One of the most remarkable features of adipose tissue is its capacity to expand in a non-neoplastic manner. Impaired adipose tissue expandability, such as that occurring in lipodystophy, leads to ectopic accumulation of lipids in liver and muscle, insulin resistance and metabolic disease 31
. Expandability depends on angiogenesis, but the underlying mechanisms of this process in adipose tissue are largely unknown. The method described here allows an accurate and reproducible measurement of new capillary branch formation from human adipose tissue. An advantage of this assay compared to others, such as the chick chorioallantoïc membrane model 32
, is that the human tissue is the sole source of cells and thereby differences observed result exclusively from properties inherent to this tissue.
Two findings were made using this approach. First, we find that SQ adipose tissue has a higher capillary density per adipocyte and higher angiogenic growth capacity compared to VIS. Because a higher angiogenic capacity was seen even after normalization to initial capillary density, these results suggest the existence of qualitative differences in angiogenic expandability between SQ and VIS adipose tissue that are revealed ex-vivo. Consistent with this view is the finding that the expression of multiple genes involved in angiogenesis varies significantly among these tissues. At least one factor previously shown to be pro-angiogenic in an adipose tissue-specific context, ANGPTL4 20
, is expressed at higher levels in human SQ adipose tissue. Further studies of the role of ANGPTL4, as well as of additional pro- and anti- angiogenic genes differentially expressed between SQ and VIS adipose tissue will be necessary to define the molecular basis for their differing angiogenic capacity.
The mechanism that determines SQ and VIS adipose tissue angiogenic capacity may underlie important physiological differences between these depots. One of these differences is that, while expansion of SQ adipose tissue is associated with protection from metabolic disease 18
, expansion of VIS adipose tissue is not. Indeed, the risk of diabetes and coronary artery disease correlates strongly with relative visceral adiposity, rather than with BMI per se 14, 17
. The mechanisms responsible for this risk are not clear; the results shown here suggest that expanding VIS adipose tissue may not be as well vascularized, potentially leading to hypoxia, impaired secretion of adipokines 33
, and inflammation 34
, traits that are associated with VIS adipose tissue and risk of metabolic disease.
The second finding made in this study is that capillary density and angiogenic potential of SQ adipose tissue decrease with increasing BMI. These results are consistent with the recent report of capillary dropout and lower oxygen tension in SQ adipose tissue from obese individuals 35
. Capillary density and angiogenic potential of SQ adipose tissue decrease to a similar extent between overweight (BMI < 36) and obese (BMI > 36) individuals, so decreased angiogenic potential ex-vivo might only reflect initial lower capillary density, rather than a qualitative decline in expandability between these populations. Indeed, the negative correlation between SQ angiogenic capacity and BMI was surprising, because our previous studies in hyperphagic mice demonstrated increased angiogenic capacity with increased adiposity 20
. A difference between these studies, however, is that the human population studied here compares overweight with morbidly obese individuals, whereas the previous study compared lean to overweight mice. Thus, it is possible that angiogenic capacity increases during the transition of lean to overweight, but is unable to continue to increase proportionally to adipocyte size and/or number during the progression to extreme obesity. However, the finding that within morbidly obese individuals the impairment in SQ angiogenic growth ex-vivo does not correlate with decreased capillary density of the originating tissue suggests that qualitative alterations in angiogenic capacity may also accompany extreme obesity. In any case, the data suggest that in morbid obesity SQ angiogenesis is insufficient to achieve a level of vascularization appropriate for the expanded tissue.
The negative correlation between SQ angiogenic capacity and BMI could be due to the metabolic alterations that accompany obesity. Consistent with this view is the finding that SQ angiogenic capacity negatively correlates with the increased insulin resistance seen between overweight and obese individuals (not shown), and within morbidly obese individuals undergoing gastric bypass surgery (). One possibility is that production of pro-angiogenic factors by adipocytes may be compromised by insulin resistance 36
. While adipocyte-derived pro-angiogenic factors such as leptin 37
increase with adipose tissue mass, other adipocyte-secreted factors such as adiponectin decrease in response to increased cell size or stress 38
. Further studies on the molecular mechanisms that drive and limit adipose tissue angiogenesis and their sensitivity to insulin should provide answers to these questions.
A decreased angiogenic capacity in morbid obesity could be a physiologically protective mechanism as a way to limit the increase in adiposity, as expansion of adipose tissue is blocked by anti-angiogenic drugs 39
. Studies to characterize the relationship between adipocyte growth, insulin sensitivity and adipose tissue angiogenesis within the spectrum of lean to obese states in humans will be necessary to answer these questions.