Depot-Specific Differences and Insufficient Subcutaneous Adipose Tissue Angiogenesis in Human Obesity

Abstract

Background Adipose tissue expands in response to excess caloric intake, but individuals prone to deposit visceral (VIS) instead of subcutaneous (SQ) adipose tissue have higher risk of metabolic disease. The role of angiogenesis in the expandability of human adipose tissue depots is unknown. The objective of this study was to measure angiogenesis in VIS and SQ adipose tissue, and to establish whether there is a relationship between obesity, metabolic status and the angiogenic properties of these depots. Methods and results Angiogenic capacity was determined by quantifying capillary branch formation from human adipose tissue explants embedded in Matrigel, and capillary density was assessed by immunohistochemistry. SQ adipose tissue had a greater angiogenic capacity compared to VIS, even after normalization to its higher initial capillary density. Gene array analyses revealed significant differences in expression of angiogenic genes between depots, including an increased SQ expression of ANGPTL4, which is pro-angiogenic in an adipose tissue context. SQ capillary density and angiogenic capacity decreased with morbid obesity, and SQ, but not VIS, adipose tissue angiogenic capacity negatively correlated with insulin sensitivity. Conclusions These data imply that SQ adipose tissue has a higher capacity to expand its capillary network compared to VIS, but this capacity decreases with morbid obesity. The decrease correlates with insulin resistance, suggesting that impairment of SQ adipose tissue angiogenesis may contribute to metabolic disease pathogenesis.

Dietary obesity-associated Hif1α activation in adipocytes restricts fatty acid oxidation and energy expenditure via suppression of the Sirt2-NAD+ system

“…This is remarkable, considering that subcutaneous adipocytes are associated with greater lineage plasticity than visceral adipocytes (Cinti 2009). On the other hand, the observed Hif1a depot specificity may relate to the fact that visceral adipocytes are subjected to a greater degree of hypoxia and adipose tissue hypoperfusion than subcutaneous WAT (Gealekman et al 2011), thus possibly hypersensitizing visceral WAT to tissue and adipocyte hypertrophy-induced hypoxia. Based on our data, it is possible that Hif1a inactivation promotes a brown adipocyte-like phenotype in visceral adipocytes through its capacity to induce mitochondrial biogenesis and function.…”

Adipose morphology and metabolic disease

“…Thus, after exposure to a high-fat diet, SAT appears to undergo hypertrophic growth preferentially, leading to larger adipocytes relative to those in VAT. The contrasting growth dynamics of VAT and SAT are of biomedical importance because the reduced expandability of SAT is associated with insulin resistance (Gealekman et al, 2011;Virtue and Vidal-Puig, 2008). In line with these observations, the treatment of obese diabetics with thiazolidinidiones (TZDs) leads to greater weight gain, preferential lipid deposition in SAT and improved insulin sensitivity (Fonseca, 2003;Nichols and Gomez-Caminero, 2007).…”

AMPK, insulin resistance, and the metabolic syndrome

“…Also requiring study is why some obese people remain insulin sensitive, whereas the majority of them are insulin resistant. In addition to the possibilities already discussed, such factors as alterations in capillary density and permeability (136,137), differences in collagen VI deposition (53,138,139), the release of LPS from bacteria by the gut microbiome (140)(141)(142), alterations of lipid droplet proteins such as FSP27 (CIDEC) that regulate the rates of lipid deposition and lipolysis in adipose tissue (19,143), and events that cause an imbalance between nutrient load and mitochondrial function (144), need to be considered. With respect to the microbiome, AMPK activity is significantly increased in tissues of germfree mice (145) and in mice treated with antibiotics (146), suggesting that AMPK suppression by factors released by bacteria of the gastrointestinal tract or other sites may be a normal occurrence.…”