Role of Subcutaneous Adipose Tissue in Metabolic Complications of Obesity

Abstract

B ody fat distribution is known to contribute to determining the overall risk for metabolic complications of obesity. Central/upper body fat distribution has been associated with increased insulin resistance,¹ a common denominator for the clustering of abnormalities defining the metabolic syndrome and heighted risk for both type 2 diabetes and cardiovascular disease. On the other hand, peripheral/lower body distribution of fat has been associated with reduced risk of metabolic complications of obesity.^2,3

Given these associative data, much work has been done to identify potential mechanisms involved. Heterogeneity in physiologic characteristics of different adipose tissue depots has suggested that adipose tissue from the intraperitoneal area, or visceral adipose tissue, could be the major culprit in the pathogenesis of hepatic steatosis, dyslipidemia, and systemic insulin resistance to glucose disposal in central obesity, whereas subcutaneous adipose tissue has been thought to play a protective role. Unfortunately, the infrequent distinction between subcutaneous abdominal and subcutaneous peripheral adipose tissue and, most importantly, the methodological limitations in measurement of various adipose tissue areas have been a major obstacle to significant progress in better understanding the role of specific adipose tissue depots in the pathogenesis of metabolic complications of central obesity. As a result, current clinical guidelines are still using waist circumference, an approximate indicator of upper body fat content, as a factor to identify the metabolic syndrome and increased risk for cardiovascular disease. It should be kept in mind that increased waist circumference does not always indicate increased visceral adiposity and instead can also indicate increased subcutaneous abdominal adiposity.⁴ This distinction is often overlooked in clinical studies and contributes to misinterpretation of results.

Computed tomography (CT) scan measurements of one or a few levels of the abdomen have been used to assess areas of fat content in the visceral and subcutaneous abdominal adipose tissue. Although this method has been validated in measures of areas of fat, its precision in measuring volumes of adipose tissue in the whole compartment (visceral or subcutaneous) remains unclear. Given the wide volume distribution of subcutaneous fat as compared to visceral fat, the possibility that variability in subcutaneous abdominal adipose tissue volume and mass are underestimated in these studies is a major source of potential errors in data interpretation. Even less evidence is available regarding the validity of dual-energy X-ray absorptiometry (DEXA) scanning in quantifying visceral and subcutaneous abdominal adipose tissue. Here it is important to note that when we used a validated magnetic resonance imaging (MRI) method to measure the mass of adipose tissue in visceral and subcutaneous adipose compartments, we were able to identify an association between subcutaneous abdominal adipose tissue and systemic insulin for any level of total body fat content.⁴ Our findings have been replicated by other investigators,⁵ and growing literature is providing a mechanistic link between subcutaneous abdominal adipose tissue and systemic insulin resistance. For example, Jensen et al.⁶ demonstrated that subcutaneous adipose tissue has a much larger impact on fatty acid metabolism than visceral adipose tissue. Because fatty acid circulating in plasma plays a major role both in hepatic steatosis and systemic insulin resistance to glucose disposal, these studies support a mechanistic role of subcutaneous adipose tissue in the pathogenesis of the metabolic syndrome and its complications.

Inflammation in adipose tissue has also been identified as possible mechanistic mediator of systemic insulin resistance. Recent work in various ethnic groups has clearly shown that subcutaneous abdominal adipose tissue has increased inflammation, as indicated by macrophage infiltration and formation of “crown-like” structures that correlate with increased insulin resistance,⁷ increased markers of low-grade systemic inflammation, and presence of the metabolic syndrome.⁸ Increasing fat accumulation in subcutaneous adipose tissue could determine increased adipocyte size and risk for local inflammatory mechanism activation. Following these results, it seems reasonable to conclude that increased fat deposition in subcutaneous abdominal areas plays a detrimental role in metabolic health. On the other hand, subcutaneous abdominal fat content has also been inversely related to insulin resistance.⁹ Although some of these studies were conducted with adequate methodology, they often lack concomitant functional measures of adipose tissue and are limited to overweight or moderately obese subjects. Recently, decreased adipogenic potential of subcutaneous adipose tissue has been shown to be associated with the metabolic syndrome.¹⁰ This condition is also associated with increased adipocyte size. Therefore, it is possible that the presence of large adipocytes is an indicator of decreased adipogenic potential in subcutaneous adipose tissue and, at the same time, a trigger for increased macrophage infiltration and inflammatory process activation. This view is supported by our studies in Asian Indians who have migrated to the United States, and compared to non-Hispanic white Americans have excessive systemic insulin resistance relative to their degree of obesity; they were shown to have increased adipocyte size in the subcutaneous abdominal adipose tissue¹¹ as well as increased low-grade systemic inflammation.¹²

Recent work on adipose tissue angiogenesis has also provided important insights into potential mechanisms of heterogeneity in the systemic metabolic impact of specific adipose tissue compartments. In these studies, angiogenic capacity of subcutaneous adipose tissue was shown to decrease with increasing body mass index (BMI), whereas it did not change in visceral adipose tissue.¹³ Because decreased angiogenic capacity of subcutaneous adipose tissue is correlated with insulin resistance, these data can be interpreted as an indication of a role of subcutaneous adipose tissue angiogenic deficiency in the pathogenesis of metabolic complications of obesity.

Whether angiogenic capacity is mechanistically linked to decreased adipogenic potential of subcutaneous abdominal adipose tissue remains to be established. However, it is worth considering an emerging global mechanistic view: Increasing fat accumulation in subcutaneous adipose tissue in the presence of caloric excess may proceed until a “tipping” point is reached. This tipping point is reached when increasing adipocyte size and decreasing angiogenesis sets the right environment for local inflammation, exhaustion of adipocyte differentiation potential, and preferential deposition of excessive calories in alternative adipose tissue areas, such as the visceral adipose tissue and liver. At this point, variability in visceral fat mass and hepatic steatosis will become the best correlates of insulin resistance. This is more likely to occur within a cohort of overweight and obese subjects than in a cohort with larger range of adiposity. We also envision the possibility that based on the genetic/environmental milieu this hypothetical tipping point is reached at different levels of body fat excess and may not even be reached at all. This condition would identify obesity with excessive subcutaneous fat mass relative to visceral and lack of increase in insulin resistance. In this case, increased fat accumulation in subcutaneous adipose tissue will be seen as having a protective effect regarding insulin resistance. Therefore, differences in study subjects can explain much of the apparent discrepancy in the literature regarding fat distribution and insulin resistance or metabolic syndrome.

Taken together, the data thus far available seem to point to a potential mechanistic role of both visceral and subcutaneous abdominal adipose tissue in the pathogenesis of insulin resistance and metabolic syndrome. Future progress in the field can be only made if the existing focus of visceral adiposity as the determinant of metabolic complications of obesity is replaced by a more integrated view of functional heterogeneity in adipose tissue depots, which as a whole contribute to regulating systemic lipid and glucose metabolism, thus globally influencing the risk for metabolic complications of an unhealthy lifestyle at any level of general adiposity. Future studies on integrated adipose tissue function will better elucidate the mechanisms involved in the pathogenesis of insulin resistance and its metabolic complications both in obese and in nonobese people.

Author Disclosure Statement

No competing financial interests exist.

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