Peroxisome proliferator-activated receptors and your ticker

Everyone knows by now that having diabetes raises the risk for heart disease in various forms. Wouldn't it be interesting to understand the biological reasons for this connection? Well, it turns out that various factors seem to be relevant, and one of them involves a variety of paths that all pass through the territory of a rather interesting protein called PPAR-γ.

Not only is PPAR-γ implicated in processes related to both diabetes and heart disease, but it turns out that some drugs used to control diabetes also affect the risk of heart disease – because of PPAR-γ.

We'll begin the discussion by looking at recent research on how PPAR-γ affects heart function.

First, of course, we should explain what a peroxisome proliferator-activated receptor is. The name is somewhat off-putting, and nowadays most people just write PPAR. It's also a bit of a historical artifact, in that this class of proteins was first investigated in connections with peroxisomes, which are cellular organelles that participate in the metabolism of fatty acids. That's an important clue right there, because if we are dealing with fat metabolism, there may well be connections with conditions such as obesity and cardiovascular disease.

It turns out that is only a part of what PPARs are connected with.

A PPAR is not a cell surface receptor. Instead it is a nuclear receptor, meaning that it's a protein found in the interior of cells that (like a surface receptor) is activated when it connects with hormones and similar molecules. Such molecules that bind to a receptor are called ligands.

Initially, the ligands in question were known to cause proliferation of peroxisomes, but now many other kinds of ligands that activate PPARs have been identified.

Once a PPAR has been activated it can affect the expression of many different genes, because it acts as a transcription factor.

Three important PPARs are known: PPAR-α, PPAR-β (also called PPAR-δ), and PPAR-γ. It's the last of these we'll be concerned with here. In fact, PPAR-γ seems to affect many cellular processes related to metabolism and other things. Recent research that we may discuss another time (see here) has shown that there are about 5300 sites in the DNA of a fat cell that PPAR-γ can bind to, and hence potentially affect the expression of nearby genes. So it's not surprising that PPAR-γ is involved in quite a lot of cellular business.

Incidentally, all three PPARs are produced from the same gene, with the variant forms being due to alternative splicing.

The research we want to highlight here deals with how PPAR-γ is linked with the daily rise and fall of heart rate and blood pressure. Such things that are part of the normal circadian rhythm, in animals, are usually regulated from the central nervous system. But that doesn't seem to be the only regulator:

What Makes The Heart 'Tick-tock' (12/2/08)

Researchers have new evidence to show that the heart beats to its own drummer, according to a report in the December issue of the journal Cell Metabolism. They've uncovered some of the molecular circuitry within the cardiovascular system itself that controls the daily rise and fall of blood pressure and heart rate. The findings might also explain why commonly used diabetes drugs come with cardiovascular benefits, according to the researchers.

"This is the first study to demonstrate that a peripheral clock plays a role in the circadian rhythm of blood pressure and heart rate," said Tianxin Yang of the University of Utah and Salt Lake Veterans Affairs Medical Center.

While much progress has been made over the years in understanding the body's master clock in the brain, the new study offers one of the first glimpses into the biological function of peripheral clocks in maintaining the circadian rhythms of tissues throughout the body, the researchers said.

There has already been reason to suspect that PPAR-γ is involved in this:

Earlier studies suggested a role for the nuclear receptor called peroxisome proliferator-activated receptor-γ (PPAR-γ) in clock function. PPAR-γ is perhaps best known as the molecular target for a class of widely prescribed and effective diabetes drugs called thiazolidinediones (TZDs), including rosiglitazone (trade name Avandia) and pioglitazone (trade name Actos). Those diabetes drugs are known to come with a side benefit: they have protective effects on the cardiovascular system.

The new research shows that the circadian variation in heart rate and blood pressure is disrupted simply by eliminating PPAR-γ from cardiovascular cells. The elimination was effected by working with two strains of mice in which suitable genes had been knocked out:

The researchers found that both knockout strains showed a significant reduction of circadian variations in blood pressure and heart rate. .... The mice also showed declines in variation of norepinephrine/epinephrine in their urine—a measure of activity of the sympathetic nervous system, which plays a key role in heart rate and blood pressure.

The animals had impairments in the rhythmicity of the major clock genes, including Bmal1, a transcription factor that controls the activity of other core clock components, they report. By treating the mice with the diabetes drug rosiglitazone, they were able to increase the activity of Bmal1 in the animals' aortas, the largest artery of the body that issues blood from the heart, and further study showed that the core clock gene is directly controlled by PPAR-γ.

What, more precisely, is the role of PPAR-γ in affecting rhythmicity? Apparently the effect is indirect, due to its abillity to activate Bmal1, which is known to be an important clock protein. This is indicated because rosiglitazone seems to be able to compensate for missing PPAR-γ.

Interestingly, other recent research has shown that the sirtuin protein SIRT1 also affects Bmal1. (See here.) this may be significant, since SIRT1 has gene-silencing effects that depend on nutritional factors.

What other processes is PPAR-γ involved with? Better-known than its effect on cardiovascular circadian rhythm is its role in fatty acid storage and glucose metabolism, and hence its connection with diabetes. But we'll have to look at that another time.

Further reading:

Protein Found to Set the Heart's Cadence (12/2/08) – Science News article

Tags: circadian rhythm

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.

Tags: adiponectin, longevity, cancer, reactive oxygen species