Subcutaneous thigh fat was, independently of abdominal fat depots, related to more favourable levels of glucose and lipids in black and white subjects, except to glucose levels in women. This paper also showed that waist circumference was related to both visceral fat and subcutaneous fat, and that waist circumference better represented visceral fat at a low BMI. Apart from reflecting subcutaneous thigh fat, thigh circumference also represented muscle, in particular in men.
This study has some limitations. First, because we investigated a relatively healthy and well-functioning population, we may have underestimated the true associations. The results should therefore not be extended to the general population. Second, because of the cross-sectional design of the study, causality cannot be assumed. Longitudinal analyses, however, are also limited because body composition values are not stable over time, particularly in the elderly. Finally, the anthropometric analyses were performed in people without known diabetes or dyslipidaemia, which could also create a bias when generalizing to the total population.
Visceral fat was the strongest independent correlate of unfavourable glucose and lipid levels, which supports the hypothesis that visceral fat, in particular, contributes to the higher non-esterified fatty acid (NEFA) levels, which are directly released in the portal vein leading to the liver. In the liver, NEFA play an important role in the development of insulin resistance, by reducing hepatic insulin clearance, increasing gluconeogenesis and increasing dyslipidaemia [7, 24]. In addition, because of increased NEFA levels, NEFA also accumulate in non-adipose tissue (i.e. ectopic fat storage) such as muscle, the pancreas and the liver, which contributes to and exacerbates insulin resistance and type-2 diabetes [13–18]. We found that abdominal subcutaneous fat was also related to unfavourable glucose and lipid levels, even after adjustment for visceral fat area. This may indicate that also abdominal subcutaneous fat contributes to higher NEFA levels.
In contrast with abdominal subcutaneous fat, subcutaneous thigh fat was independently related to more favourable levels of glucose and lipid levels, which confirmed our hypothesis of low subcutaneous fat as a risk factor. It has been proposed that subcutaneous thigh fat acts as a “metabolic sink” for circulating NEFA . Because of differences in lipolytic activity between abdominal subcutaneous fat and subcutaneous thigh fat [10, 11], subcutaneous thigh fat is more likely to take up NEFA from the circulation, and therefore protects other organs against high NEFA exposure. In this manner, ectopic fat storage is prevented which leads to a lower risk of insulin resistance [12, 13].
Fat cells are known to secrete many signalling factors, some of which may be involved in the development of insulin resistance . Examples include leptin, adiponectin, interleukin-6, tumour necrosis factor-alpha, plasminogen activator inhibitor-1, and many more. There are known regional differences in the secretion of leptin, adiponectin and interleukin-6 between visceral and abdominal subcutaneous fat [26–28]. It might be possible that there are also regional differences in secretion of these adipokines between abdominal subcutaneous and subcutaneous thigh fat, which could contribute to the different associations of these fat depots with glucose and lipid levels. More research in this area is clearly needed.
The independent relationship between larger leg fat mass measured by DXA and more favourable glucose and lipid level variables has been found in a number of studies, in both middle-aged and elderly subjects [1, 8, 9]. When we used the DXA measurements from the Health ABC Study, we observed similar associations (unpublished results). The limitation of DXA is that it cannot distinguish between visceral and abdominal subcutaneous fat in the trunk, and between intermuscular and subcutaneous fat in the legs. By use of CT, we found that the protective association of DXA leg fat with glucose and lipid levels was because of the subcutaneous thigh fat, and not intermuscular thigh fat. Previously, in a small group of obese men (aged 29–42 years), femoral adipose tissue by CT was also found to be negatively associated with triglycerides and positively with HDL-cholesterol , and similar results were found in women . Also, in a small sample of black women leg fat seemed to be independently related to better lipid levels . In the current work we confirmed these observations using CT measurements in a large elderly population, including both black and white people, and extended the observations by including glucose levels as outcome measures.
Previously, we found larger leg lean mass by DXA (which is mainly muscle mass) to be related to lower glucose levels, independent of trunk fat and leg fat mass , which could also be confirmed in the Health ABC Study when we used DXA measurements (unpublished results). However, we did not observe any relationship with thigh muscle area if using CT data, after adjustment for abdominal and thigh fat depots. CT and DXA generally agree in measuring muscle and fat mass, if similar regions are compared [32, 33]. However, it is possible that the thigh muscle area from a single-slice CT scan is not representative of the muscle mass of the total leg as is measured by DXA. Similarly, this could also be the reason for not finding a relationship with intermuscular fat. More detailed measurements of total muscle might be needed to appropriately assess the relationship with the metabolic profile.
There was a difference between black and white participants in body composition in our study, which is also known from previous studies [34–36]. Black persons have generally less visceral fat compared with white persons, whereas the subcutaneous fat (either abdominal or at the thigh) is higher, for any level of total body fat. Black people had a better lipid profile in our data, which has also been found previously [36, 37]. It has been shown that in both sexes black persons have higher LPL activity and lower HL activity compared with white persons , which may explain these differences in lipid profile and fat distribution. It has been suggested that because of these differences between enzyme activity, black persons are more likely to store their lipids in subcutaneous fat depots, which in turn will lead to a better lipid profile. However, we did not find a statistically significant difference between races in the relationship between different fat depots and glucose and lipid levels. The difference between black and white people in glucose and lipid levels might be explained by the relative amounts of different fat depots, rather than by the relationship between these fat depots and glucose and lipid levels per se.
WHR is generally used as measure of abdominal fat distribution, presumably reflecting visceral fat [38, 39]. A higher WHR, however, can also be caused by a smaller hip circumference. By use of DXA measurements it has recently been shown that the hip circumference not only represents fat accumulation in the legs, but is also related to the lean mass in the legs . In the same study the waist circumference mainly reflected fat mass in the trunk. It remained unclear whether this was mainly caused by the visceral or subcutaneous fat depot. In the present paper we show that abdominal subcutaneous fat depot mainly determines the waist circumference, particularly in persons with a higher BMI. Clearly, the WHR does not simply represent visceral fat accumulation only. It has been suggested that increased abdominal fat accumulation may be less hazardous in older than in younger persons, because anthropometric measures of abdominal obesity were not related to (cardiovascular) mortality in the elderly, and it has been shown that lipolysis in visceral fat, which causes free fatty acid flux, is reduced with ageing . Our study shows, however, that if more precise measures of body composition are taken, visceral fat is still hazardous in older adults.
In conclusion, high visceral fat and high abdominal subcutaneous fat are both independently associated with unfavourable glucose and lipid levels. In contrast, high subcutaneous thigh fat is independently associated with more favourable glucose (in men) and particularly lipid levels (in both sexes), if the abdominal fat depots are taken into account. These results underline the importance of accurate measures of regional body composition in health-risk research. Further research is needed to elucidate underlying pathophysiological mechanisms. Waist circumference reflects different fat depots at different levels of BMI, and thigh circumference reflects both fat and muscle tissue. Caution is needed when interpreting anthropometric measurements.