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

Stress and weight gain

There is, apparently, truth to the idea that people under stress may gain weight – and it's not just that people simply choose to escape their problems by eating. And this is only one of the reasons stress isn't good for your general health.

Scientists Discover Key To Manipulating Fat; Pathway Also Explains Stress-induced Weight Gain

In the paper, the Georgetown researchers describe a mechanism they found by which stress activates weight gain in mice, and they say this pathway -- which they were able to manipulate -- may explain why people who are chronically stressed gain more weight than they should based on the calories they consume.

The key to the process that was found is a peptide (small protein) neurotransmitter called neuropeptide Y (NPY). NPY is produced under conditions of stress, as a by-product of the "fight-or-flight" response mediated by the sympathetic nervous system. An animal under conditions of chronic stress will have higher levels of NPY. The hormone was discovered 25 years ago, and earlier research indicates that it acts in the brain to increase appetite. (Although other aspects of the response may suppress appetite, which is why some overly stressed people may be emaciated.) The appetite-suppressing hormone leptin acts by inhibiting the activity of neurons that contain NPY.

What the new research found, however, is that, more importantly, NPY, acting outside the brain in adipose tissue, also alters an animal's metabolism to increase storage of fat:

As part of the study, Zukowska and her team examined the effect of several forms of chronic stress that mice in the wilderness can encounter, such as exposure for an hour a day over a two-week period to standing in a puddle of cold water or to an aggressive alpha mouse, and they conducted the experiments in combination with a regular diet or with a high-fat, high-sugar diet. Stressed animals fed a normal diet did not gain weight, but stressed mice given a high-fat diet did. In fact, the researchers found these mice put on more weight than expected given the calories they were consuming.

"They gained twice as much fat as would be expected, and it was all in their belly area," Kuo said. Stressed versus non-stressed animals ate the same amount of food, but the stressed animals processed it differently, she said, explaining, "the novel finding here is that NPY works on fat tissue, not in the brain."

In part, the research showed that NPY experimentally delivered in a mouse activated a G-protein coupled receptor called (naturally) a neuropeptide Y2 receptor (Y2R). (This is just one of 5 known NPY receptors.) Activation of Y2R was observed to promote storage of fat in adipose tissue:

[The] pathway involves two players -- a neurotransmitter (neuropeptide Y, or NPY) and the receptor (neuropeptide Y2 receptor, or Y2R) it activates in two types of cells in the fat tissue: endothelial cells lining blood vessels and fat cells themselves. In order to add fat selectively to the mice they tested, researchers injected NPY into a specific area. The researchers found that both NPY and Y2R are activated during stress, leading to apple-shape obesity and metabolic syndrome.

So NPY can lead to increased fat storage. But the converse is, happily, also true: blocking the NPY receptor shrinks fat:

Both the weight gain and metabolic syndrome, however, were prevented by administration of Y2R blocker into the abdominal fat.

Metabolic syndrome, you recall, comprises several undesirable elements, such as hyperglycemia, high blood pressure, central obesity, decreased HDL cholesterol, and elevated triglycerides. All of these can lead to more serious health problems, such as diabetes and cardiovascular disease. So there is the possibility that blocking Y2R could be beneficial to humans:

"We are hopeful that these findings might eventually lead to control of metabolic syndrome, which is a huge health issue for many Americans," [the study's senior author, Zofia Zukowska] said. "Decreasing fat in the abdomen of the mice we studied reduced the fat in their liver and skeletal muscles, and also helped to control insulin resistance, glucose intolerance, blood pressure and inflammation. Blocking Y2R might work the same way in humans, but much study will be needed to prove that."

Another account of this research reports expressions of optimism for development of human drugs to control stress-induced health problems:

Stress can be fattening, study finds

Mary F. Dallman of UC San Francisco said in an editorial in the same journal: "A large gap in our understanding of how chronic stressors lead to abdominal obesity has been filled…. Their results were remarkable and have profound implications for new drug development."

But it's not a sure thing. There is another hormone, called PYY, Pancreatic Peptide YY, or Pancreatic Peptide YY_3-36. PYY is structurally similar to NPY and in fact can activate some NPY receptors. It has been found to decrease appetite when it activates NPY receptors in the brain. At least two biotech companies (Amylin and Nastech) have investigated using PYY directly as a drug to induce weight loss. So far this effort has had only mixed results.

Here's another report on the research discussed above: How we can stop stress from making us obese. And here's a blog post that raises some good questions about this research: Scientists Stressed About Weight Loss.

Apart from the effects of NPY, chronic stress can cause a variety of health problems besides weight gain, obesity, and their knock-on effects. Robert Sapolsky of Stanford has done copious research into the ill effects of chronic stress. He points out that the fight-or-flight response of animals in the wild, which is activated during periods of acute danger (predators), and is adaptive in those circumstances, can turn harmful when stress is chronic, as happens frequently with primates such as humans:

Why Do Humans And Primates Get More Stress-related Diseases Than Other Animals?

Why do humans and their primate cousins get more stress-related diseases than any other member of the animal kingdom? The answer, says Stanford University neuroscientist Robert Sapolsky, is that people, apes and monkeys are highly intelligent, social creatures with far too much spare time on their hands.

"Primates are super smart and organized just enough to devote their free time to being miserable to each other and stressing each other out," he said. "But if you get chronically, psychosocially stressed, you're going to compromise your health. So, essentially, we've evolved to be smart enough to make ourselves sick."

Tags: stress, obesity, weight gain, neuropeptide Y