It is well documented that obesity is associated with an increased risk of cardiovascular disease and higher overall mortality. Obesity also correlates with increased risk of Alzheimer’s disease and many types of cancer. It has been estimated that severe obesity may shorten lifespan by up to ten years (1). This is comparable to the effect of smoking.
Obesity is usually defined as an elevated body mass index (BMI). It is characterized by the accumulation of fat in our body.
But, what’s wrong with walking around with some extra weight? Why is excess body weight associated with increased risk of heart disease, cancer and premature death?
When we discuss obesity, we often tend to look primarily at body weight itself. This may be misguided. In fact, body fat does much more to our health than take up space and increase weight.
Fat cells are biologically active, and their function or dysfunction may affect our health in many ways. For example, fat cells produce and secrete important biologic substances. One of these substances is called adiponectin. In fact, adiponectin could represent one of the missing links between obesity and increased risk of diabetes, heart disease, and cancer.
The body can store extra energy as fat in adipose tissue. Adipose tissue is a loose connective tissue that is mainly composed of cells called adipocytes. It is is mainly located beneath the skin (subcutaneous fat) and around the internal organs (visceral fat).
It is possible to assess how much of our body weight is composed of fat. Although it may vary a lot, men and women of normal weight have about 15 percent and 30 percent body fat respectively.
Adipose tissue appears to be an important endocrine organ. It produces hormones such as leptin and estrogen as well as cytokines that play an important role for cell signaling. Cytokines secreted by adipose tissue are called adipokines.
Visceral Fat and Subcutaneous Fat
Body shape and the regional distribution of fat appear more important for health than the total amount of adipose tissue. For example, it has been shown that the accumulation of fat around the internal organs may be more harmful than fat accumulation elsewhere. Excess accumulation of this type of fat is termed visceral obesity.
In the 1940s, Professor Jean Vague from the University of Marseille noted that women normally had twice as much fat mass as men (2). However, he also found that the metabolic complications associated with obesity were much less common among women than men.
Vague defined two different body shapes. Android obesity or apple shape refers to the accumulation of fat in the upper body are. Gynoid obesity or pear shape refers to the accumulation of fat on the hips and thighs. The latter is more common among women than men. This is very well demonstrated in Pierre-Auguste Renoir’s painting above.
Visceral fat accumulation is associated with insulin resistance, high blood pressure, high levels of triglycerides, low levels of HDL-cholesterol, small dense LDL particles, and increased risk of diabetes and cardiovascular disease.
However, subcutaneous fat appears much more innocent than visceral fat. In fact, recent studies suggest that abdominal subcutaneous fat is not associated with risk factors for cardiovascular disease (3). This suggests a possible protective effect of subcutaneous fat.
In the 1990s, scientists found a protein secreted by adipocytes and named it adiponectin (4).
Although adiponectin is secreted only from adipose tissue, the plasma concentration of adiponectin is much lower in obese subjects than in non-obese healthy volunteers.
Plasma levels of adiponectin are especially low in individuals with visceral obesity. It is believed that adiponectin deficiency may play an important role for many of the negative metabolic consequences of visceral fat accumulation. The clinical term for low plasma levels of adiponectin is hypoadiponectinemia.
So, although adiponectin is produced by adipose tissue, its production is abnormally low in obese individuals, in particular, those with visceral obesity.
Some adipokines may negatively affect health. For example, many adipokines are pro-inflammatory and may support chronic low-grade inflammation in the body. On the other hand, adiponectin is protective and appears to reduce inflammation.
Studies show that low levels of adiponectin are associated with raised levels of several different markers of inflammation (5).
Adiponectin and Obesity
Obese people have lower blood levels of adiponectin than normal weight individuals (6,7). Furthermore, reduction of obesity increases adiponectin levels (8,9). Overall, it appears that losing weight through diet, exercise, medications and surgery will increase adiponectin levels in blood.
Low adiponectin levels are more strongly associated with the amount of visceral fat than subcutaneous fat (10).
Development of subcutaneous fat is is an active process in infancy, adolescence and pregnancy (11). In middle aged and elderly people, over nutrition does not lead to an effective storage of energy as subcutaneous fat (12). Instead, visceral fat accumulation becomes more common.
Lifestyle factors such as overeating and physical inactivity in young and middle-age appear to increase the risk of visceral obesity.
Dysfunction of adipose cells is more common in visceral fat tissue than subcutaneous fat tissue. Such dysfunction may cause an unbalance in the production of adipokines leading to overproduction of offensive adipokines and under production of defensive adipokines such as adiponectin (11).
Adiponectin, Insulin Resistance and Type 2 Diabetes
Obesity is associated with high prevalence of insulin resistance and type 2 diabetes.
Several clinical studies have shown that low production of adiponectin correlates with the development of insulin resistance and type 2 diabetes (13).
Adiponectin appears to promote an insulin-sensitizing effect (14). It has been suggested that downregulation of adiponectin could be a mechanism whereby obesity could lead to insulin resistance and diabetes. Thus, in theory, increasing the availability of adiponectin might reverse insulin resistance and thereby decrease the risk of diabetes.
Adiponectin and Lipid Abnormalities
High levels of triglycerides and low levels of HDL cholesterol are commonly found in people with obesity or metabolic syndrome. High triglyceride/HDL cholesterol ratio is associated with increased risk of cardiovascular disease.
Adiponectin levels correlate positively with HDL-cholesterol and negatively with triglycerides.
Experimental studies have suggested that adiponectin promotes synthesis of HDL cholesterol (15).
Therefore, low levels of adiponectin may be important for some of the lipid abnormalities associated with obesity.
Adiponectin and Non-Alcoholic Fatty Liver Disease (NAFLD)
Non-alcoholic fatty liver disease (NAFLD) is common among people with obesity. It may increase the risk for liver cirrhosis and cancer of the liver.
Experimental studies have found that adiponectin antagonizes excess lipid storage in the liver (18).
Adiponectin and Cancer
Obesity is associated with increased risk of cancer. This relationship has been highlighted by the US National Cancer Institute.
Several studies suggest that adiponectin may play a role in cancer. Low plasma levels of adiponectin have been linked to some types of breast cancer (19), endometrial cancer (20), prostate cancer (21) and colorectal cancer (22).
It is not known whether adiponectin deficiency plays a causative role when it comes to cancer risk. Furthermore, it has not been shown that increasing adiponectin levels will reduce the risk of cancer.
Adiponectin and Coronary Artery Disease
Studies also suggest that low levels of adiponectin may be predictive of future coronary events (25).
Animal studies indicate that adiponectin administration may protect heart muscle cells from injury from loss of blood flow (26)
Clinical Use of Adiponectin Measurements
Adiponectin circulates in relatively high concentrations in blood and is easily measured. However, the use of adiponectin measurements has so far been confined to clinical trials and has not yet spread into clinical practice. Nevertheless, the potential to use adiponectin as a biologic risk marker certainly exists.
Adiponectin concentrations might also be used to decide on the aggressiveness of interventions and to monitor treatment. For example, it has been suggested that adiponectin levels may be used to monitor the efficacy of interventions in patients with metabolic syndrome (27). Other studies suggest that adiponectin levels may be used to monitor the anti-inflammatory effects of statin therapy (28). Change in adiponectin levels may also reflect the metabolic effects of diabetes therapies (29).
Reference Values for Adiponectin
The Mayo Clinic (Mayo Medical Laboratories) has presented the following reference ranges for adiponectin measurements in blood.
|Body Mass Index||Adiponectin mcg/mL|
|Body Mass Index <25||Males 4-26
|Body Mass Index 25-30||Males 4-20
|Body Mass Index >30||Males 2-20
Adiponectin as a Therapeutic Target
The favorable effects of adiponectin could be increased either by directly administering adiponectin by injection or by using treatment that increases its plasma levels.
Manufactured adiponectin has been administered by infusion in animal studies. However, the molecular complexities of adiponectin have made its production as a therapeutic agent difficult (30). Scientists are also looking at agents that could enhance adiponectin secretion from adipose tissue or mimic adiponectin effects on its receptors (31).
Statins, thiazolidinediones, angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers are examples of pharmaceutical drugs that have been found to elevate circulating levels of adiponectin.
Studies have also found that nutraceutical compounds such as fish oil, safflower oil, conjugated linoleic acid, grape-seed extract, green tea extract, taurine and resveratrol are able to elevate plasma levels of adiponectin (32).
Losing weight, caloric restriction and physical exercise (33) can raise adiponectin levels.
Recently, phenolic compounds such as raspberry ketones have been marketed for weight loss. One of their proposed mechanisms of action is to raise adiponectin levels. However, there is no clinical evidence for such an effect in humans.
The Take-Home Message
Adiponectin is a protein secreted by adipose tissue. Adiponectin levels are lower among obese people than those who are normal weight. Visceral fat accumulation is associated with lower adiponectin levels than subcutaneous fat accumulation.
Low adiponectin levels may reflect dysfunction of adipose tissue among obese individuals.
Low levels of adiponectin are associated with inflammation, lipid abnormalities, insulin resistance and increased risk of diabetes, NAFLD, coronary heart disease, and cancer. A causative role of adiponectin remains to be proven.
Although adiponectin may be used as a biologic marker to assess risk and monitor treatment, adiponectin measurements are seldom performed in clinical practice.
Lifestyle interventions, some pharmaceutical drugs, and a few nutraceutical compounds may raise adiponectin levels.