Reference
Obesity frontier
ADIPOKINES: NEW AREAS OF RESEARCH ON THE OBESITY FRONTIER
The area of obesity research is getting hotter ever over the past years. The driving force can be manifolds. Firstly, obesity is a chronic disease that has become a major health problem in most industrialized countries because of its high prevalence, medical illnesses, and economic impact. In the United States, 26% adults are reported to be obese and approximately 60% of adults are overweight. It is estimated that obesity is responsible for 300,000 deaths per year, and that the direct costs (medical expenses) of obesity exceed $50 billion per year, ranking obesity as the second most expensive of all chronic diseases.
Secondary, obesity is associated with increased occurrence of numerous diseases including hypertension, dyslipidaemia, insulin resistance, type 2 diabetes, and metabolic syndrome. Obesity also predisposes to several other independent diseases like asthma, breast cancer, stroke, osteoarthritis, and non-alcoholic liver steatosis. In addition, obesity is accompanied by generalized inflammation, characterized by increased plasma CRP levels as well as by dys-regulated cytokine production by monocytes, lymphocytes and other immune cells. Moreover, the presence of obesity has long been associated with the presence of endothelial and vascular dysfunction, which provides partial explanation of how does obesity may lead to cardiovascular diseases.
Thirdly, recent studies have shown that adipose tissue is no longer considered to be an inert energy storage organ, but is emerging as an active participant in regulating physiological and pathologic processes, including immunity and inflammation. There are two kinds of adipose tissues in mammals: white adipose tissue, which takes up the vast majority in the organism and is thought to be the site of energy storage, and brown adipose tissue, which is mainly found in human neonates and is important for the regulation of body temperature through non-shivering thermogenesis. In addition to the most abundant cell type, adipocytes, the white adipose tissue also contains endothelial cells, fibroblasts, leukocytes and most importantly macrophages whose number presented in the adipose tissue directly correlates with obesity. Many soluble factors have been identified from the adipose tissue and are so called as adipocytokines or adipokines. Some of the adipokines are mainly produced by the adipose tissue like leptin, resistin, adiponectin or visfatin, while others are also synthesized in other tissues like TNF-a, IL-6, MCP-1, and IL-1. Because all of these factors can act in an autocrine, paracrine or endocrine manner in the organisms, adipokines are thought to serve as mediators linking obesity, inflammation, immunity and other obesity related diseases.
Obesity results from long-term positive energy imbalance, that is, energy intake is greater than energy expenditure which leads to lipogenesis (fat synthesis) over lipolysis (fat destruction). In human body, homeostasis or the relative constancy of the internal environment is controlled by the central nervous system (CNS), among which the regulation of human appetite (feeding or fasting) is located in the hypothalamic arcuate nucleus. The arcuate nucleus produces neuropeptides and neurotransmitters which intertwine with the human immune system to form a neuroimmune network that mediates the physiological control of energy homeostasis.
There are two groups of hypothalamic neurons toward food intake. When body energy is in surplus, the POMC/CART neurons produce anorexigenic (appetite decreasing) peptides. Pro-opiomelanocortin (POMC) and cocaine and amphetamine-regulated transcript (CART) are the two representatives of this group. POMC is a precursor protein, tissue specific posttranslational processing of which yields various bioactive fragments, such as adrenocorticotropic hormone (ACTH), alpha-melanocortin stimulating hormone (MSH alpha), and beta-endorphin. Binding of these peptides to melanocortin receptors (MC3R, MC4R) induces a powerful anorectic effect. CART was also found be co-localized with POMC, and its expression in the hypothalamus is up-regulated by psychostimulants as cocaine and amphetamine. CART exerts anorectic function, genetic mutations of which lead to eating disorders including obesity and anorexia. Other anorexigenic neuropeptides include bombesin, cholecystokinin (CCK), motilin, nesfatin-1, neurotensin, neuromedins, neuropeptide B, K, and W, serotonin, somatostatin, vasoactive intestinal peptide (VIP), and urocortin. The other group of hypothalamic neuron is called NPY/AgRP neurons. When body energy is in deficit, the NPY/AgRP neurons express orexigenic neuropeptides (appetite stimulating) to stimulate food intake and decreased energy expenditure. Neurotransmitters falling into this group include neuropeptide Y (NPY) and agouti-related portein (AgRP), orexins, galanin, cannabinoids, and melanin concentrating hormone (MCH). In addition to the neuromodulators, peripheral signals from stomach/gut, pancreas, adipose tissue, and other endocrine glands (such as thyroid hormones, catecholamines, and gonadal steroids) may also act on the arcuate nucleus through either NPY/AgRP or the POMC/CART pathways. Apart from its well recognized digestive and absorptive functions, the gut also produces peptides that have autocrine, paracrine, and endocrine functions. Several dozens of gut hormones have been characterized, elevating gut to be the largest endocrine organ in the body, with the adipose tissue being a close second. Some of the gut hormones such as CCK, glucagon-like peptide 1 (GLP-1), peptide YY (PYY), ghrelin, neuromedin B, gastric releasing peptide (GRP), and Apo A-IV were also found in the brain. Ghrelin is a 28aa orexigenic hormone predominantly produced in the stomach to have appetite stimulating function. Obestatin is 23-residue peptide, derived from post-translational processing of the prepro-ghrelin gene. Obestatin has been initially reported to be the endogenous ligand for GPR39 for counteracting ghrelin-stimulated food intake. However, recent reports observed no effects of obestatin on GPR39-transfected cells in various functional assays. The function of obestatin still remains unknown. Other anorexigenic gut hormones include PYY, CCK, gastric inhibitory peptide (GIP), GLP-1, oxyntomodulin (OXM), Apo A-IV, enterostatin, and oleylethanolamide.
Insulin secreted from pancreas -cell plays an important role in glucose homeostasis. Insulin is a 5.8kd hormone and is derived from the proinsulin precursor by removing the center portion of the molecule (C-peptide), and the joining of the remaining A- and B- chains through disulfide bonds. In insulin abundance the anorexigenic pathway prevails, with increased energy expenditure, increased thermogenesis and diminished food intake. Decreased insulin serum concentrations lead to activation of the orexigenic pathway, resulting in low metabolic rate and enhanced appetite. Obesity, in particular visceral obesity, is associated with resistance to the effects of insulin on peripheral glucose and fatty-acid utilization. Insulin resistance, together with the associated hyperinsulinaemia and hyperglycaemia, and the presence of pro-inflammatory mediators might lead to the development of type 2 diabetes mellitus and atherosclerotic cardiovascular disease. In addition to insulin, amylin, glucagon, and pancreatic polypeptide (PP) are among the other anorexigenic polypeptides produced by pancreas that inhibit food intake. Amylin is a 37-residue polypeptide hormone that is co-secreted with insulin from the pancreatic beta cells during meals. Amylin appears to work in concert with insulin to regulate plasma glucose concentrations in the bloodstream, suppressing the postprandial secretion of glucagon and slowing the rate of gastric emptying.
Peptides from the adipose tissue are attracting tremendous interest recently. Because adipokines can function as hormones to influence energy homeostasis and regulate neuroendocrine activity, they are thought to provide an important link between obesity, inflammatory disorders, metabolic syndrome, and cardiovascular diseases. Leptin and adiponection are the best known adipokines predominantly produced by the adipose tissue. Leptin is coded by the obese (ob) gene, disruption of which leads to obesity. Leptin is primary known as the negative regulator in food intake via the POMC/CART pathway. Later, different kinds of leptin receptors were widely found throughout the central nerve system and the cardiovascular and immune system, indicating its wider range of biological activities. Adiponection (also known as Acrp30, AdipoQ, APM-1 and GBP28) exists as a full-length 30kd protein as well as a globular form containing only the C-terminal globular domain. The full length adiponection can exit as a trimer (LMW), a hexamer (MMW), or 12 to 18-mer (HMW). In contrast to the majority of secreted proteins from adipose tissue, which are elevated in obesity, adiponectin appears to be either decreased or unaltered. Adiponectin circulates at high concentrations in human serum (several milligram per milliliter), and is best known for its role in the regulation of insulin sensitivity. Adipose tissue also secretes adipsin, resistin, visfatin, vaspin, RBP-4, IL-1 , IL-6, TNF , MCP-1, and a number of other factors. Resistin is a small protein secreted by adipose tissue and circulates as a homodimer. Resistin receives its name from its apparent induction of insulin resistance in mice. Visfatin (also known as PBEF) is an insulin-mimetic adipokine that was originally discovered in liver, skeletal muscle and bone marrow as a growth factor for B lymphocyte precursors. It is a nicotinamide phosphoribosyltransferase enzyme that catalyzes first step in the biosynthesis of NAD from nicotinamide. Similarly to insulin, visfatin in vitro enhanced glucose uptake by myocytes and adipocytes, and inhibited hepatocyte glucose release. Vaspin is an adipokine recently identified as a member of the serine protease-inhibitor family. It is strongly expressed in visceral adipose tissue and is stimulated in mouse and human obesity. RBP4 is a recently identified adipokine secreted by adipocytes. It belongs to the lipocalin family and is the specific carrier for retinol (vitamin A alcohol) in the blood. PAI-1 is strongly associated with visceral obesity, insulin resistance, and metabolic syndrome. PAI-1 plasma levels correlate with body mass index and increased waist circumference, and decrease after weight loss. TNFa expression is increased in the adipose tissue of obese subjects. It is thought to be a mediator of insulin resistance. A substantial amount of IL-6 is produced by adipose tissue. Plasma IL-6 correlates with obesity, insulin resistance,a nd cardiovascular disease. MCP-1 is shown to impair insulin stimulated glucose uptake in cultured adipocytes. MCP-1 is secreted by adipocytes, which attracts macrophages to adipose tissue and promotes their IL-1 and TNFa release. In effort to facilitate the obesity research, Raybiotech provides not only specific antibodies and antigens, but also offers multiple levels of research kits. For quantitative purpose, we offer ELISA kits for individual proteins as well as adipokine quantibody arrays for detecting multiple factors in one experiment. For qualitative analysis, we offer sandwich ELISA based arrays (membrane or glass) as well as label based arrays.
