The main findings of this manuscript are: 1) CAV-1 gene expression was significantly decreased in visceral adipose tissue of obese subjects (Figure 1); in fact, this is the first large study evaluating the expression of CAV-1 in adipose tissue. CAV-1 gene expression has been previously reported in a sample of 15 subjects . 2) CAV-1 gene expression in whole adipose tissue was significantly associated with the expression of lipogenic genes and fasting triglycerides; 3) CAV-1 gene expression was significantly increased in mature adipocytes compared with SVC fraction from both visceral and subcutaneous adipose tissue (Figure 3A and 3B); 4) the expression of CAV-1 was significantly decreased in mature adipocytes from the visceral fat compartment; and 5) CAV-1 gene expression did not change significantly during differentiation of human preadipocytes from lean or obese subjects.
The type of fat depot (subcutaneous vs. visceral) and obesity status significantly influenced these associations. In non-obese subjects, with a wide range of CAV-1 in visceral adipose tissue (v-CAV-1), significant and positive associations of v-CAV-1 with the main lipogenic genes were observed. Decreased expression of v-CAV-1 of obese subjects, with a relatively low range of v-CAV-1, could have led to the absence of relationship with lipogenic genes in this obese group. CAV-1 gene expression is known to be controlled by sterol-regulatory-element-binding protein (SREBP) , one of the main transcriptional factors involved in lipogenesis, so these findings should be interpreted in this context.
Fasting triglycerides were not linked to v-CAV-1 in obese and non-obese subjects. sc-CAV-1, however, was associated with lipogenic genes (FAS, ACACA, SREBP-1c, PGC-1 and Spot-14 ) and fasting triglycerides only in obese subjects. Those obese subjects with decreased sc-CAV-1 had the highest fasting triglyceride concentrations, paralleling, to some extent, the observations of hypertriglyceridemia in CAV-1 knockout mice . The question remains why only decreased sc-CAV-1 and not decreased v-CAV-1 was linked to increased triglycerides. In fact, we found that CAV-1 gene expression in adipocytes was significantly higher than in SVF in both subcutaneous and visceral fat depots. Even though, when we compared adipocyte fractions, only CAV-1 expression in subcutaneous adipose tissue was negatively associated with fasting triglycerides. In this sense, the protective "metabolic" role of subcutaneous adipose tissue is increasingly recognized . CAV-1 expression in subcutaneous adipose tissue could be the reflection of a protective role of CAV-1 in the metabolism of triglycerides.
CAV-1 gene expression did not change significantly during differentiation of human pre-adipocytes despite a significant increase of FAS gene expression, a marker of adipocyte differentiation. This is in contrast to what has been observed in 3T3-L1 cells, in which CAV-1 gene expression increases during differentiation [15–17]. This finding suggests that CAV-1 is not under the control of adipogenic factors in human adipocytes but influenced by other components located in the microenvironment of the adipose tissue. For instance, CAV-1 gene expression has been detected in macrophages under the influence of lipopolysaccharide [18, 19], a bacterial product known to be increased in human obesity [20, 21]. However, we cannot exclude that human pre-adipocytes have already entered into senescence. In fact, increased caveolin-1 has been described as a cause for the declined adipogenic potential of senescent human mesenchymal stem cells.
On the other hand, the inverse association between CAV-1 gene expression and fasting glucose, glycated hemoglobin and fasting triglycerides in SVC from visceral fat could reflect the differential metabolic activity of the visceral fat depot.
Decreased expression of v-CAV-1 is in contrast with previous findings in women, in whom both v-CAV-1 and sc-CAV-1 were increased among obese women . However, this latter study was performed in young women. Estrogen receptors have been reported to associate with and regulate the production of CAV-1 [23, 24]. It is thus possible that the confounding effects of estrogens in pre-menopausal women could have played a role in these discrepant results.
A remarkable reduction in the expression of the genes controlling lipogenic enzymes, namely SREBP-1c, and genes coding lipogenic enzymes (FAS, phosphoenol pyruvate carboxykinase (PEPCK), ATP citrate-lyase, pyruvate carboxylase) [25–27] has been demonstrated in obesity, a situation in which hypertriglyceridemia is frequently present despite that triglyceride synthesis and lipogenic genes are positively correlated. In CAV-1 null mice the impaired triglyceride clearance took place in the setting of normal total and hepatic lipoprotein lipase activity, and reduced hepatic very low-density lipoprotein (VLDL) secretion.