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 impact 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 “the metabolic syndrome” www.americanheart.org/presenter.jhtml?identifier=534.

Patients have the metabolic syndrome when three or more of the following indicators are present:  insulin resistance, hypertension, central abdominal obesity, elevated triglycerides, and low high-density lipoproteins (HDL, or “good” cholesterol).¹ Obesity, insulin resistance, hypertension, impaired glucose tolerance or diabetes, and the metabolic syndrome are readily associated with an abundance of adipose tissue, often concentrated in the abdomen. Twenty-four percent of adults have the metabolic syndrome, and the incidence increases to 43.5% for people over age 60.¹ The incidence is also startling among adolescents: one in 10 adolescents aged 12 to 19 have metabolic syndrome, and one four are overweight.¹

Fat has now been 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 diabetes, hypertension, and atherosclerosis. Adipokines that have been identified include:

• Adiponectin
• Leptin
• Interlukin-6
• Tumor necrosis factor-alpha
• Plasminogen activator inhibitor-1
• Resistin
• Visfatin

There are many other substances that are secreted by fat that are being studied, but remain unnamed.^2,3 Adipose tissue serves as a storehouse for triglycerides www.americanheart.org/presenter.jhtml?identifier=4778. 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.³

Adipo — what?

Adiponectin is the most abundant adipokine that adipose tissue secrets. 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 www.nlm.nih.gov/medlineplus/ency/article/000171.htm, especially among people with diabetes. In fact, it’s rapidly gaining recognition as a biomarker of the metabolic syndrome.³

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 men because testosterone inhibits adiponectin.³

Research has revealed that adiponectin is also expressed in bone-forming cells in the femur and tibia. Ongoing research suggests adiponectin plays a role in bone homeostasis and may represent a link between fat and body weight to bone density.⁴ Adiponectin increases bone mass by activating bone forming cells (osteoblasts) and suppressing the cells that break down bone (osteoclasts).⁵

Adiponectin receptors have also been found in skeletal muscle cells, supporting a connection between physical activity and anti-inflammatory and atheroprotective effects of adiponectin.⁶

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.³ 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 and 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.³

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.³

IL-6, TNF-a, PAI-1

Inflammatory proteins (also known as cytokines) secreted by body fat include interlukin-6 (IL-6), tumor necrosis factor-alpha (TNF-a), and plasminogen activator inhibitor-1 (PAI-1). These proteins impair the ability of insulin to move glucose out of the blood stream and promote the development of plaque in arterial linings.⁷ PAI-1, along with fibrinogen, increases the risk for developing 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 are diminished, 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.³

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.⁸

Visfatin has also been associated with the development of metabolic derangements among children. One study revealed that obese children have nearly twice the levels of visfatin than do children with healthy weights.⁸

The fat-blood pressure connection

Visceral obesity has been identified as the most important risk factor for developing 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.⁹ 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.⁹

Body fat plays yet another role in the regulation of blood pressure. Angiotensinogen, a fat-secreted peptide involved in maintaining blood pressure and volume, and other fat-secreted components of the renin-angiotensin system (RAS) regulate blood pressure.⁹ 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 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 ARBs, such as irbesartan [Avapro] and losartan [Cozaar]).¹⁰

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.⁹

Location … location … location

People who are obese are more likely to have low adiponectin levels. But don’t rely solely on the scale to give you clues.¹¹ Waist circumference is a more reliable marker than body mass index in predicting adiponectin levels. As circumference increases, circulating adiponectin levels diminish.³

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.¹²

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.¹¹ Adiponectin appears to affect the production of pro-inflammatory cytokines including IL-10 and IL-1RA, resulting in an inadequate immune response.¹¹ 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 developing gallstones.¹³

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 www.acc.org/media/ patient/chd/ischemic.htm, coronary artery disease www.nlm. nih.gov/medlineplus/ency/article/007115.htm, and acute coronary syndrome www.emedicine.com/EMERG/topic31.htm 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.¹⁴ People with low levels of serum adiponectin are also likely to have high levels of triglycerides and low levels of HDL.¹¹

Oddly though, not all cardiac-related disorders are associated with low adiponectin levels. People with congestive heart failure www.nlm.nih.gov/medlineplus/heartfailure.html who have significantly high levels of adiponectin have a higher risk for death.¹⁵

Research has established a correlation between leptin and risk for cerebrovascular disease. A study of 276 people experiencing a first stroke revealed that men with high leptin levels developed stroke faster than men with low leptin levels. This correlation was not evident among the women in the study.¹⁶

A connection has also been established 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.^17,18,19 A connection has been established between adiponectin levels and the severity of diabetic retinopathy www.mayoclinic.com/health/diabetic-retinopathy/ DS00447, with significantly lower levels of adiponectin found among people with proliferative diabetic retinopathy.²

Connections have been identified between adipokine levels in both osteo and rheumatoid arthritis. Because of the ability of adiponectin to reduce the immune response, it appears to serve a protective function to mediate the destruction of cartilage found in these disorders. Adiponectin has been found in the synovial fluid, cartilage, and bone of people with osteoarthritis.²⁰ A marked increase in the levels of adiponectin, leptin, and visfatin has been found among people with rheumatoid arthritis.²¹ In time, these discoveries may lead to disease-modifying or curative medications.

Adiponectin levels have also been implicated as a culprit in polycystic ovary syndrome www.pcosupport.org. Women with PCOS have been found to have significantly lower levels of adiponectin than women without PCOS.²²

Adipocytes even play a role in utero, and promoting weight loss among overweight women contemplating 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.²³ Infants who experience intrauterine growth restriction, often born small for gestational age, are more likely to develop insulin resistance and have higher circulating levels of adiponectin.²³

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 into a “self-preservation” mode. In severely restricted low-calorie diets, the secretion rate of leptin decreased significantly.²⁴

The diabetes-insulin resistance connection

Regardless of the amount of body fat, leptin and adiponectin levels are clearly associated with insulin resistance.⁷ Circulating adiponectin levels in adults are inversely related 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 helping clinicians to differentiate Type 1 and Type 2 diabetes among adolescents and children. When measured among children with diabetes, adiponectin and leptin levels were normal among those with Type 1 diabetes while adiponectin levels were significantly lower and leptin levels markedly elevated among children with Type 2 diabetes.²⁵

Oolong tea has been shown to be beneficial for people with diabetes, particularly for patients with risk factors associated with the development and progression of atherosclerosis. In one study of 22 people with diabetes and coronary artery disease, after one month of Oolong tea consumption, 1 liter a day, adiponectin levels increased, hemoglobin A1c levels decreased, and low-density lipoprotein (LDL, or “bad” cholesterol) particle size increased. These benefits were not seen when Oolong tea consumption was discontinued.²⁶

Treatment with extended-release niacin has also been shown to be effective in increasing the levels of adiponectin. In one study, after four weeks of treatment, adiponectin levels were found to increase by 54% with a dose of 1,000 mg and by 94% with a dose of 1,500 mg daily. Niacin did not lower leptin levels and only moderately lowered resistin levels, leading to less favorable circumstances for the development or progression of atherosclerosis.²⁷ While this link may be significant, it’s important to remind patients who may be led by study findings to self-medicate with over-the-counter niacin to check with their prescribing healthcare provider before beginning therapy.

Are 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 related to central obesity. Unfortunately, insulin sensitivity, levels of adiponectin, and risk factors for coronary heart disease were not found to improve markedly after liposuction from initial studies. However, emerging evidence from some research studies has shown some beneficial effects on decreasing insulin resistance and vascular inflammation among very obese patients after liposuction.²⁸

Two options for treating obesity have demonstrated effectiveness in reducing undesirable metabolic markers. Sibutramine (Meridia) improves fat distribution and insulin resistance and increases serum adiponectin levels. But this medication has limitations as it may cause an increase in pulse and blood pressure.²⁹

Prescribed for weight loss, orlistat (Xenical) has also been found to have desirable effects, including lowering lipids and improving insulin sensitivity. It reduces leptin and increases adiponectin — benefits resulting from the drug’s blocking intestinal absorption of a percentage of dietary fat, fat that 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 impacts, but because it is now available in an OTC half-strength version marketed under the name Alli. Users must be forewarned, however, because orlistat has numerous adverse effects that many patients cannot tolerate, including flatulence and oily stools that at times can be “explosive.”²⁹

How can nurses 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.³⁰ 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.³¹

Awareness of cultural ties with the 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 very high incidence of metabolic syndrome.^32,33,34

Nurses can also encourage early identification of the metabolic syndrome by promoting frequent health screening measures, including measurement of waist circumference and blood pressure and screening for lipid profile abnormalities and elevated fasting and postprandial glucose levels. A team approach may also be helpful; consider referring patients who have or are at risk for the metabolic syndrome to a registered dietitian or other reputable diet and lifestyle modification program. Adolescents who are still growing may require a program emphasizing lifestyle changes and increased physical activity rather than intensive low-calorie diets. Nurses can also serve as role models to promote healthy lifestyle choices for patients by maintaining a healthy weight and making good nutritional choices themselves. Emerging evidence points to a Mediterranean diet www.americanheart.org/presenter.jhtml?identifier=4644 as having beneficial effects on adiponectin levels. A diet containing whole grains, nuts, less meat, and alcohol in moderation has been found to increase adiponectin levels.³⁵

Medications to know about

Two drugs used to 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.²

Look for other drugs in the not-too-distant future designed to treat 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 be used to reduce cardiovascular diseases, and the osteoblastic-promoting properties may be used as potential treatments for osteopenia and osteoporosis.⁵

A fat future?

Scientific discoveries have enabled 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 capable of sensing a person’s nutritional and metabolic status and releasing hormones and enzymes including adiponectin, leptin, and free fatty acids. Weight loss has been advocated for years as a health-promoting measure — now add to its benefits the reduction of metabolic risks.