin
Proinflammatory, lipolytic, reduces sensitivity to insulin
Activates the alternative complement pathway
Stimulates triacylglycerol synthesis in WAT
Precursor of angiotensin II, involved in regulating arterial blood presssure
Inhibits plasminogen activation, blocking fibrinolysis
Initiates the coagulation cascade
Stimulates vascular proliferation (angiogenesis) in WAT
Insulinomimetic predominantly produced by visceral fat
Vasodilator and inducer of vascular neoformation
Preadipocyte proliferation & differentiation, adipocyte development & apoptosis
Stimulates proliferation & differentiation of adipocytes
Stimulates differentiation & development of adipocytes
Immunoregulator with paracrine action in WAT
Hydrolysis stimulating enzyme in the TAG of lipoproteins (chylomicron & VLDL)
Transfers cholesterol esters between lipoproteins
Protein component of lipoproteins, especially VLDL
Regulates many processes, inflammation, blood coagulation, ovulation & gastric acid secretion
Produced by action of aromatase;principal source of oestrogen in men & postmeopausal women
Generated by 11-hydroxysteroid dehydrogenase, type II, transforms cortisone into corisol in WAT
Biological actions are not very clear yet, but are related to control
Table 2 presents the individual receptors found in adipose tissue and their effects.
Table 2: Individual receptors and their effects
Principal biological effects
Leptin (+) Lypolisis and lipid oxidation
Insulin (+) Lipogenesis & glucose capture & (-) lypolisis
Glucocorticoids (+) Lypolisis
Glucagon (+) Lypolisis
Catecholamines (+) Lypolisis
T3 and T4
T3 and T4 (+) Lypolisis
Sexual steroids Regulate adipocyte development
IGF-1 (+) Adipogenesis
GH (+) Lypolisis
Prostaglandins (-) Lypolisis
TNFÎ± (+) Lypolisis & increase insulin resistance
IL-6 (-) LPL, (+) Lypolisis
Adenosine (-) Lypolisis & (+) glucose capture
Adiponectin (+) Insulin sensitivity
Gastrin Regulates leptin expression
CCK Regulates leptin expression
GIP (+) Synthesis of FFA & TAG
GLP1 (+) Synthesis of fatty acids
ASP (+) Synthesis of TAG
ANP Modulates glucose metabolism
Angiotensin II (+) Lipogenesis, induces insulin resistance
Bradykinin Increases sensitivity to insulin
EGF Regulates adipocyte differentiation
TGF-Î² Blocks adipocyte differentiation
Melatonin Synergizes the action of insulin
Many effects of adipose tissue have been demonstrated in abnormalities ie deficiency or excess. When the production of these cytokines is not properly regulated then this manifests in metabolic disorders, atherosclerosis and cardiovascular disease.
The key role of adipose tissue is in metabolism through mobilisation of fatty acids during the fasting catabolic state and storage of triglycerides during the anabolic fed sate.
It has a demonstrated role in inflammation via the production of the key enzymes XX. This has a further impact on the development of atherosclerosis and subsequent cardiovascular risk.
While many aspects of the endocrinological functions of adipose tissue have recently come to light more research is required to elicit further functions and completely understand the physiology of adipose tissue. With increasing global health questions around metabolic disorders and obesity, research in this area has the potential to impact significantly on our understanding and treatment of these issues.