Adipose tissue is an important endocrine organ that secretes numerous protein hormones into circulation. These factors are generally referred to as adipocytokines or adipokines. In addition to secreting cytokines, adipose tissue secretes proteins that influence energy metabolism, which is of great interest to the understanding and treatment of type 2 diabetes. Their relative roles in modifying appetite, insulin resistance and atherosclerosis are the subjects of intense research, as they may be modifiable causes of morbidity in people with obesity.
A sampling of Adipokine Related Products:
In order to understand the genetic basis of obesity, several monogenic murine obesity models have been characterized.The obesity associated with Ay mice may be due to ectopic expression of a secreted protein Agouti. Agouti protein (132 aa in human) is normally expressed in skin but its ubiquitous expression causes obesity. Agouti is a paracrine-signaling molecule that affects pigmentation by inhibiting the melanocortin receptor 1 (MCR-1).
Resistin is an adipose-derived cytokine (adipokine) whose physiological function and molecular targets are largely unknown. Studies have shown that Resistin suppresses insulin's ability to stimulate glucose uptake. It is postulated that Resistin might be an important link between obesity and Type 2 diabetes. Other studies have indicated that Resistin expression is severely suppressed in obesity and that it may act as a feedback regulator of Adipogenesis.
Leptin, the product of the ob (obese) gene, is produced in the adipose tissue, and is considered to play an important role in appetite control, fat metabolism and regulation of body weight. It targets the central nervous system, particularly hypothalamus, affecting food intake. Leptin levels are high in most obese individuals. Studies have shown that it may also influence the reproductive function.
This month's Special:
Biologically Relevant Noggin, N3100-05E
|Expression of pluripotent stem cell markers of hES colonies cultured in the presence of Noggin (N3100-05E,10-20pg/ml) expressed in human cells. A. Green TRA1-60 B. Green SSEA-4 C. Green TRA1-81 D. OCT 3/4 (Blue=Nuclear)
Noggin is a secreted homodimeric glycoprotein that is an antagonist of bone morphogenetic proteins (BMPs). During culture of human embryonic stem (hES) cells without feeder layer or conditioned medium (but with addition of FGF basic), the addition of Noggin allows the stem cells to maintain their undifferentiated, pluripotent state. Commercially available Noggin products are produced in a variety of forms none of which are authentic: non-glycosylated protein expressed in E. coli; glycosylated Fc-fusion protein expresed in NS0, for example. USBiological supplies Noggin in a stable, engineered human 293 cell expression system. The protein is expressed as an authentic glycosylated, disulfide-linked dimer.
Leptin, Adiponectin and Visfatin
White and brown adipose tissues (WAT and BAT, respectively) play a central role in body weight and energy expenditure. WAT is the major site for energy storage via triglyceride synthesis and mobilization via lipolysis. BAT, which expresses UCP1 (uncoupling protein 1), can generate heat by "uncoupling" the respiratory chain of oxidative phosphorylation within mitochondria. The process of uncoupling means that when protons transit down the electrochemical gradient across the inner mitochondrial membrane, the energy from this process is released as heat rather than being used to generate ATP. UCP1 plays an important role in thermoregulation in hibernating animals, neonates, and it contributes to rodent cold- and diet induced thermogenesis.
White adipose tissue can be further broken down into two different types of cells. They are subcutaneous fat and visceral fat. Subcutaneous fat is found just beneath the skin that insulates the body, absorbs trauma, and is a reserve energy source. Visceral fat or abdominal fat is located inside the abdominal cavity packed in between internal organs and torso. An excess of visceral fat is known as central obesity. There is a strong correlation between central obesity and cardiovascular disease and insulin-resistance.
Adipose tissue has traditionally been considered an energy storage organ, but over the last decade, it has been newly understood as an endocrine organ. The concept of white adipose tissue (WAT) as an endocrine organ originated in 1995 with the discovery of leptin and the description of its wide-ranging biological functions. To maintain normal body functions, each adipocyte secretes diverse cytokines and bioactive substances into the surrounding environment.
Many adipokines have been identified. They all integrate in a communications network with other tissues and organs such as the skeletal muscle, adrenal cortex, brain and sympathetic nervous system. They participate in appetite and energy balance, immunity, insulin sensitivity, angiogenesis, blood pressure, lipid metabolism and hemostasis.
plasminogen activator inhibitor-1 (PAI-1)
C-reactive protein (CRP)
This short review will focus on three adipokines involved in the obesity-diabetes connection; leptin, adiponectin and visfatin.
Leptin (from the Greek leptos, meaning thin) is a protein hormone with important effects in regulating body weight, metabolism and reproductive function. The protein is ~16kD and is encoded by the obese (ob) gene. Leptin is expressed predominantly by adipocytes, which fits with the idea that body weight is sensed as the total mass of fat in the body. It is secreted into the blood, secretion proportional to body fat, where it travels to the brain causing a decrease in appetite.
Using the ob/ob mice that were thought to lack a satiety signal, Friedman and colleagues found 'ob' to code for a gene that they called leptin (1). Mice deficient in this gene are morbidly obese and this obesity can be reversed by giving the mice leptin. The leptin receptor was subsequently found in 1995 and is a member of the cytokine receptor family (2).
Although leptin is a circulating signal that reduces appetite, in general, obese people have an unusually high circulating concentration of leptin (3). These people are said to be resistant to the effects of leptin, in much the same way that people with type 2 diabetes are resistant to the effects of insulin. The high sustained concentrations of leptin from the enlarged adipose stores result in leptin desensitization. The pathway of leptin control in obese people might be flawed at some point so the body doesn't adequately receive the satiety feeling subsequent to eating.
Adiponectin is a hormone produced in fat cells that increases the effectiveness of insulin. Studies show that when we have plenty of adiponectin, not only is our insulin production lower; our blood sugar is better controlled, which decreases our risk of diabetes and heart disease. Furthermore, people who have plenty of adiponectin generally have better controlled weight. When we gain weight, adiponectin production goes down. Weight that is gained in the belly, as opposed to weight gained in the hips and thighs, is the weight that dramatically reduces adiponectin production. Adiponectin levels can be increased through exercise. In one study, adiponectin levels rose 260% after two to three bouts of brisk exercise despite unchanged body weight, and even remained elevated after 10 weeks (4).
Another adipokine implicated in the obesity-diabetes saga is the newly discovered molecule visfatin. This adipokine is secreted by visceral fat and has been found to have glucose lowering effects similar to that caused by insulin. Visfatin and insulin stimulate muscle and adipose cells to take up glucose and restrain glucose release from hepatocytes (5,6). Visfatin has different properties to insulin, however, in that its levels are constant regardless of food intake whereas insulin levels change depending on the feeding state. Visfatin also has significantly lower intracellular levels compared to insulin but interestingly it acts on the insulin receptor but not competitively. This may mean that visfatin is a mimetic of insulin but its levels are low enough so that it does not interfere with the actions of insulin. Research is continuing in this adipokine as a potential therapy for the treatment of type 2 diabetes mellitus.
Adipocytes are is no longer considered just a storage depot, the ugly culprits that are blamed when clothes get annoyingly tight in the wrong places, but instead, it is becoming increasingly apparent that adipose tissue is an active endocrine and paracrine organ that releases bioactive mediators that influence homeostasis, as well as inflammation, coagulation, fibrinolysis, insulin resistance, diabetes, and atherosclerosis. Although the cause-and-effect association has not been definitively established, the available evidence indicates that visceral fat is an important link in the negative health effects of metabolic syndrome.
1. Zhang et al. (1994) Nature, 372:425
2. Tartaglia et al. (1995) Cell 83:1268-1271
3. Considine R.V. et al.,(1996). N Engl J Med 334:292–295.
4. Kriketos, A. et al. Diabetes Care, (2004) 27:629-630.
5. Fukuhara et al. (2005) Science 307:426-450
6. Hug & Lodish, (2005) Science. 307:366-367.