Inhibitor of Differentiation-3 Mediates High Fat Diet-Induced Visceral Fat Expansion

Abstract

Objective Inhibitor of differentiation-3 (Id3) has been implicated in promoting angiogenesis, a key determinant of high fat diet (HFD)-induced visceral adiposity. Yet the role of Id3 in high fat diet (HFD)-induced angiogenesis and visceral adipose expansion is unknown. Methods and Results Id3−/− mice demonstrated a significant attenuation of HFD-induced visceral fat depot expansion compared to WT littermate controls. Importantly, unlike other Id proteins, loss of Id3 did not affect adipose depot size in young mice fed chow diet or differentiation of adipocytes in vitro or in vivo. Contrast enhanced ultrasound revealed a significant attenuation of visceral fat microvascular blood volume in HFD-fed mice null for Id3 compared to WT controls. HFD induced Id3 and VEGFA expression in the visceral stromal vascular fraction (SVF) and Id3−/− mice had significantly lower levels of VEGFA protein in visceral adipose tissue compared to WT. Furthermore, HFD-induced VEGFA expression in visceral adipose tissue was completely abolished by loss of Id3. Consistent with this effect, Id3 abolished E12-mediated repression of VEGFA promoter activity. Conclusions Results identify Id3 as an important regulator of HFD-induced visceral adipose VEGFA expression, microvascular blood volume, and depot expansion. Inhibition of Id3 may have potential as a therapeutic strategy to limit visceral adiposity.

Id transcriptional regulators in adipogenesis and adipose tissue metabolism

“…Further studies in Id3 −/− mice also did not reveal any significant changes in the metabolic phenotypes when they were fed a regular diet compared to wild-type mice. Nevertheless, when the mice were fed a HFD, expansion of visceral adipose depots was significantly reduced in Id3 −/− mice, whereas, such a reduction was not observed in other WAT locations (54). Accordingly, Id3 expression was more abundant in visceral compared to subcutaneous WAT, and Id3 expression was elevated in response to HFD only in visceral but not in subcutaneous adipose tissues of wild-type mice.…”

“…However, a recent study demonstrated that overexpression of Id3 did not result in any detectable changes in the expression of GLUT4, another marker of adipocyte differentiation. They also did not detect any significant differences in Oil-Red-O lipid staining between control and Id3-overexpressing cells or between wild-type and Id3 −/− MEFs that were induced to differentiate into adipocytes, suggesting that either overexpression or lack of Id3 did not alter the adipocyte differentiation program (54). Timing of analysis and the choice of adipocyte markers might have partially contributed to these conflicting observations in these two studies.…”

“…Accordingly, Id3 expression was more abundant in visceral compared to subcutaneous WAT, and Id3 expression was elevated in response to HFD only in visceral but not in subcutaneous adipose tissues of wild-type mice. Due to impaired visceral WAT expansion, Id3 −/− mice were protected from HFD-induced obesity (54). However, no detectable differences were observed in the expression pattern of adipocyte differentiation markers such as aP2 or C/EBPα in visceral adipocytes, indicating that reasons other than defects in adipocyte differentiation are primarily responsible for the observed reduction in visceral adiposity in Id3 −/− mice.…”

Up-regulation of the Sirtuin 1 (Sirt1) and Peroxisome Proliferator-activated Receptor γ Coactivator-1α (PGC-1α) Genes in White Adipose Tissue of Id1 Protein-deficient Mice

“…Id3, on the other hand, has been shown to inhibit the transcription of the adiponectin gene, which encodes an adipocyte specific hormone whose levels are inversely correlated with obesity and insulin resistance and has protective effects against metabolic disorders (26). Id3 also promotes adipose tissue growth by facilitating angiogenesis through VEGF factor A expression (27). Id1 Ϫ/Ϫ mice have also been shown to have decreased body weight and fat mass (22).…”

Targeting Angiogenesis as Treatment for Obesity

“…1 The authors first demonstrate that the inhibitor of differentiation-3 (Id3) is expressed in adipose tissue and induced during obesity. Fractionation and immunohistochemistry of the adipose tissue revealed that high-fat diet feeding and the ensuing development of obesity results in increased Id3 expression in endothelial cells.…”