August 13, 2008 — Being obese does not necessarily mean that a patient has other risk factors for heart disease, two new studies show — it all depends on where the excess fat is stored, with liver fat having the worst profile [1,2].

The studies are both published in the August 11/25, 2008 issue of the Archives of Internal Medicine.

In the first study, the researchers, led by Dr Norbert Stefan (University of Tubingen, Germany), report that a metabolically benign obesity that is not accompanied by insulin resistance and early atherosclerosis exists in humans and that 25% of the obese subjects in their study fell into this category.

The problem is not just visceral fat

Previous studies have suggested that visceral fat — fat deposited in the abdomen — is associated with an increased risk of diabetes and heart disease. But Stefan et al found that while the amount of visceral fat was a powerful signal of insulin resistance in subjects with normal body weights or those who were overweight but not obese, the predictive effect of visceral fat was relatively weak in obese patients. Rather, excess fat in the liver was the main predictor of insulin resistance and atherosclerosis in obese individuals.

Stefan commented to heartwire : "We wanted to investigate why some obese people are still insulin sensitive while others with a similar body mass are insulin resistant." They studied 314 white adults who had either a family history of type 2 diabetes mellitus, a body-mass index of greater than 27, or a previous diagnosis of impaired glucose tolerance or gestational diabetes.

All subjects underwent magnetic resonance imaging (MRI) scans to measure total body fat, visceral fat, subcutaneous fat, and fat content in ectopic tissues (liver and skeletal muscle). Waist measurement was also recorded, as was glucose tolerance, and atherosclerosis was assessed by carotid intima media thickness (IMT) measured with high-resolution ultrasonography.

Subjects were divided into four groups: normal weight, overweight, obese — insulin sensitive (upper quartile of insulin sensitivity), and obese — insulin resistant (lower 3 quartiles of insulin sensitivity), and the researchers examined how fat distribution was related to insulin sensitivity and atherosclerosis, with particular emphasis on the two obese groups.

Liver fat: The worst culprit

Results showed that while visceral fat was higher in obese patients who were insulin resistant than obese patients who were insulin sensitive, this result was not significant. But both intramuscular and liver fat were significantly higher in the obese patients with insulin resistance than in those who were insulin sensitive, with the largest differences seen in liver fat. There was no difference in levels of subcutaneous abdominal fat, total body fat, or body-mass index in the insulin-sensitive or insulin-resistant obese patients. Stefan commented: "We found that the most harmful fat distribution pattern in obese people was that of high liver fat, followed by high intramyocellular [muscle] fat. Visceral fat is also bad, but not as bad as liver or muscle fat."

Unexpectedly, the obese insulin-sensitive group had almost identical insulin sensitivity as the normal-weight group, and their carotid IMT measurements were not statistically different. "This suggests that these patients have a relatively benign obesity," Stefan noted. He continued: "I am not saying that it is okay to be obese — it is still not as healthy as being normal weight even if you have the relatively benign type of obesity. But it is still desirable to be able to identify those obese patients with the highest risk of diabetes and heart disease. I would tell all obese patients to try to lose weight with diet and exercise, but I would go one step further and consider pharmacological treatment or other measures as well for those who are showing the high-risk profile of obesity."

But he added: "The problem is that we cannot easily identify individuals with high levels of liver and muscle fat. This needs to be done with MRI scans, and these are expensive, so it is not feasible to do this for all obese patients. So for the time being for clinical practice, waist circumference gives us some idea of risk, and more information can be ascertained from taking blood insulin measurements, with the highest levels of insulin signifying highest risk. This is probably the best easy measurement to give a good idea of risk. So waist and insulin measurements are a good start. But I would still advocate MRI scans of obese patients with a family history of diabetes or heart disease to identify those at highest risk."

Different body size phenotypes

The second study was conducted by a group led by Dr Rachel Wildman (Albert Einstein College of Medicine, Bronx, New York). They note that there is increasing recognition that the disease risks associated with obesity may not be uniform, which has resulted in the investigation of body size phenotypes. They set out to find out more about the prevalence of each of six body size phenotypes — normal weight with and without cardiometabolic abnormalities, overweight with and without cardiometabolic abnormalities, and obese with and without cardiometabolic abnormalities.

To do this, they analyzed data from 5440 participants in the National Health and Nutrition Examination Surveys (NHANES) 1999-2004. Cardiometabolic abnormalities included hypertension; raised triglycerides, fasting plasma glucose, and C-reactive protein; insulin resistance and low high-density lipoprotein (HDL).

Results showed that 23.5% of normal-weight adults were metabolically abnormal, whereas 51.3% of overweight adults and 31.7% of obese adults were metabolically healthy. Factors associated with cardiometabolic abnormalities among normal-weight individuals were older age, lower physical-activity levels, and larger waist circumference, and factors associated with lack of cardiometabolic abnormalities among overweight and obese individuals were younger age, non-Hispanic black race/ethnicity, higher leisure-time physical-activity levels, and smaller waist circumference.

The researchers conclude: "Among US adults, there is a high prevalence of clustering of cardiometabolic abnormalities among normal-weight individuals and a high prevalence of overweight and obese individuals who are metabolically healthy."

Noting that this data set does not include information on the amount of visceral and subcutaneous adipose tissue or work-related physical activity, which may be relevant to defining and evaluating body size phenotypes, they say that "further studies into the behavioral, hormonal or biochemical, and genetic mechanisms underlying these differential metabolic responses to body size are needed and will likely further the identification of possible obesity intervention targets and improve cardiovascular disease screening tools."

A tale of two sites

In an accompanying editorial [3], Dr Lewis Landsberg (Northwestern University Comprehensive Center on Obesity, Chicago, IL) says that both these reports demonstrate the detrimental effect of visceral fat accumulation and its surrogate, waist circumference. Noting that insulin resistance, glucose intolerance, lipid abnormalities, and hypertension (all components of the metabolic syndrome) also track with the central abdominal form of obesity, he adds that understanding the pathophysiologic mechanism of insulin resistance may be of value to clinicians as they advise their obese patients who are at risk for cardiovascular disease.

The study by Stefan and colleagues was supported by the Deutsche Forschungsgemeinschaft and the European Community's FP6 EUGENE2 (European Network on Functional Genomics of Type 2 Diabetes). Three of the study authors have obtained funding. The remaining study authors have disclosed no relevant financial relationships.

In the study by Wildman and colleagues, the authors have disclosed no relevant financial relationships.

Dr. Landsberg has disclosed no relevant financial relationships.

Sources

1. Stefan N, Kantartzis K, Machann J, et al. Identification and characterization of metabolically benign obesity in humans. Arch Intern Med. 2008;168:1609-1616.
2. Wildman RP, Muntner P, Reynolds K, et al. The obese without cardiometabolic risk factor clustering and the normal weight with cardiometabolic risk factor clustering: prevalence and correlates of 2 phenotypes among the US population: (NHANES 1999-2004). Arch Intern Med. 2008;168:1617-1624.
3. Landsberg L. Body fat distribution and cardiovascular risk. A tale of two sites. Arch Intern Med. 2008;168:1607-1608.

The complete contents of Heartwire , a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.

Clinical Context

Study Highlights

• Stefan and colleagues
  • 314 white adults in Germany at high risk for type 2 diabetes participated in the study.
  • Participants underwent measurement of total, visceral, and subcutaneous abdominal fat using MR tomography. In addition, MR spectroscopy was used to measure fat content in the liver and skeletal muscle.
  • Subjects also completed a glucose tolerance test and an ultrasound examination to determine carotid IMT.
  • Participants were divided into groups according to BMI and, in obese individuals, whether they were insulin resistant or insulin sensitive.
  • The main outcome of the study was to determine potential factors that could promote a metabolically benign obesity, which was defined by insulin sensitivity.
  • The mean age of participants was 45 years.
  • Total body fat, visceral fat, and waist circumference were similar in obese participants regardless of insulin sensitivity.
  • Intramuscular fat concentrations were lower in the obese insulin-sensitive group vs the obese insulin-resistant group.
  • Liver fat concentrations were higher in insulin-resistant obese adults (9.8%) vs insulin-sensitive obese participants (4.3%).
  • As expected, insulin sensitivity decreased with the progression from normal weight to overweight and obesity. However, values for insulin sensitivity were nearly identical between normal-weight participants and obese insulin-sensitive adults.
  • Carotid IMT was lowest in individuals with a normal weight. However, this mean value was not significantly lower than that of the insulin-sensitive obese group, and insulin-sensitive obese participants had lower carotid IMT vs insulin-resistant obese adults.
• Wildman and colleagues
  • Researchers examined 6036 participants in the 1999 – 2004 National Health and Nutrition Examination Surveys cohort. Only subjects without a history of underweight or cardiovascular disease were included in the analysis.
  • The authors identified 6 metabolic outcomes (elevated blood pressure, hypertriglyceridemia, fasting glucose levels, high-sensitivity C-reactive protein, insulin resistance, and reduced high-density lipoprotein cholesterol levels) and compared these outcomes with BMI category (normal weight, overweight, or obesity).
  • Participants with 0 or 1 metabolic abnormality were considered metabolically normal, whereas higher rates of metabolic disorders were defined as abnormal.
  • 23.5% of normal-weight adults were metabolically abnormal. Older age, reduced levels of physical activity, and larger waist circumference predicted higher rates of metabolic abnormality in normal-weight adults.
  • 51.3% and 31.7% of overweight and obese adults, respectively, were metabolically normal. Younger age, higher levels of physical activity, and smaller waist circumference predicted higher rates of metabolic normalcy in overweight and obese adults.
  • Overweight and obese non-Hispanic black adults were more likely to be metabolically normal vs overweight and obese individuals from other racial and ethnic groups.
  • Sex did not significantly affect the rates of metabolic normalcy across different categories of BMI.

Pearls for Practice

• In the current study by Stefan and colleagues, the concentration of fat in the liver was most significant in determining insulin sensitivity in obese adults.
• In the current study by Wildman and colleagues, physical activity, waist circumference, and age were all independent factors associated with maintaining a lower rate of cardiovascular risk factors regardless of weight. Sex did not significantly affect this outcome.

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