A closer look at adiponectin

Whether insulin or leptin or adiponectin or PPAR gamma or NF KB or a bajillion cytokines are the proximate mediators of obesity or atherosclerosis is hardly the point, is it?

Kurt G. Harris MD

Although biochemistry can be marvelously exiting we must not lose sight of the bigger picture. It is increasingly unlikely that any one tiny substance is going to be our savior.

Still, adiponectin would be a good candidate. Adiponectin is indeed popular these days. If you type it in Pubmed you get about 7150 hits of which a whopping 4800 of these are from after 2006

Leptin is adiponectins evil twin brother 
Whereas leptin is considered a pro inflammatory substance which may contribute to the development and progression of autoimmune responses, adiponectin seem to act as an anti-inflammatory factor. If your adiponectin level is low, you want to increase it. Leptin is generally high in obesity and lifestyle diseases while adiponectin is low. In vitro studies indicate that leptin promotes human breast cancer cell proliferation while adiponectin exhibits anti-proliferative actions.

Despite being produced almost exclusively by the fat tissue (lymphocytes also produce it) obese persons usually have low adiponectin levels. Expression of the mRNA responsible for the production of adiponectin is significantly decreased in the adipose tissue of obese mice and humans, which may explain why this occurs.

Adiponectin has showed numerous inverse correlations with weight, BMI, insulin, glucose, HOMA, atherogenic lipid profiles, cancers, liver disease, and dementia and so on. In short, adiponectin seems to positively correlate with anything positive.

Adiponectin itself may be antiatherosclerotic, as it acts as an endogenous antithrombotic factor and inhibits macrophage activation and foam cell accumulation, both being critical cytologic elements of atheromas. Stroke, coronary heart disease, steatohepatitis, insulin resistance, nonalcoholic fatty liver disease, and a wide array of cancers have been associated with decreased adiponectin levels. 

Wozniak et al 2009 

Serum adiponectin concentrations are inversely associated with obesity, insulin resistance and type 2 diabetes in rodents and humans, whereas increased serum adiponectin concentrations are associated with improved insulin sensitivity.

If you are overweight with good insulin sensitivity it means your fat tissue is doing its job, that there is minimal endoplasmatic reticulum stress, minimal inflammation and that you probably have a high adiponectin level.

Morrison et al (2010) examined 108 obese girls of who 31 was identified with having paradoxically high adiponectin levels. In these 108 obese girls, adiponectin levels at age 16 years independently predicted HDL level (positive) and waist circumference (negative), insulin level (negative), and glucose (negative) at age 23. Paradoxically high adiponectin levels at age 16 was a negative independent predictor for waist circumference, HOMA-IR and for the components of the metabolic syndrome at age 23.

Adiponectin and rodents
Most of what we know about adiponectin is from rodent studies. T. Yamauchi and colleagues showed that decreased expression of adiponectin correlates with insulin resistance in mouse models of altered insulin sensitivity. They propose that adiponectin decreases insulin resistance by increasing fatty acid oxidation and thus decreasing triglyceride content in muscle and liver in the obese mice. In lipoatrophic insulin resistant mice the resistance was completely reversed by administering a combination of physiological doses of adiponectin and leptin. When administered separately the resistance was only partially improved. The results from these trials are of course interesting and important, but the authors naturally concluded that “...adiponectin might provide a novel treatment modality for insulin resistance and type 2 diabetes,” thus missing the bigger picture by a mile.

In normal mice adiponectin administration has been shown to improve insulin sensitivity and lower glucose levels.

The insulin sensitizer agonist with the marvelous name of peroxisome proliferator-activated receptor-gamma (PPARg) stimulates adiponectin production in fat tissue. Adiponectin is thought to be part of this agonist's mechanism for lowering circulating fatty acids and increasing fat oxidation. The increase in insulin sensitivity by adiponectin might be simply from the increased fatty acid oxidation ameliorating fat cell overload.

Additionally, adiponectin has a direct effect on glucose uptake in skeletal muscle and adipose tissue and may increase the glucose transporter (GLUT4) translocation to the plasma membrane. Interestingly, pro-inflammatory cytokines, such as TNF-α and IL-6 are potent inhibitors of adiponectin gene expression or protein secretion.

In the early 2000 Matthias Blüher and colleagues produced a strain of the genetically engineered FIRKO mouse. This mouse lacks insulin receptors in the fat tissue. An inability to store energy in fat tissue and especially to take up glucose is normally very harmful. The FIRKO mice are immune to the dietary induced obesity used in other mice. However they live quite a lot longer than normal mice. Due to its genetic defect the FIRKO mouse have normal insulin sensitivity and normal glucose homeostasis. Despite its lean shape the FIRKO mouse also over express adiponectin. Transgenic mice lacking adiponectin on the other hand show impaired insulin sensitivity and an abnormal glucose homeostasis.

The over expression of adiponectin could be what saves the FIRKO mouse from the normally observed ill effects of adipocyte insulin resistance.

Intravenous injections of adiponectin in rodents have increased adiponectin in the cerebrospinal fluid which indicates brain transport. When injected directly into the brain adiponectin decrease body weight in rodents mainly by increasing energy expenditure.

The leptin deficient ob/ob mice respond particularly well to adiponectin injections both in brain and serum and shows increased thermogenesis, weight loss and reduction in serum glucose and lipid levels after injections.

One proposed mechanism for the coexistence of obesity and insulin resistance is endoplasmatic reticulum stress caused by the growing adipocytes. Obesity induces ER stress in mouse adipose tissue, which also correlates with reduced adiponectin levels. Suppressing ER stress increases adiponectin levels in 3T3-L1 adipocytes in vitro and alleviates diet induced adiponectin downregulation in mice.

Adiponectin, diet and weight loss
The best way to increase adiponectin is to lose weight as adiponectin increases in plasma with fat loss. Shai et al fond a significant increase in adiponectin level during both weight-loss and maintenance phases despite dissimilar macronutrient intakes.

Severely obese women has significant less fasting and postprandial (medium carb diet) adiponectin compared to lean women.

Sidika E Kasim-Karakas gave 22 healthy postmenopausal women a eucaloric low fat – high carb diet for 4 months followed by the same diet (15%fat) only energy restricted for 8 months. The researchers wondered whether energy restriction would modulate the inflammatory response to a high carb diet. The eucaloric diet decreased adiponectin from 16.3 to 14.2mg/L (P<0.05). The energy restricted diet increased adiponectin from 14.2 back to 16.3.

During the eucaloric phase, the low-fat – high carbohydrate diet exerted unfavorable effects on several inflammatory markers. The energy restricted low-fat – high-carbohydrate diet caused weight loss and affected inflammatory markers favorably thus indicating a protective role of energy restriction on the inflammatory effect of high carbohydrate feeding.

Pischon et al recently reported that in the 532 male participants of the Health Professionals Follow-Up Study, serum adiponectin concentrations correlated inversely with the glycemic load and positively with the total fat content of the diet.

Hypoadiponectinemia is as mentioned associated which the metabolic syndrome with all its components and also correlate with non alcoholic fatty liver disease (NAFLD). There is however much indicating that low GI diet in these conditions increases adiponectin level.

Keogh et al (2008) explains that adiponectin seem to only increase in the face of substantial but not moderate weight loss. Keogh et al found no effect of weight loss on adiponectin level either by a low carbohydrate or low fat diet. The weight loss was 6-7kg in 8 weeks. However Keogh had previously found an improvement in adiponectin after 12 months but not after 3 months, which suggests a delayed weight loss response on adiponectin.

Hivert et al looked at blood samples from the Nurses' Health Study. They found that in the women who did not develop diabetes, baseline levels of adiponectin were associated with significantly greater weight gain after adjusting for age, BMI, physical activity, diet, and other factors. The women in the highest quintile of adiponectin gained 3.18 kg compared to women in the lowest quintile who gained 0.80 kg over 4 years. There was no such association in the women who did develop diabetes. The finding might indicate that higher adiponectin production by adipocytes might be a sign of healthier adipose tissue with further capacity to store fat. This is supported by the finding that a good fat storing ability seems to protect against insulin resistance.

Weight reduction has been found to increase plasma adiponectin in both obese and diabetic patients. Exercise interventions of short duration that does not alter body weight or body fat does not change adiponectin levels. Layman et al (2005) found that an exercise regimen that reduced body fat increased adiponectin levels. The positive changes in adiponectin remained even when controlling for changes in body fat.

Other effects
In vitro studies suggest that adiponectin plays an important role in nitric oxide (NO) generation which is an important function for arterial elasticity. Impaired NO generation plays a role in endothelial dysfunction and atherosclerosis. Decreased plasma adiponectin correlates with impaired insulin-stimulated nitric oxide synthase activity in skeletal muscles and also severity of insulin resistance in people with type 2 diabetes. This finding may provide one link between reduced plasma adiponectin levels and accelerated atherosclerosis in type 2 diabetes.

Adiponectin also affects endothelial progenitor cells which play an important part in repairing damages to the vasculature. Adiponectin seem to inhibit EPC apoptosis in vitro.

A Japanese study found a correlation between cognitive impairment and adiponectin. Plasma adiponectin was significantly higher in people with mild cognitive impairment and people with Alzheimer’s disease compared to normal controls.

Smoking lowers adiponectin

As with many other biological substances adiponectin level varies with day and night and feeding/fasting. This lends caution to interpretation of adiponectin results.