The Adipocyte – from a mere fat store to the primary member of appetite regulation
The traditional view of the adipocyte was that of a fat storage cell. A cell responsible for storing excess fats and then making them available for use as energy upon demand. The realisation however that the adipocyte can secrete signalling messengers, called adipokines, and act as an endocrine cell brought the study of obesity out of the shrink’s office and into the scientist’s laboratory.
There are two different types of adipose tissue, white and brown. White adipose tissue (WAT) is the fat storage tissue and brown adipose tissue (BAT) produces heat. BAT is commonly called ‘baby fat’ as it is present in babies but converts to WAT in adulthood. This conversion is performed by mitochondrial uncoupling protein 1 (UCP1), which is activated by the diet, in the mitochondria. Mice that are genetically made to express UCP1 in their WAT have been found to become obesity resistant. This fact has sparked interest in a possible treatment for obesity, by identifying what causes the UCP1 to stop working and so convert BAT to WAT, and then finding a way to stop that so that excess energy is released as heat rather than stored in WAT resulting in obesity (Cinti 2006).
Fat cells were first considered to be able to sense energy demands and signal to decrease food intake in the 1950’s. However it was not until Coleman in 1973, using parabiosis, provided evidence that a circulating factor existed that signalled information about the body's energy requirements. This idea was not supported at the time but again became an exciting prospect when Siiteri, (1987) examined the role of obesity in cancers of the reproductive tract and found that adipocytes secreted the hormone oestrogen which is implicated in breast and endometrial cancers. Oestrogen is produced by the aromatase enzyme which is present in many tissues including adipose. The production of oestrgen has been found to be accelerated in people that are obese as more adipose tissue means more oestrogens and so a higher incidence of cancers in the reproductive tract in obese individuals. Another exciting prospect which supported the adipocyte as a regulator of energy stores came when adipsin, a serine protease, was also discovered to be secreted by adipocytes (Cook et al, 1985, Flier et al, 1987) and has since been found to be deficient in some animal models of obesity.
Figure 1: Examples of some of the molecules that are secreted from adipocytes
Adipokines – The elusive link between obesity and diabetes?
Obesity brings with it associated complications including cardiovascular problems, some cancers and type 2 diabetes mellitus. As cases of obesity are increasing in adults, so are cases of diabetes but perhaps more alarmingly is the increase in obesity related diabetes in children. The reason for the strong relationship between obesity and type 2 diabetes mellitus (T2DM) is still largely unknown and so there is currently a lot of research into how obesity can lead to T2DM.
In 2001, an article in the Washington Post read, ‘Hormone may be key to diabetes’ (Washington Post, Jan 18th, 2001). This miracle hormone was resistin, a molecule secreted from adipocytes of white adipose tissue. This molecule had been found to be involved in the emergence of T2DM. Resistin blood serum levels were found to be significantly increased in cases of obesity and it was found to interfere with the actions of insulin and with glucose tolerance, causing insulin resistance in mice. This was also supported by research showing that deliberately induced diabetes, caused by provision of a high fat diet, caused obesity and significantly elevated resistin levels in mice. These effects could be subsequently reversed by administration of a resistin antibody (Steppan et al, 2001). This discovery sparked excitement among scientists as resistin appeared to be a candidate for the missing link between obesity and T2DM. However studies in humans provided disappointing results, showing no significant differences between blood serum resistin levels in lean and obese people and no differences between serum resistin levels in healthy and diabetic people (Lee et al, 2003, Heilbronn et al, 2004). These conclusions imply that resistin does not play a role in obesity related diabetes and it does not appear to be governed by adiposity. What the function of resistin is in the human physiological system remains to be found but identification of its downstream signalling pathways and the second messenger systems it activates will provide a clue to this. The disappointing differences observed between humans and mice may be due to differences in energy metabolism and in genetic differences between the species with the mouse resistin gene not identical to the human gene, indeed only showing 59% homology (Lee et al, 2003).
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 (Fukuhara et al, 2005, Hug & Lodish, 2005). Whilst showing the same affects, visfatin has different properties to insulin 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 T2DM.
So at last, fat is no longer considered just a lowly fat store, the ugly culprit who is blamed mercilessly when the clothes you wore last summer are annoyingly tight in the wrong places, but instead a sexy, dynamic cell that tries its best to maintain the body's energy homeostasis. Many other molecules have been identified that are secreted by adipocytes, including those not involved in energy homeostasis eg. the cytokines.
By far the most exciting discovery concerning adipokines occurred in 1994 when adipocytes were discovered to secrete leptin, a signalling molecule considered to be satiety signal.
The criteria for classifying a satiety signal are (Beglinger & Degen, 2006):
- It must reduce the size of a meal
- This must then be reversed upon application of a receptor antagonist or if the signal is removed
- The signal must not result from illness
- Secretion must be induced by eating and ingesting.
Flier J et al. 1987. Severly Imparied Adipsin Expression in Genetic and Acquired Obesity. Science. 237. pp405-408 - Realisation that the fat cell is more than just a fat storage molecule
Steppan et al. 2001. The Hormone Resisten Links Obesity to Diabetes. Nature. 409. pp307-312 - First discovered resistin as a link between obesity and diabetes.
Fukuhara et al. 2005. Visfatin: a protein secreted by visceral fat that mimics the effects of insulin. Science. 307. pp426-430 - Discovery of another protein secreted from fat that may provide the link between obesity and diabetes