Sunday, June 08, 2008

Adiponectin, longevity, and cancer

Adiponectin is a hormone that is made exclusively in adipose (fat) tissue and secreted into the blood stream. It modulates a number of metabolic processes, such as glucose regulation and production of energy from fatty acids.

We had a long note on adiponectin last September (here), which has turned out to be very popular. That article summarized a number of research results concerning adiponectin that have appeared in the last few years. Undoubtedly, much of the interest in adiponectin is a result of its relevance to such things as weight control, diabetes, inflammation, cardiovascular disease, and kidney disease.

Some research that was reported in April had more to say about the relation to kidney disease:

Fat-cell Hormone Linked To Kidney Disease (4/22/08)
Reduced levels of a hormone produced by fat cells and linked to the development of insulin resistance may also be related to a higher risk of kidney disease, according to a study led by researchers at the University of California, San Diego School of Medicine and Thomas Jefferson University. ...

The new findings show that the hormone, adiponectin, produced by fat cells, circulates in the blood and acts to both suppress inflammation -- known to be a contributor to diabetes and cardiovascular disease -- and to reduce protein in the urine.

"A deficiency in adiponectin could be the major reason why obese patients develop the initial signs of kidney disease," said principal investigator Kumar Sharma.

The research showed that adiponectin promotes proper function of kidney cells called podocytes:
A network of fine capillaries in the kidney acts as a filter to prevent proteins in the blood from being secreted into the urine. This filter is made up of three components, one of which -- the podocyte cell -- serves to regulate albuminuria.

"We discovered that the hormone adiponectin, produced by fat cells, is directly linked to the healthy function of podocytes," said Sharma.

While that's interesting, it's not clear that this activity has much to do with adiponectin's effect on metabolism through favoring the use of fats as a source of energy instead of glucose. This may be a case where an important hormone really does have unrelated effects on different physiological systems.

Earlier research on adiponectin suggested that it served as a signal of low levels of available food calories, and hence caused the body to favor metabolism of stored fat as an energy source. This could well be related to the known effects of calorie restriction on longevity. Indeed, some research from last November suggested that longevity is promoted because metabolism of fat generates a lower level of reactive oxygen species than does metabolism of glucose:

Fat Hormone May Contribute To Longevity (11/21/07)
Using a mouse model of longevity, Terry Combs and colleagues report that changes in metabolism can indeed increase longevity. They demonstrated that long-lived Snell dwarf mice burn less glucose and more fatty acids during periods of fasting, and as a result produce fewer free radicals.

The key to this switch may be adiponectin, a hormone produced by fat cells that helps lower glucose production and stimulates cells to use fat for energy instead. The researchers found that Snell mice had three times as much adiponectin in their blood as control mice; Snell mice also had fewer triglycerides in their cells, indicative of higher fat metabolism.

The benefit of burning fats instead of glucose for energy is that it produces fewer oxygen radicals which can damage cells and exacerbate the effects of aging. Confirming this, Combs and colleagues found far less free radical damage.

Given that reactive oxygen species are also linked to increased inflammatory response and DNA damage, and that both of these effects are linked to cancer, it's not too surprising to find that variations in the gene for adiponectin may affect cancer risk:

Gene Variations May Predict Risk Of Breast Cancer In Women (5/2/08)
According to a recent study, led by Virginia Kaklamani, MD, an oncologist at Northwestern Memorial Hospital and assistant professor of medicine, Northwestern University Feinberg School of Medicine, variations of the adiponectin gene, which regulates a number of metabolic processes, may increase a woman’s risk of developing breast cancer. ...

Dr. Kaklamani’s research, which is published in the May 1 issue of Cancer Research, suggests some women are born with different characteristics in the adiponectin gene which can alter its function and increase the risk of breast cancer. This finding, coupled with previous studies that have found a correlation between low levels of adiponectin in the body and cancer risk, suggest adiponectin may be the third gene linked to breast cancer among women with no previous family history of breast cancer. If confirmed through additional studies, adiponectin could be used along with TGF-beta and CHEK2, genes that have already been linked to breast cancer, to create a genetic testing model that will allow clinicians to more accurately predict breast cancer risk.

Further reading:

Happy fat: Calorie restriction modulates adipocyte gene expression – 7/17/07 blog article that discusses research relating calorie restriction to adiponectin

Adipogenic signaling in rat white adipose tissue: Modulation by aging and calorie restriction – abstract of the research discussed in the preceding item.

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