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

Resveratrol

Resveratrol, of course, is somewhat famous as the substance in red wine that is widely believed to be able to retard aging and promote longevity. There are various hypotheses as to how it might do this, and several may turn out to be correct, as they are not mutually exclusive. There is experimental evidence supporting several of these hypotheses.

Ironically, however, it may be that the amount of resveratrol available in red wine is not sufficient to account for the experimentally supported effects, and there may be other substances in red wine that account for whatever anti-aging properties red wine may have.

Among the properties of resveratrol that might explain an ability to promote longevity are its antioxidant characteristics or other abilities to impede cancer. Resveratrol also has anti-inflammatory properties. Yet another hypothesis is that resveratrol is able to stimulate sirtuin proteins. These proteins are hypothesized to promote longevity, and they may also explain the known longevity-enhancing effects of calorie restriction.

I plan to write about both sirtuins and calorie restriction soon, but right now let's just focus on resveratrol. The most recent news about resveratrol concerns its anti-cancer properties:

Red Wine Compound Shown To Prevent Prostate Cancer

Researchers at the University of Alabama at Birmingham (UAB) have found that nutrients in red wine may help reduce the risk of developing prostate cancer.

The study involved male mice that were fed a plant compound found in red wine called resveratrol, which has shown anti-oxidant and anti-cancer properties. Other sources of resveratrol in the diet include grapes, raspberries, peanuts and blueberries.

The magnitude of the observed effect was substantial:

In the study resveratrol-fed mice showed an 87 percent reduction in their risk of developing prostate tumors that contained the worst kind of cancer-staging diagnosis. The mice that proved to have the highest cancer-protection effect earned it after seven months of consuming resveratrol in a powdered formula mixed with their food.

Other mice in the study, those fed resveratrol but still developed a less-serious form of prostate cancer, were 48 percent more likely to have their tumor growth halted or slowed when compared to mice who did not consume the compound, the UAB research team said.

Unfortunately, the amount of resveratrol (in proportion to body weight) the mice received to achieve these effects would not be very practical for humans to get from wine:

The amounts used in the UAB mice studies were the equivalent of one person consuming one bottle of red wine per day, which is not advisable. Since drinking alcohol in excessive amounts can have harmful health effects, doctors generally recommend moderate red wine consumption, which is an average of two drinks a day for men and one drink a day for women.

Actually, the amounts used are the equivalent of far more than one bottle of wine per day – see further discussion on this below.

Unfortunately, too, this research doesn't address various questions we'd really like answers to. Does resveratrol have a similar effect with other cancers? What is the mechanism by which resveratrol affects cancer?

Here's a blog post at Futurepundit with more on this research, and in particular some suggestions about connection with sirtuins: Resveratrol Reduces Prostate Cancer In Mice

Let's now go back a little way in time, to November 2006, when resveratrol made a big splash with apparent longevity-enhancing effects of a different kind.

Red Wine Molecule Extends Lifespan Of Fat Mice Lives By Reversing Obesity-Related Gene Pathways (11/2/06)

Researchers have used a single compound to increase the lifespan of obese mice, and found that the drug reversed nearly all of the changes in gene expression patterns found in mice on high calorie diets--some of which are associated with diabetes, heart disease, and other significant diseases related to obesity. The research, led by investigators at Harvard Medical School and the National Institute on Aging, is the first time that the small molecule resveratrol has been shown to offer survival benefits in a mammal.

Importantly, one of the other principal investigators in this research is David Sinclair, who has been one of the main researchers studying sirtuins (see references in the Futurepundit post mentioned above), has done previous work with resveratrol (in non-mammals), and whose research has also been somewhat controversial. Some relevant background:

Resveratrol is found in red wines and produced by a variety of plants when put under stress. It was first discovered to have an anti-aging properties by Sinclair, other HMS researchers, and their colleagues in 2003 and reported in Nature. The 2003 study showed that yeast treated with resveratrol lived 60 percent longer. Since 2003, resveratrol has been shown to extend the lifespan of worms and flies by nearly 30 percent, and fish by almost 60 percent. It has also been shown to protect against Huntington's disease in two different animal models (worms and mice).

Here's what the researchers say about the sirtuin connection:

Investigators identified resveratrol while looking for compounds that activate Sir2, an enzyme linked to lifespan extension in yeast and other lower organisms. For the last 70 years, scientists have been able to increase the lifespan of a variety of species by reducing their normal food consumption by 30 to 40 percent - a diet known as calorie restriction. Through this research, scientists identified Sir2 as a key contributor to life extension. Without Sir2, for example, fruit flies see none of the benefits from either calorie restriction or treatment by resveratrol. The mammalian version of the Sir2 gene is SIRT1, which has the same enzymatic activity as Sir2, but modifies a wider variety of molecules throughout cells. Indicators in this study show that resveratrol might also be activating SIRT1 in mice, as well as other known longevity pathways.

The experiments divided their mice into three categories: standard diet (SD), high-calorie diet (HC), and high-calorie diet with resveratrol (HCR). Among other findings, there were some which looked specifically at standard indicators of diabetes.

In humans, high calorie diets can increase glucose and insulin levels leading to diabetes, cardiovascular disease, and non-alcoholic fatty liver disease. In the HC fed mice, researchers found biomarkers that might predict diabetes, including increased levels of insulin, glucose and insulin-like growth factor-1 (IGF-1). Conversely, the HCR fed group had significantly lower levels of these markers, paralleling the SD group. For example, a standard diabetes glucose test on the HCR fed group found considerably higher insulin sensitivity, meaning the HCR group had a lower disposition toward diabetes than the HC fed group. Lower insulin levels also predict increased lifespan in mice.

All-in-all, this appears to be a pretty comprehensive piece of research. However, there are a couple of flies in the ointment. Most importantly, as with the prostate cancer research reported above, the mice received rather high doses of resveratrol – much higher, even, in Sinclair's study. The following article by Nicholas Wade explains it pretty well:

Yes, Red Wine Holds Answer. Check Dosage. (11/2/06)

The mice were fed a hefty dose of resveratrol, 24 milligrams per kilogram of body weight. Red wine has about 1.5 to 3 milligrams of resveratrol per liter, so a 150-lb person would need to drink 750 to 1,500 bottles of red wine a day to get such a dose.

Dr. Richard Hodes, director of the National Institute on Aging, which helped support the study, also said that people should wait for the results of safety testing. Substances that are safe and beneficial in small doses, like vitamins, sometimes prove to be harmful when taken in high doses, Dr. Hodes said.

One person who is not following this prudent advice, however, is Dr. Sinclair, the chief author of the study. He has long been taking resveratrol, though at a dose of only five milligrams per kilogram. Mice given that amount in a second feeding trial have shown similar, but less pronounced, results as those on the 24-milligram-a-day dose, he said.

So Sinclair is taking about one fifth the dose as his mice – still something like the equivalent of 150 to 300 bottles of wine per day. It's probably a good idea not to expect that drinking even a bottle a day will provide any significant protection against diabetes. The recognized fact that there does appear to be some health benefit to people who consume moderate amounts of wine must therefore be due either to other effects of resveratrol (anti-oxidant, anti-inflammatory, for example), or else to other substances in wine.

It is possible that dietary supplements containing more concentrated resveratrol might help, but probably not any currently on the market, as Wade notes:

Many companies sell the substance, along with claims that rivals’ preparations are inactive. One such company, Longevinex, sells an extract of red wine and knotweed that contains an unspecified amount of resveratrol. But each capsule is equivalent to “5 to 15 5-ounce glasses of the best red wine,” the company’s Web site asserts.

A couple of other problems are that the longevity-enhancing effects of resveratrol – or even calorie restriction, for that matter – have not yet been demonstrated in human trials, and that the lack of human trials also leaves open the question of possible harmful side-effects at high dosage, given the other properties of resveratrol (anti-oxidant, anti-inflammatory).

And if all that weren't enough to worry about, the connection between resveratrol and sirtuins is still not clearly demonstrated to general scientific satisfaction. As Wade writes,

“It hasn’t really been clearly shown, the way a biochemist would want to see it, that resveratrol can activate sirtuin,” said Matt Kaeberlein, a former student of Dr. Guarente’s who does research at the University of Washington in Seattle. Sirtuin is the protein produced by the SIRT-1 gene.

Dr. Sinclair said experiments at Sirtris had essentially wrapped up this point. But they have not yet been published, so under the rules of scientific debate he cannot use them to support his position. In his Nature article he therefore has to concede that “Whether resveratrol acts directly or indirectly through Sir-2 in vivo is currently a subject of debate.

Sinclair is working with a start-up biotech company (Sirtris Pharmaceuticals) that is developing pills containing resveratrol and similar molecules for eventual use in humans. But it almost always takes 5 to 10 years to guide a new drug – which must show measurable beneficial effects for specific diseases as well as safety – through clinical trials in humans, in order to gain approval from the FDA.

Other reports on this research: here, here, here, here, here, and here.

Results of this study were followed closely by those of another study, which apparently was funded by Sirtris:

Red wine compound boosts athletic endurance (11/16/06)

High doses of a compound found naturally in grape skins and red wine can improve muscle endurance in mice, and the compound also keeps them slim, a new study shows. ...

Johan Auwerx at the Institute of Genetics and Molecular and Cell Biology in Illkirch, France, and colleagues placed mice on a high-fat diet. Half of those mice received daily amounts of up to 400 milligrams of resveratrol per kilogram of body weight. ...

After three weeks, the mice on the resveratrol supplements weighed only about 20% more than mice on a standard diet. But those on the high-fat diet that did not receive the supplement weighed 60% more than the control mice. The resveratrol also improved the rodents endurance in fitness tests, and seemed to have no toxic side effects.

Mice on the high-fat diet that also took resveratrol were able to run twice as far on a treadmill as those on the same diet but without the supplement, even after the animals’ weight differences were taken into account.

Note that the dose of 400 mg per kg of body weight is about 17 times as much as was used in Sinclair's study. One has to wonder whether these dosage levels have been reported correctly. It would seem to make more sense to use similar dosages so that similar studies of this sort would be more comparable to each other.

Another report on this research suggests a possible explanation for the results:

A Second Pour of Good News About Substance in Red Wine (11/17/06)

Additional experiments on the animals' cells indicate the substance works by increasing the activity of an enzyme known as SIRT1, boosting the number and activity of structures inside cells called mitochondria, the researchers said. Mitochondria are like power plants inside cells, burning fat and providing energy. They tend to get revved up by exercise, and deteriorate with age.

Mice fed resveratrol had more muscle tissue resembling that of a trained athlete, sharply increasing their endurance. They could run twice as far before collapsing as mice that did not receive the substance.

The researchers in this study also had something to say about the connection with sirtuins in humans:

In addition to the mouse experiments, the researchers also produced evidence supporting the theory that SIRT1 plays a key role in longevity in humans in an accompanying analysis of 123 Finnish adults. The subjects born with certain variations of the SIRT1 gene had faster metabolisms, naturally burning energy more efficiently, indicating the same pathway works in humans, too.

According to a third report, Sirtris has actually (as of last November) begun phase 1 clinical trials in humans of their more potent formulation of resveratrol:

Red Wine Compound Could Boost Endurance (11/17/06)

But if you think that drinking more wine or taking resveratrol supplements might turn you into a super-athlete, think again, said Sirtris CEO Dr. Christoph Westphal.

"Native resveratrol from red wine or nutraceuticals cannot reach therapeutic levels in man," he said. "You would need to drink hundreds of glasses of red wine or take hundreds of nutraceutical pills in a day to get a therapeutic dose."

According to Westphal, the company has completed two phase 1 studies with 85 human volunteers of an improved formulation of resveratrol which reaches therapeutic levels in man and is safe.

In addition, Sirtris has started giving diabetic patients its resveratrol compound in a 28-day phase 1 trial to test the safety of the drug and to see how it affects glucose levels.

Another report on this study: here.

Just about 10 days later additional cold water was thrown on the notion that resveratrol in red wine is responsible for the apparent benefits of wine drinking for cardiovascular health. Whatever virtues resveratrol may actually have, there simply isn't enough of it in wine to make a difference. Instead, other substances in wine are more likely to deserve the credit:

Forget Resveratrol, Tannins Key to Heart Health from Wine (11/29/06)

Resveratrol, a molecule found in the skin of red grapes, among other places, has been found to have a host of health effects, most recently prolonging the life spans of obese mice. But the natural wonder drug does not play a role in the beneficial effects of wine drinking, according to research published in the November 28 issue of Nature. "There are some fascinating effects of resveratrol in animal systems," notes plant biochemist Alan Crozier of the University of Glasgow. "To get similar doses into humans through red wine, you would have to consume more than 1,000 liters of red wine a day."

... Using the endothelial cells that line human artery walls, the researchers tested which compounds in wine had the greatest effect. The tests showed that flavonoids called oligomeric procyanidins--essentially condensed tannins, the compounds that impart bitterness to young reds--suppressed production of the peptide responsible for hardening arteries. Such procyanidins can make up as much as 50 percent of the bioactive compounds in a given wine, the researchers observed. "Resveratrol," Crozier notes, "is available at one one-hundredth or one one-thousandth of the levels of procyanidin." Corder adds: "The role of resveratrol in the health benefits of wine has been popularized without any scientific evidence to support it, given the amounts needed for these actions are approximately 1,000-fold greater than could be achieved by wine consumption."

Other reports of this research: here, here.

Unfortunately, some people have perhaps gone off the deep end where resveratrol is concerned. In spite of the tiny amount of it that's actually in red wine, some folks have actually invested their time in charting that amount in different wines and spinning fantasies about adding information on resveratrol content to wine labels:

Resveratrol Content Varies Among Red Wines (4/20/07)

“The long-term aim is for people to be able to go along to the supermarket and to be able to know at a glance the levels of resveratrol contained in the wines they are choosing,” said Dr Hoffman.

Such information, if ever provided, will serve no other purpose than (wine merchants hope) sell more wine, but otherwise be next to useless.

However, one should not conclude that resveratrol has been over-hyped and is nothing but one of the latest "neutraceutical" scams. The problem is that it's a natural substance that hasn't been specifically optimized as a therapeutic drug – especially while in the form of just one biologically active trace ingredient in wine.

Many researchers, including David Sinclair, are hard at work to find a better form or chemical analogue of resveratrol. Sirtris Pharmaceuticals is also working hard to that end. The following article from January of this year profiles the company and its CEO. The profile is mostly from a business perspective, but there's a lot about resveratrol itself in it, so it's worth reading, despite its length:

Can red wine help you live forever? (1/19/07)

[I]f [Sirtris] succeeds, its medicines may retard the onset or progression of a whole slew of age-related diseases, from diabetes to Alzheimer's to cancer. The drugs may also have an extremely provocative side effect: They might extend life span. You have to go back to the advent of antibiotics in the first half of the 20th century to find such broad therapeutic potential.

There's much more to say about Sirtris and about the related scientific issues of calorie restriction and sirtuin proteins. But that will have to wait for later.

-------

Further information:

Via Eye on DNA I see some new research by David Sinclair and others has just been reported, dealing with calorie restriction: New Clue To Why Eating Fewer Calories Can Help You Live Longer.

There's a lot of information on resveratrol, as well as the related topic of sirtuins, at the Ouroboros blog. In fact, the whole blog is about the biology of aging. For resveratrol see here, and for sirtuins see here.

Tags: resveratrol, sirtuins, aging, longevity, diabetes, cancer, calorie restriction, caloric restriction

Adiponectin

As we noted in this article back in July, there are several hormones and neurotransmitters that have noteworthy effects on appetite and eating behavior, and as a result are of much interest with respect to weight gain (or loss) and obesity. The two mentioned in that article were NPY and PYY. The protein leptin is another hormone of this sort. It is often discussed in connection with obesity, because it is believed to increase metabolism and decrease appetite (as a signal of satiety). Another hormone, ghrelin, is produced in the stomach as a signal of hunger, and so it increases appetite.

A lot of research is currently appearing that deals with these substances and others, and how they are related to fat metabolism and obesity. I intend to discuss some of this research, and will begin with yet another hormone – adiponectin, which is produced exclusively in adipose tissue, i. e. fat, and hence the name. (Leptin is also produced in adipose tissue.) Unsurprisingly, adiponectin is involved in a number of metabolic processes, such as glucose regulation and the metabolism of fat for energy production.

Levels of adiponectin are inversely correlated with body mass index (BMI), and it seems to play a role in helping to stave off or ameliorate disorders such as obesity, diabetes, and atherosclerosis.

Let's begin with some older research first.

Fat Cell Hormone Causes Weight Loss (4/23/04)

Researchers at the University of Pennsylvania School of Medicine have established in an animal model that the hormone adiponectin secreted by fat tissue acts in the brain to reduce body weight. In contrast to leptin, a related hormone, adiponectin can cause weight loss by raising metabolic rate while not affecting appetite. ...

When adiponectin, which is involved in glucose and lipid metabolism, was introduced into the cerebrospinal fluid of normal mice, they showed no changes in food intake, but their metabolism rose. "The animal burns off more calories, so over time loses weight, which was very fascinating because we knew that leptin caused weight loss by suppressing appetite and increasing metabolic rate," explains [lead author Rexford] Ahima. "Here we have another fat hormone that can cause weight loss but without affecting intake."

To summarize, both leptin and adiponectin are produced in fat tissue, and both lead to increased metabolic rate. Leptin is known to be a satiety signal that also acts on the brain to decrease appetite. Although this older research suggests adiponectin has little effect on the central nervous system, we shall see that later research contradicts this.

From just about the same time we have the following, which found high levels of adiponectin in human milk, and therefore might explain the known association between breastfeeding and reduced risk of obesity later in life:

Study Detects Protein In Human Milk Linked To Reduced Risk Of Obesity (5/3/04)

The protein is adiponectin, which is secreted by fat cells and affects how the body processes sugars and lipids -- fatty substances in the blood. It's been suggested that adiponectin is involved in the metabolic syndrome, which includes insulin resistance, obesity, type 2 diabetes and coronary artery disease and occurs in 20-25 percent of adults. Higher levels of adiponectin have been associated with less disease.

If adiponectin is present in human milk, the Cincinnati Children's researchers theorized, the protein could have an influence over the metabolic "programming" of infants. That is, it could affect adiposity, or "fatness," later in life.

High levels of adiponectin were found in samples of human milk.

The researchers also confirmed the presence of leptin in human milk. Leptin is another protein produced by fat that appears to play an important role in the regulation of body fat. Leptin is a satiety hormone, involved in the state of being "full."

Adiponectin levels, however, are substantially greater than leptin in human milk, according to [lead author] Dr. [Lisa] Martin

Before we get to the latest research, here's some additional, earlier research involving adiponectin. In most of these studies, the main focus was on something else, but adiponectin was recognized as playing an important role:

Metabolic 'Footprint' May Be New Measure Of Obesity Risk In Kids (3/8/04)

Levels of a fat protein, called adiponectin, is significantly lower in overweight children and young adults. ... Adiponectin adheres to blood vessel walls, possibly protecting them by fighting inflammation at a cellular level.

Scientists Discover Obesity Disrupts Appetite Hormone, May Sabotage Body's Cues For Hunger, Fullness (7/1/04)

In addition to lower levels of ghrelin overall, the obese men showed higher levels of leptin and lower levels of adiponectin than the lean men.

Fat May Promote Inflammation, New Study Suggests (4/6/05)

In 15 study participants without diabetes, higher levels of the "bad" proteins, interleukin 6 and tumor necrosis factor alpha, were associated with a lower ability to respond to insulin and use glucose. On the other hand, higher levels of the "good" protein adiponectin were associated with an increased ability to use glucose. ... "This suggests that low production of adiponectin in subcutaneous fat is linked with an elevated risk of heart disease."

Researchers Consider Possible Mechanistic Links Between Obesity And Asthma (5/12/05)

There are also changes in the blood levels of hormones derived from fat tissue in the obese that may affect the airways. One of these hormones, leptin, is pro-inflammatory and obese individuals have higher leptin levels than lean individuals. Leptin is found at higher levels among asthmatics regardless of the extent of obesity. In contrast, blood levels of another hormone, adiponectin, which has anti-inflammatory properties, are actually lower among obese individuals.

Researchers Find Lack Of Protein In Obese People Is Risk Factor For Kidney, Heart Disease (11/28/05)

Researchers have found that mice with low levels of the protein hormone adiponectin may also have high levels of a protein called albumin which, in humans, may be a sign of kidney disease. ... To prove the relationship, they also studied mice without adiponectin (“adiponectin knockout”) compared to wild-type mice whose levels were normal. The team found that the knockout mice had three times the level of urine albumin than the wild-type mice. ... In a separate study ... researchers measured the adiponectin levels of a group of obese African American adolescents. They found similar results—subjects who had a low level of adiponectin also had the condition known as albuminuria—as indicated by high levels of the protein albumin in their urine. Albuminuria is an indicator for kidney disease.

Fat-generated Hormone Drives Energetic Capacity Of Muscle (7/6/06)

The fat-generated hormone adiponectin plays an important role in the energetic capacity of skeletal muscle, according to a new study. ... Adiponectin is unusual among fat hormones in that its levels generally decline in those who are obese. The researchers report evidence in people and mice, linking low adiponectin levels to insulin resistance and reductions in the number of "cellular power plants" called mitochondria in skeletal muscle. The findings suggest that therapies designed to boost the adiponectin signal might prove beneficial for the treatment of insulin resistance and diabetes.

New Research Could Help Women Facing High Risk Of Stillbirth (9/17/06)

They particularly looked at a key signalling molecule, mainly produced by fat cells, called adiponectin. This is known to have anti-diabetic properties as well as anti-inflammatory and anti-atherogenic actions (it prevents blood clotting which can block arteries). ... Observations showed that adiponectin levels were higher in pregnant women with type 1 diabetes at all stages of the study compared with the non-diabetic patients. Leptin levels were not different. Furthermore, they have identified adiponectin receptors on the human placenta and detected that the placenta also produces adiponectin. The researchers believe that the fetus produces adiponectin to protect itself from an adverse environment.

Weight-loss Supplement Shows Good And Bad Traits (2/1/07)

The researchers monitored insulin sensitivity in all mice throughout the study. They also monitored levels of adiponectin, a hormone secreted by fat tissue and thought to play a role in insulin resistance. “Adiponectin helps regulate insulin levels,” Belury said. “Lowered levels are associated with obesity and type 2 diabetes.” The researchers found that CLA [conjugated linoleic acid] supplementation significantly decreased body fat in the first group of mice, but at the same time excessive amounts of fat accumulated in the animals' livers. Belury and her colleagues linked this accumulation of fat in the liver to increased insulin resistance. ... But the group of mice given [insulin-sensitizer] rosiglitazone injections while on a CLA-rich diet neither lost weight nor became insulin resistant. “The drug kept adiponectin levels steady during the weeks the mice consumed CLA,” Belury said. “We think that's what kept the animals from becoming resistant to insulin.

Anti-obesity Drug May Prevent And Treat Obesity-related Liver Disease (7/4/07)

Treatment with rimonabant also normalized levels of adiponectin, a hormone that plays a key role in metabolic disorders. It is noteworthy that these results were not (or were only slightly observed) in the control animals eating the same diet but not given rimonabant, which demonstrates the beneficial effects of the drug compared to diet alone. "Our hypothesis is that the multi-protective effects of rimonabant may be mediated for a large part by both the reduction in pro-inflammatory cytokines such as TNFa and the increase in anti-inflammatory and protective cytokines or hormones such as adiponectin," the authors conclude.

In most of these earlier studies, something other than adiponectin was the main focus, yet adiponectin was recognized to have several beneficial effects, such as counteracting inflammation and insulin resistance. These effects in turn help control disorders such as diabetes, atherosclerosis, and fatty liver disease.

But let's look now at recent studies aimed at examining adiponectin itself. First off, concerning adiponectin and inflammation:

Fat Protein Cuts Blood Vessel Inflammation, May Help Heart, Scientists Find (6/24/07)

A natural substance secreted by fat cells can protect blood vessels from the damaging effects of inflammation, one of the factors that contribute to heart disease. Researchers at Jefferson Medical College have shown for the first time in an animal model that the substance – a protein called adiponectin – helps prevent immune system white blood cells from binding to the inside of blood vessel walls.

Importantly, adiponectin acted not only on leukocytes adhering to blood vessel walls, but also on inflammatory cytokines:

The scientists also looked at the effects of adiponectin on inflammation in normal mice. They gave mice a substance, TNF-alpha, which caused the release of inflammatory substances called cytokines. Injecting the mice with the active adiponectin-fragment reversed the effects of the cytokines and the resulting inflammation.

Inflammation is common in cardiovascular disease.

The next research takes a closer look at how adiponectin acts in the central nervous system:

Insulin Sensitizer Also Serves As Energy-conserving Signal To The Brain (7/12/07)

A fat-derived protein known for its effects on the liver and skeletal muscle might also serve as an energy-conserving signal to the brain during periods of starvation, suggests a new study in the July issue of Cell Metabolism, a publication of Cell Press. The substance, known as adiponectin, acts on the brain to boost appetite and slow energy expenditure in an effort to maintain adequate fat stores during lean times, the researchers report.

First off, there is the question of whether adiponectin even reaches the central nervous system.

The researchers now report evidence in mice that adiponectin receptors are present in the hypothalamic region of the brain and that some forms of the chemical enter the cerebrospinal fluid from the blood.

Then, supposing adiponectin reaches the central nervous system, there is the question of what effect, if any, it has there.

Once in the brain, adiponectin enhances the activity of a metabolic enzyme called AMP-activated protein kinase (AMPK) to stimulate greater food consumption.

Moreover, the researchers found that adiponectin decreased energy expenditure. They also showed that blood and spinal fluid adiponectin levels in the brain normally increase during fasting and decrease after refeeding, suggesting that adiponectin acts mainly during food shortages.

So this research claims that adiponectin increases appetite, unlike leptin, which has the opposite effect. Further, adiponectin leads to lower activity and energy expenditure, thus conserving available energy supplies. But such effects are reversed if adiponectin is absent:

In adiponectin-deficient mice, AMPK activity in the brain slowed, causing the animals to eat less and expend more energy. That action, in turn, made the animals resistant to becoming obese even on a high-fat diet. Moreover, animals lacking adiponectin lost more fat after 12 hours of fasting than normal mice did.

If indeed adiponectin tends to lead to lower activity levels and energy expenditure, one has to ask whether it promotes fat storage or even obesity. The next, and latest, research – which received a lot more attention outside specialist literature than research mentioned above – dramatically suggests that is the case.

The research began with mice genetically engineered to lack leptin. Without this satiety hormone, the mice overate and became quite obese. However, when a subgroup of these mice were engineered to overproduce adiponectin, they ate even more, and became almost twice as obese:

‘World's fattest mouse’ appears immune to diabetes (8/23/07)

The “world’s fattest mice”, genetically engineered to overproduce a key hormone, weigh five times as much as normal mice do – but bizarrely do not develop diabetes, reveals a new study. The findings shed light on how current diabetes medications work and point to new drug targets to treat the disease, say the study's researchers.

Philipp Scherer at the University of Texas Southwestern Medical Center in Dallas, Texas, US, and his colleagues studied mice that had been genetically engineered to overeat. The mice gorged on food because they lacked the ability to produce an important appetite-suppressing hormone called leptin.

The researchers then bred a subgroup of these leptin-deficient mice to overproduce another key hormone that gets released by fat cells, called adiponectin, by about threefold. Under normal circumstances, an increase in adiponectin levels signals that an animal has entered "starvation mode" because it has not eaten for some time.

All of the leptin-deficient mice ate non-stop, but those bred to overproduce adiponectin packed on almost twice as much weight by the end of the 20-week experiment.

Incidentally (or maybe not) it was Dr. Scherer who discovered adiponectin, in 1994.

Obviously, the most interesting outcome of this research is that the mice that overproduced adiponectin did not develop diabetes, in spite of their obesity.

Interestingly, none of the rodents that made extra adiponectin developed symptoms of diabetes, such as high blood sugar. By comparison, all of the other leptin-deficient mice developed this disease during the course of the experiment.

So why might that be?

When Scherer and his team examined the distribution of body fat within the mice, they found that the obese rodents with an abundance of adiponectin had a great deal of fat stored under the skin, but very little fat within organs such as the liver.

This unusual allocation of fat might explain why the animals remained in good health – extra fat in the liver can make the organ less sensitive to insulin, thereby leading to diabetes.

Scherer firmly believes that the distribution of fat can make all the difference in terms of whether obesity will lead to diabetes. "It's a little bit like real estate; it's location, location, location."

But wait, isn't ("type 2") diabetes mostly due to an inability to use insulin – insulin resistance? The original press release on the research ties insulin resistance directly to storage of fat in the wrong places:

Key Hormone Protects Obese Mice From Diabetes (8/28/07)

"The continual firing of adiponectin generated a 'starvation signal' from fat that says it is ready to store more energy," he said. "The mice became what may be the world's fattest mice, but they have normal fasting glucose levels and glucose tolerance.

"This indicates that the inability to appropriately expand fat mass in times of overeating may be an underlying cause of insulin resistance, diabetes and cardiovascular disease."

This discovery also suggests that in people who have low adiponectin levels fat cells don't send the signal that they're ready to accept fat, Dr. Scherer said. Instead, the fat is stored in dangerous places -- liver, heart and muscle tissues -- where it can cause inflammation and pave the way for disease.

There's at least one question left to which I don't see an obvious answer: If adiponectin is produced in fat cells ("white adipose cells", to be exact), why is it negatively correlated with obesity? That is, at least in humans, we've seen that lower levels of adiponectin go along with obesity.

That's odd. Is there some mechanism that turns off adiponectin production? Evidently so, if adiponectin normally acts as a signal of food deprivation. But exactly what is the mechanism? Would interfering with the mechanism, to keep adiponectin levels high, be worthwhile for preventing insulin resistance, inflammation, and other problems? Even if weight gain, due to increased appetite, also resulted? Needs further research, I guess.

Additional references on this research:

• Being Fat Needn't Be All Bad News (8/27/07)
  
• Diabetes study: Fat is all about the location (8/24/07)
  
• 'World's Fattest Mice' Immune To Diabetes (8/23/07)
  
• Obesity Doesn't Always Spur Diabetes (8/23/07)
  
• Adiponectin protects obese mice from diabetes (8/26/07)
  

Tags: adiponectin, diabetes, obesity, atherosclerosis

The role of hostility, anger, and depression in inflammation

Hasn't it "always" been known that anger and hostility raises one's blood pressure? However that may be, a recent study shows that the connection of hypertension with chronic anger and hostility may involve a disturbed immune system and inflammation – in addition to the well-known blood vessel constriction that is a part of the "fight or flight" stress response.

Hostile Men Could Have Greater Risk For Heart Disease

Men who are hostile and prone to frequent intense feelings of anger and depression could be harming their immune systems and putting themselves at risk for coronary heart disease as well as related disorders like type 2 diabetes and high blood pressure, a new study finds.

The results were found in a 10-year study of U. S. veterans of the Vietnam war.

The men had a series of blood levels taken on three occasions between 1992 and 2002. Researchers measured two immune system proteins known as C3 and C4. Both are markers of inflammation, which is the body’s response to injury or infection. Changes in C3 and C4 are associated with a number of diseases, including some that negatively can affect the arteries around the heart, such as diabetes.

Men whose psychological screening showed the highest level of hostility, depressive symptoms and anger had a 7.1 percent increase in their C3 levels, while men with low levels of these attributes showed no change over the 10-year study period.

Here's another report on this research: Hostility, anger linked to chronic inflammation

But a 2004 study had already demonstrated a stronger correlation between psychological variables and a marker of inflammation (C-reactive protein):

Anger, Hostility And Depressive Symptoms Linked To High C-reactive Protein Levels

Researchers at Duke University Medical Center have discovered that otherwise healthy people who are prone to anger, hostility and mild to moderate depressive symptoms produce higher levels of a substance that promotes cardiovascular disease and stroke.

The substance, C-reactive protein (CRP), has garnered considerable attention for its role in both promoting and predicting cardiovascular disease and stroke in initially healthy people. It is produced by the liver in response to inflammation, and inflammation has recently been shown to underlie the plaque that forms inside arteries as they clog.

The Duke study is the first to link this combination of negative psychological attributes with higher levels of CRP in people without traditional risk factors for heart disease...

More specifically,

121 healthy men and women were asked to complete standard personality questionnaires in which they described their psychological attributes, including anger, hostility and depression. The volunteers did not have any pre-existing conditions -- such as smoking, high blood pressure, diabetes or heart disease -- that would predispose them to having high CRP levels. High-sensitivity blood tests were then conducted to measure CRP levels.

Respondents who were prone to anger, had high hostility levels, and showed mild to moderate symptoms of depression had two to three times higher CRP levels than their calmer counterparts. The more pronounced their negative moods, the higher CRP levels they had, the study showed.

In addition, the researcher had previously shown a relation between the psychological variables and another inflammatory substance (interleukin-6):

[H]ostile people who exhibit symptoms of depression have higher levels of stress hormones and circulating levels of an inflammatory substance called interleukin 6, another marker of inflammation that has been shown to predict heart disease in initially healthy people.

A number of other studies have demonstrated relationships between psychological stress conditions and disease states that involve the immune system, such as this one from 2006:

Anger And Hostility Speed Up Decline In Lung Power

The authors point out that hostility and anger have been associated with cardiovascular disease, death, and asthma, and that previous research has suggested that changes in mood can have short term effects on the lungs.

Anger and hostility will alter neurological and hormonal processes, which in turn may disturb immune system activity, producing chronic inflammation, suggest the authors.

An accompanying editorial comments that the physiological components of anger and stress overlap, and stress is well known to affect the immune system.

Bottom line: Get control over anger and depression if you want to stay healthy.

Of course, this is all closely related to what I discussed just a couple of weeks ago on stress and weight gain and in particular the extensive research of Robert Sapolsky summarized here.

Additional references:

• Coping With Stress Improves Cholesterol
  
• High Hostility May Predict Heart Disease More Than Other Risk Factors Such as Cholesterol and Smoking
  
• Hostility is among best predictors of heart disease in men
  

Tags: inflammation, stress, anger, hostility, depression, cardiovascular disease, hypertension

Brain Plays Key Role In Diabetes Therapy

One of the complexities of understanding diabetes (recent discussion here) is that the body's reaction to insulin is rather variable. If too little insulin is available, glucose is not well absorbed from the bloodstream. Too much glucose in the blood (hyperglycemia) can lead to serious complications such as cardiovascular disease, nerve damage, kidney failure, and glaucoma. On the other hand, too much insulin can cause the body to become resistant to insulin's effects, which again leads to hyperglycemia.

So the body needs to need to be regulate insulin levels fairly closely. It now appears that the brain is part of a properly functioning insulin reglatory system.

Brain Plays Key Role In Diabetes Therapy

[T]he researchers examined the brain's effect on insulin sensitivity in rats with diabetes due to a lack of so-called pancreatic beta cells, which normally secrete insulin. The rats' condition mimics type I, or juvenile, diabetes, a form of the disease that begins in childhood most often due to autoimmune destruction of cells in the pancreas, which leave the organ unable to produce insulin.

The researchers infused the brains of the diabetic rats with a chemical that limits the function of an enzyme involved in the normal insulin response before injecting the animals with the hormone. Without the normal brain response to insulin, the hormone therapy's efficacy for reducing blood sugar fell by about 35%, Schwartz said. Furthermore, they found that gene therapy interventions designed to increase the brain's insulin response heightened the animals' response to therapy about 2-fold.

Tags: diabetes, insulin, medicine

High-fat diet and type 2 diabetes

Diabetes (which appears in several different forms) has been a difficult disease to understand in detail. The main diagnostic indication of diabetes is poor regulation of levels of glucose in the blood -- either too much glucose (hyperglycemia) or too little (hypoglycemia). From these conditions (if not treated) follow various other seriously harmful effects, including arterial disease, nerve damage, kidney failure, damage to the eyes, and gangrene in the extremities.

Insulin is the hormone which is most responsible for proper regulation of glucose levels. The body produces insulin only in the beta cells of the pancreas. Its primary function is to get glucose out of the blood by causing it to be taken up by cells, where the glucose is either stored or used for energy production.

This process can fail in two different ways. In the first case, a persistent excess of glucose can cause overproduction of insulin by the beta cells if those cells themselves are undamaged. This in turn leads to insulin resistance, in which other body cells do not take up glucose properly even in the presence of insulin. A common cause of this is excessive amounts of carbohydrates in a person's diet.

In the second case, not enough isulin is proudced, either because the beta cells have been damaged or else because they are inhibited in some way. One way that beta cells can actually be destroyed is in an autoimmune condition. Typically, but not necessarily, this occurs before adulthood, and so this has been called juvenile onset diabetes or (more commonly now) type 1 diabetes.

Diabetes that occurs (usually in adulthood) without major damage to beta cells is referred to as type 2 diabetes (formerly called adult onset diabetes). If this type isn't the result of insulin resistance (the first case above), it is due to underproduction of insulin in the beta cells. This circumstance has been the hardest to understand. Sometimes it appears to be genetic, but may also be triggered by obesity and/or a high-fat diet. New research is beginning to illuminate how this comes about.

Researchers Discover Mechanistic Link Between High-Fat Diet and Type 2 Diabetes

Howard Hughes Medical Institute researchers have discovered a molecular link between a high-fat, Western-style diet, and the onset of type 2 diabetes. In studies in mice, the scientists showed that a high-fat diet interferes with a genetic mechanism they discovered that promotes insulin production, resulting in the classic signs of type 2 diabetes.

In an article published in the December 29, 2005, issue of the journal Cell , the researchers report that knocking out a single gene encoding the enzyme GnT-4a glycosyltransferase (GnT-4a) disrupts insulin production. Importantly, the scientists showed that a high-fat diet suppresses the activity of GnT-4a and leads to type 2 diabetes due to failure of the pancreatic beta cells.

The enzyme GnT-4a was suspected of being involved in the problem because it is highly expressed in the pancreas. The same enzyme is also found in mice, so researchers studied mice in which the gene for GnT-4a was disabled.

The studies showed that GnT-4a has an important effect on another protein, called Glut-2, which is important in beta cells. Glut-2 normally occurs on the surface of a beta cell, and it enables the cell to sense the amount of glucose in the blood. The cell produces insulin in proportion to the blood glucose level. What GnT-4a does is to attach a sugar-like molecule called a glycan to Glut-2 -- a process called glycosylation. If there's not enough GnT-4a, the process doesn't occur, and Glut-2 is unable to situate on the beta cell membrane, which makes the cell unresponsive to glucose, which inhibits insulin production. It was already known that a deficiency of Glut-2 on beta cell surfaces occurs in patients with type 2 diabetes.

This fact alone indicates why diabetes can be a genetic condition: If both parents have diabetes as a result of defective GnT-4a genes, their offspring may have the same problem. (It would be a recessive trait.)

But what was really interesting was that the researchers found that when mice with normal GnT-4a genes were fed a high-fat diet, the levels of GnT-4a enzyme were also decreased. Somehow a high-fat diet inhibits the expression of GnT-4a genes, but the exact mechanism is still not clear.

As far as obesity is concerned, it's often the result of a diet that is too high in fat, but it's not clear whether obesity per se also affects GnT-4a. So it seems still undetermined whether the association of obesity with diabetes is because the two conditions have a common cause (too much fat), or whether something extra is going on.

But in any case, there's now more evidence that high-fat diets are not a good thing.

Tags: diabetes, health, medicine, insulin