Body fat is more than just a layer of insulation — or something we may wish we had less of during swimsuit season. Scientists are making surprising discoveries about the effect of body fat on health. These new findings can give us clues to our patients’ underlying diseases or disorders. They can also pinpoint patients with risk factors so we can educate them about lifestyle changes before it’s too late.

The amount of stored fat and its distribution on the body appear to be important indicators of underlying metabolic complications, especially the lipid abnormalities found with metabolic syndrome.

Patients have metabolic syndrome when three or more of the following indicators are present: central abdominal obesity, elevated triglycerides, hypertension, insulin resistance and low high-density lipoproteins (HDL, or good cholesterol).¹ Obesity, insulin resistance, hypertension, impaired glucose tolerance or diabetes, and metabolic syndrome are readily associated with an abundance of adipose tissue, often concentrated in the abdomen. Thirty-five percent of adults have metabolic syndrome, and the incidence increases with obesity and physical inactivity.¹ The incidence is also startling among adolescents: one in three children between ages 2 to 19 is overweight or obese.²

Fat is now recognized as an active endocrine organ responsible for secreting adipokines, hormones and proteins that regulate metabolic processes and affect the risk for developing many disorders, including atherosclerosis, diabetes and hypertension. Adipokines that have been identified include —

• Adiponectin
• Leptin
• Interlukin-6 (IL-6)
• Tumor necrosis factor-alpha (TNF-a)
• Plasminogen activator inhibitor-1
• Resistin
• Visfatin

Many other substances secreted by fat are being studied, but remain unnamed.^3,4 Adipose tissue serves as a storehouse for triglycerides. It’s a collection of lipid-filled cells (adipocytes) surrounded by a connective matrix that possesses a rich vascular and nerve supply, with immune cells, all working together to control energy homeostasis and neuroendocrine functions.⁴

Adipo — What?

Adiponectin is the most abundant adipokine that adipose tissue secretes. Adiponectin affects insulin sensitivity, enhances fatty acid oxidation and supports a multitude of functions. If levels are too low, it plays important roles in hyperglycemia, dyslipidemia and inflammatory processes that increase the risk for atherosclerosis, especially among people with diabetes. In fact, it’s rapidly gaining recognition as a biomarker of metabolic syndrome.⁴

Adiponectin helps insulin move glucose from the bloodstream into the cells to be used as fuel or to be stored for later use. Levels are significantly higher in women than in men because testosterone inhibits adiponectin.⁵

Research reveals that adiponectin is also expressed in bone-forming cells in the femur and tibia. Research suggests adiponectin plays a role in bone homeostasis and may represent a link between fat and body weight to bone density.⁶ Adiponectin increases bone mass by activating bone-forming cells (osteoblasts) and suppressing the cells that break down bone (osteoclasts).⁷

Adiponectin receptors are also in skeletal muscle cells, which support a connection between physical activity and anti-inflammatory and atheroprotective effects of adiponectin.^{8 (Level B)}

Leptin and Appetite

The hormone leptin helps suppress appetite. It is produced primarily by adipocytes. However, low levels are also expressed from skeletal muscle, the stomach and intestine, and the placenta.⁴ Leptin targets receptors in the hypothalamus to regulate appetite and metabolism. Leptin levels are increased by glucose, insulin, chronic use of glucocorticoids and estrogens. Androgens, growth hormone and inflammatory cytokines decrease leptin levels.

Leptin deficiency can be a congenital or acquired condition. It is responsible, in part, for hypogonadism, amenorrhea, thyroid suppression and impaired thermoregulation. Elevated leptin levels are directly associated with increased subcutaneous fat, especially among women. Women have higher leptin levels than men.⁴

Weight gain causes fat cells to release more leptin, which reduces appetite and promotes burning of calories. With weight loss, less leptin is released, appetite is increased and caloric burning diminishes. Overeating and subsequent obesity appear to impair this process and lead to a resistance to leptin — the brain no longer responds to control the appetite and enhance caloric burning. This has been defined as hyperleptinemia.⁴

IL-6, TNF-a, and PAI-1

Inflammatory proteins (also known as cytokines) secreted by body fat include IL-6, TNF-a and plasminogen activator inhibitor-1 (PAI-1). These proteins impair the ability of insulin to move glucose out of the bloodstream and promote the development of plaque in arterial linings.⁹ PAI-1, along with fibrinogen, increases the risk for blood clots.

Fat-Derived Resistin

Resistin is a fat-derived hormone with levels that directly correlate with obesity; as levels of resistin increase, levels of dopamine and norepinephrine released from the hypothalamus diminish, causing an increased appetite. Resistin also worsens insulin sensitivity and increases the storage of body fat. The presence of resistin is extremely low in human adipose tissue, and its role and other potential sites of production have not been extensively studied.⁴

Visfatin — An Insulin Mimic

Visfatin is a protein with actions similar to insulin. It is produced in great quantity by visceral fat (fat abundant around the abdomen) and, to a lesser extent, by subcutaneous fat (abundant around the buttocks and other subcutaneous areas including the hips and thighs). Unlike insulin, visfatin levels do not vary with food consumption. It promotes glucose uptake in fat and muscles and reduces glucose production in the liver.¹⁰

Visfatin has also been associated with the development of metabolic derangements among children. Obese children have nearly twice the levels of visfatin than do children with healthy weights.¹⁰

The Fat-Blood Pressure Connection

Visceral obesity has been identified as the most important risk factor for hypertension and cardiovascular disease. Obesity has been implicated in the development of hypertension through several mechanisms: inflammatory-associated endothelial dysfunction (damage to the inside lining of arteries) and renal function abnormalities. Vascular changes are also common among obese people, including a decreased response to nitric oxide, a gaseous molecule in the blood responsible for maintaining the muscle tone of blood vessels.¹¹ Nitric oxide is responsible for the dilation of the arteries as well as muscle tone. Overproduction of nitric oxide drops blood pressure and too little increases it.

Leptin increases blood pressure by activating the sympathetic nervous system. Once activated, the sympathetic nervous system increases renal sympathetic tone, causing vasoconstriction and increased vascular resistance.¹¹

Body fat plays yet another role in the regulation of blood pressure. Angiotensinogen, a fat-secreted peptide that takes part in maintaining blood pressure and volume, and other fat-secreted components of the renin-angiotensin system (RAS), regulate blood pressure.¹¹ Abnormal sodium retention and elevated arterial pressure also occur with RAS activation. Blocking the RAS has been shown to reduce the size of fat cells and improve insulin sensitivity by increasing the concentration of adiponectin. (This increase is achieved by inhibiting angiotensin-converting enzyme with medications, such as fosinopril [Monopril] and quinapril [Accupril], or by blocking the angiotensin Type 1 receptor with an angiotensin receptor blocker, such as irbesartan [Avapro] and losartan [Cozaar]).¹²

Researchers are investigating additional neurohormonal and cardiovascular associations between adipose tissue and blood pressure. Even the mechanical compression of the kidneys from visceral fat has been theorized to play a role in renal damage.¹¹

Location … Location … Location

Obese people are more likely to have low adiponectin levels. But don’t rely solely on the scale to give you clues.¹³ Waist circumference is a more reliable marker than body mass index as a predictor for adiponectin levels. As circumference increases, circulating adiponectin levels diminish.⁴

The significance of fat distribution to health-related risks has been extensively studied. Visceral fat is called central obesity. People with this distribution are termed “apples.” People with more subcutaneous fat are the “pears.” The apple distribution is more common among men and the pear distribution among women until menopause, when some women change to apple distributions. Apples tend to fare worse than pears with respect to diabetes risk, cardiovascular disease and insulin resistance.¹⁴

Body Fat and Specific Disease States

Low adiponectin levels are significantly associated with an abundance of inflammatory markers, especially among obese people and those with the metabolic syndrome.¹³ Adiponectin appears to affect the production of proinflammatory cytokines including IL-10 and IL-1RA, resulting in an inadequate immune response.¹³ Health problems that could result include an increased risk for development of nonalcoholic fatty liver disease, liver fibrosis and hepatic necroinflammation. People with lower adiponectin levels are also at a greater risk for gallstones.¹⁵

Cardiac anatomical changes have also been associated with adiponectin levels. Decreased plasma adiponectin levels are associated with the progression of left ventricular hypertrophy and diastolic dysfunction. Ischemic heart disease, coronary artery disease and acute coronary syndrome are also associated with low plasma adiponectin levels. These disorders have been attributed to the formation of complex coronary plaque lesions that develop more readily when adiponectin levels are low.^{16 (Level B}) People with low levels of serum adiponectin are also likely to have high levels of triglycerides and low levels of HDL.¹³

Oddly though, not all cardiac-related disorders are associated with low adiponectin levels. People with congestive heart failure and significantly high levels of adiponectin have a higher risk for death.^{17 (Level B)}

Research has established a correlation between leptin and risk for cerebrovascular disease and myocardial infarction.^18,19 High levels of leptin can induce platelet aggregation and accelerate formation of firm thrombi, and they are associated with abnormal fibrinolysis. Research indicates that high plasma leptin concentrations were more likely to result in failed thrombolytic therapy.²⁰

There is also a connection between leptin levels and certain types of cancer. Elevated leptin levels have been associated with an increased incidence in the development of invasive renal, gastric and liver carcinoma.^{20,21 (Level B), 22 (Level C)} There is also a connection between adiponectin levels and the severity of diabetic retinopathy, with significantly lower levels of adiponectin in people with proliferative diabetic retinopathy.³

There are connections between adipokine levels in both osteo- and rheumatoid arthritis. Because adiponectin reduces the immune response, it appears to serve a protective function to mediate the destruction of cartilage in these disorders. Adiponectin is the synovial fluid, cartilage and bone of people with osteoarthritis.²² People with rheumatoid arthritis show a marked increase in levels of adiponectin, leptin and visfatin.^{23 (Level B)} In time, these discoveries may lead to disease-modifying or curative medications.

Adiponectin levels have also been implicated as a culprit in polycystic ovarian syndrome. Women with polycystic ovary syndrome (PCOS) have significantly lower levels of adiponectin than women who do not have PCOS.²⁴

Adipocytes even play a role in utero; promoting weight loss among overweight women who contemplate pregnancy is important for both mother and infant. Low levels of adiponectin and TNF-a are associated with increased infant birth weight and gestational diabetes.²⁵ Fetuses with intrauterine growth restriction are often born small for gestational age and are more likely to develop insulin resistance and have higher circulating levels of adiponectin.²⁶

Fat Storage and Regulation

The body strives to maintain homeostasis with respect to weight. Starvation — whether attempted as an unhealthy weight loss strategy, used as a statement of social protest or induced by restricted access to food — causes the body to shift to a self-preservation mode. In severely restricted low-calorie diets, the secretion rate of leptin decreases significantly.²⁷

The Diabetes-Insulin Resistance Connection

Regardless of the amount of body fat, leptin and adiponectin levels are clearly associated with insulin resistance.⁹ Circulating adiponectin levels in adults inversely relate to insulin resistance; the lower the level, the more likely a patient is to have insulin resistance. Adiponectin and leptin levels may also serve as diagnostic markers that help clinicians differentiate Type 1 and Type 2 diabetes among adolescents and children. In children with diabetes, adiponectin and leptin levels were normal in those with Type 1 diabetes. For children with Type 2 diabetes, adiponectin levels were significantly lower and leptin levels markedly elevated.^{28 (Level B)}

Adipokine levels can also help clinicians identify children with Type 2 diabetes who are at high risk for adverse cardiovascular outcomes.²⁹

Oolong tea can be beneficial for people with diabetes, particularly for patients with risk factors associated with the development and progression of atherosclerosis. A review of available literature reveals that people with diabetes and coronary artery disease experienced an increase in adiponectin levels, a decrease in hemoglobin A1c levels and an increase in low-density lipoprotein (LDL, or bad cholesterol) particle size with tea consumption. These benefits ceased with the discontinuation of Oolong tea consumption.³⁰

Treatment with extended-release niacin is also effective in increasing the levels of adiponectin, leading to less favorable circumstances for the development or progression of atherosclerosis. In one study, 20 men with metabolic syndrome received 1,500 mg of niacin for six weeks and experienced an increase of 88% in adiponectin levels.^{31 (Level A)} Although this link may be significant, it’s important to remind patients who self-medicate with over-the-counter (OTC) niacin to check with their prescribing healthcare providers before they begin therapy.

Is Liposuction or Diet Drugs the Answer?

Weight loss leads to metabolic benefits including reduced insulin resistance and decreased atherosclerotic risk factors. It would seem that abdominal liposuction might be a logical and rapid solution for metabolic imbalances that relate to central obesity. Unfortunately, initial studies show that insulin sensitivity, levels of adiponectin and risk factors for coronary heart disease did not markedly improve after liposuction. However, emerging evidence from some studies shows some beneficial effects on decreasing insulin resistance and vascular inflammation among obese patients after liposuction.³²

One option for obesity treatment has demonstrated effectiveness in reducing undesirable metabolic markers.³³ Prescribed for weight loss, orlistat (Xenical) can also have desirable effects, including lowering lipids and improving insulin sensitivity. It reduces leptin and increases adiponectin — benefits that result from the drug’s ability to block intestinal absorption of a percentage of dietary fat. This fat must be excreted in bowel movements. You may see a sudden and drastic increase in the use of this drug, not specifically for its desirable metabolic effects, but because it is now available in an OTC half-strength version marketed under the name Alli. However, users must be forewarned, because orlistat has numerous adverse effects that many patients cannot tolerate, including flatulence and oily stools that are explosive at times.³³

How Can Healthcare Practitioners Help?

Promoting healthy weight for patients of all ages is important, but it’s especially crucial for children and teenagers. The Centers for Disease Control and Prevention estimates that children born in 2000 will have a 33% to 39% lifetime risk of developing diabetes.³⁴ The early development of obesity can lead to leptin resistance and make weight loss difficult metabolically throughout life. It’s important to identify and encourage modification of factors that contribute to the development of the metabolic syndrome, diabetes and obesity, including a sedentary lifestyle, high-sodium and high-fat diets, and abundant consumption of high-calorie fast foods.³⁵

Awareness of cultural ties with metabolic syndrome is also important, as is a culturally competent strategy to interact with patients and teach healthy lifestyle interventions. The literature abounds with evidence that a change in diet from traditional cuisine to the less-healthy Western cuisine, combined with a more sedentary lifestyle, is significantly detrimental and leads to a high incidence of metabolic syndrome.^36-38

Healthcare practitioners also can encourage early identification of metabolic syndrome when they promote frequent health screening measures, including measurement of waist circumference and blood pressure, screening for lipid profile abnormalities, elevated fasting and postprandial glucose levels. A team approach may also be helpful; consider referring patients with or who are at risk for metabolic syndrome to a registered dietitian or other reputable diet and lifestyle modification program. Because adolescents are still growing, they may require a program that emphasizes lifestyle changes and increased physical activity rather than intensive low-calorie diets. Healthcare practitioners can also serve as role models to promote healthy lifestyle choices for patients when they maintain a healthy weight and make good nutritional choices themselves. Emerging evidence points to a Mediterranean diet as beneficial for adiponectin levels. A diet that contains whole grains, nuts, less meat and alcohol in moderation can increase adiponectin levels.^{39 (Level A)}

Medications to Know About

Drugs that can treat insulin resistance associated with diabetes, rosiglitazone (Avandia) and pioglitazone (Actos), significantly increase plasma levels of adiponectin. They also promote a fat concentration shift from central to subcutaneous areas.³⁹ The U.S. Food and Drug Administration has restricted prescribing of medications containing rosiglitazone to healthcare providers and patients enrolled in a special Risk Evaluation and Mitigation Strategy, due to data suggesting an increased risk of heart attacks in patients taking rosiglitzaone.⁴⁰

Look for other drugs in the not-too-distant future for treatment of the metabolic syndrome that will supplement or stimulate adiponectin production; such drugs would have desirable outcomes, including reducing central obesity, oxidizing free fatty acids and reducing insulin resistance. The vasoprotective actions of adiponectin may reduce cardiovascular diseases, and the osteoblastic-promoting properties may be potential treatments for osteopenia and osteoporosis.⁷

A Fat Future?

Scientific discoveries enable us to recognize that fat is more than just a layer of insulation. In excess, fat leads to unwanted multisystem health problems. We now understand that fat is an active endocrine organ that can sense a person’s nutritional and metabolic status, and release hormones and enzymes including adiponectin, leptin and free fatty acids. We can now attribute to weight loss, long advocated as a health-promoting measure, the benefit of reducing metabolic risks.

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