More resveratrol hoopla

Resveratrol is in the news. Again.

My last major note about resveratrol is here, way back last September. How time flies. I also mentioned it more briefly here, in May, in connection with cancer. (Where its effect may involve facilitating apoptosis of tumor cells.)

But resveratrol's now back in the news again, so I guess it's time for an update.

As you recall, resveratrol seems to have a number of properties that confer health benefits. For example, it is thought to be an antioxidant, an anti-inflammatory, and perhaps to activate sirtuin enzymes, which may help produce an effect similar to calorie restriction.

The big question is whether you can get the benefits from the amount of the stuff you can get in a dose of reasonable size, for a reasonable price, and without having to drink gallons of wine per day (not a great idea).

Now we have recent reports of two more research results dealing with resveratrol. One suggests a benefit in countering obesity, and the other concerns anti-aging properties that mimic calorie restriction.

Here's the finding on obesity, the relation to which of resveratrol I cannot recall having heard bandied about before:

Red Wine's Resveratrol May Help Battle Obesity (6/16/08)

Resveratrol, a compound present in grapes and red wine, reduces the number of fat cells and may one day be used to treat or prevent obesity, according to a new study.

Past research found that resveratrol protected laboratory mice that were fed a high-calorie diet from the health problems of obesity, by mimicking the effects of calorie restriction. Researchers at the University of Ulm in Germany wanted to know if resveratrol could mimic the effects of calorie restriction in human fat cells by changing their size or function. The German team used a strain of human fat cell precursors, called preadipocytes. In the body, these cells develop into mature fat cells. ...

In the cell-based study, they found that resveratrol inhibited the pre-fat cells from increasing and prevented them from converting into mature fat cells. Also, resveratrol hindered fat storage.

One would certainly expect effects like that, if they can be reproduced in living humans, to be helpful in countering obesity. But there were two other beneficial effects as well:

[R]esveratrol reduced production of certain cytokines (interleukins 6 and 8), substances that may be linked to the development of obesity-related disorders, such as diabetes and clogged coronary arteries. Also, resveratrol stimulated formation of a protein known to decrease the risk of heart attack. Obesity decreases this substance, called adiponectin.

We've discussed both of these subjects before: IL-6 and inflammation were discussed here, while adiponectin was discussed here and here.

But the intriguing connections don't even stop there. Another report on the same research suggests that the effects related to fat cells may be mediated through sirtuin proteins:

Red wine component resveratrol might fight obesity, lab tests show (6/16/08)

Resveratrol’s mechanism of action is not entirely clear, but the compound seems to activate at least one member of a family of proteins called sirtuins. While also poorly understood, some sirtuins show up in fat cells.

Previous work showed that low levels of sirtuins allowed fat cells to add fats and to proliferate freely from nascent to mature stages, a recipe for weight gain. Conversely, that work also showed that an increase in sirtuins — in that case the compound Sirt2 — kept stem cells from maturing into full-fledged fat cells and inhibited mature fat cells from filling with fats.

In the new study, resveratrol’s good effects failed to emerge in either nascent or mature fat cells engineered to lack a sirtuin called Sirt1, Wabitsch said.

As potential therapeutics, “the sirtuins are a new class in the armamentarium of diabetes and pre-diabetes management,” says Henry Anhalt, a pediatric endocrinologist at Animas Corp. in West Chester, Pa., who wasn’t involved in this study. Sirtuins seem to curb the risk of obesity, cardiovascular disease and inflammation, all of which have been correlated with development of diabetes and its complications. The finding that resveratrol seems to work through a sirtuin (Sirt1) opens up new research opportunities, he says.

As previously noted, I've had a lot to say about sirtuins, which you can refer to here.

The second recent study, which appeared about two weeks before the one just discussed, involved experiments with mice that explicitly compared the effects of resveratrol and calorie restriction:

Substance In Red Wine, Resveratrol, Found To Keep Hearts Young (6/4/08)

[T]he researchers report that low doses of resveratrol in the diet of middle-aged mice has a widespread influence on the genetic levers of aging and may confer special protection on the heart.

Specifically, the researchers found that low doses of resveratrol mimic the effects of what is known as caloric restriction - diets with 20-30 percent fewer calories than a typical diet - that in numerous studies has been shown to extend lifespan and blunt the effects of aging.

This research sharpens results that have previously been found, and also shows that the required dose of resveratrol may not be unreasonable:

Previous research has shown that resveratrol in high doses extends lifespan in invertebrates and prevents early mortality in mice given a high-fat diet. The new study, conducted by researchers from academia and industry, extends those findings, showing that resveratrol in low doses and beginning in middle age can elicit many of the same benefits as a reduced-calorie diet.

"Resveratrol is active in much lower doses than previously thought and mimics a significant fraction of the profile of caloric restriction at the gene expression level," says Tomas Prolla, a UW-Madison professor of genetics and a senior author of the new report.

Another way this research differs from earlier work is that it looks specifically at the expression of genes known to be affected by aging in several important tissue types:

The group explored the influence of the agent on heart, muscle and brain by looking for changes in gene expression in those tissues. As animals age, gene expression in the different tissues of the body changes as genes are switched on and off.

In the new study - which compared the genetic crosstalk of animals on a restricted diet with those fed small doses of resveratrol - the similarities were remarkable, explains lead author Jamie Barger of Madison-based LifeGen Technologies. In the heart, for example, there are at least 1,029 genes whose functions change with age, and the organ's function is known to diminish with age. In animals on a restricted diet, 90 percent of those heart genes experienced altered gene expression profiles, while low doses of resveratrol thwarted age-related change in 92 percent. The new findings, say the study's authors, were associated with prevention of the decline in heart function associated with aging.

Another report stresses the overlap between the effects of calorie restriction and of resveratrol:

Red wine compound seen protecting heart from aging (6/4/08)

Using a method that permits simultaneous analysis of thousands of genes at the same time, the researchers found a huge overlap in the genes whose activity were changed by resveratrol and caloric restriction.

They looked at the heart, brain and muscles, and said that the effect of resveratrol was strongest in the heart but did prevent some aging-related changes in the other tissues.

A similar news release on this research mentions an upcoming Phase I human clinical trial that will study the effects of resveratrol on older humans:

Substance in red wine found to keep hearts young (6/5/08)

Resveratrol is currently sold over-the-counter as a nutritional supplement with supposed anti-cancer, anti-viral, anti-inflammatory and anti-aging benefits, although few scientific studies have verified these claims in humans. That may soon change: Researchers at the University of Florida hope to explore the effects of resveratrol on older people in a phase 1 clinical trial, set to begin this summer.

The study will assess the supplement's effects on memory, physical performance, inflammation and oxidative damage.

It also calls attention to the possible longevity-promoting effects of resveratrol on the mitochondria of cells:

Mitochondria, the tiny power plants that keep a cell functioning, are especially vulnerable to the oxidative damage that accumulates during the aging process.

"In animal studies, (resveratrol) seems to promote mitochondrial health," said Todd Manini, also a principal investigator of the upcoming trial and an assistant professor of aging and geriatrics in the UF College of Medicine. "Mitochondria are everywhere: They're in the brain, in the muscle, the liver. So it could have kind of a global impact on many different organ systems."

New York Times science writer Nicholas Wade (who, in earlier articles, had questioned the necessary dosage of resveratrol, see here) has a cautionary article that puts this research into context of other work on resveratrol and sirtuins. Among other points, he notes that there is still plenty of room to question whether resveratrol, or something similar, will actually have health benefits in humans, for example:

New Hints Seen That Red Wine May Slow Aging (6/4/08)

Dr. Auwerx, who used doses almost 100 times greater in his treadmill experiments, expressed reservations about the new result. “I would be really cautious, as we never saw significant effects with such low amounts,” he said Tuesday in an e-mail message.

Another researcher in the sirtuin field, Dr. Matthew Kaeberlein of the University of Washington in Seattle, said, “There’s no way of knowing from this data, or from the prior work, if something similar would happen in humans at either low or high doses.”

More news reports about this:

• Red Wine Compound Helps Heart, May Slow Aging (6/5/08)
  
• Study boosts wine chemical hopes (6/4/08)
  

Update, 7/16/08: There's more recent news about resveratrol here.

Further reading:

A Low Dose of Dietary Resveratrol Partially Mimics Caloric Restriction and Retards Aging Parameters in Mice – abstract and complete technical article describing the mouse study

Low-dose resveratrol as a calorie restriction mimetic – 6/12/08 blog post with further comments on the mouse study and associated issues

Tags: resveratrol, sirtuins, aging, longevity, calorie restriction

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

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