Vascular rarefaction mediates whitening of brown fat in obesity
Ippei Shimizu, … , Sonomi Maruyama, Kenneth Walsh
Ippei Shimizu, … , Sonomi Maruyama, Kenneth Walsh
Published April 8, 2014
Citation Information: J Clin Invest. 2014;124(5):2099-2112. https://doi.org/10.1172/JCI71643.
View: Text | PDF
Research Article Endocrinology

Vascular rarefaction mediates whitening of brown fat in obesity

Abstract

Brown adipose tissue (BAT) is a highly vascularized organ with abundant mitochondria that produce heat through uncoupled respiration. Obesity is associated with a reduction of BAT function; however, it is unknown how obesity promotes dysfunctional BAT. Here, using a murine model of diet-induced obesity, we determined that obesity causes capillary rarefaction and functional hypoxia in BAT, leading to a BAT “whitening” phenotype that is characterized by mitochondrial dysfunction, lipid droplet accumulation, and decreased expression of Vegfa. Targeted deletion of Vegfa in adipose tissue of nonobese mice resulted in BAT whitening, supporting a role for decreased vascularity in obesity-associated BAT. Conversely, introduction of VEGF-A specifically into BAT of obese mice restored vascularity, ameliorated brown adipocyte dysfunction, and improved insulin sensitivity. The capillary rarefaction in BAT that was brought about by obesity or Vegfa ablation diminished β-adrenergic signaling, increased mitochondrial ROS production, and promoted mitophagy. These data indicate that overnutrition leads to the development of a hypoxic state in BAT, causing it to whiten through mitochondrial dysfunction and loss. Furthermore, these results link obesity-associated BAT whitening to impaired systemic glucose metabolism.

Authors

Ippei Shimizu, Tamar Aprahamian, Ryosuke Kikuchi, Ayako Shimizu, Kyriakos N. Papanicolaou, Susan MacLauchlan, Sonomi Maruyama, Kenneth Walsh

×

Figure 3

BAT-specific Vegfa delivery induces the rebrowning of the whitened BAT in dietary obesity.

Options: View larger image (or click on image) Download as PowerPoint
BAT-specific Vegfa delivery induces the rebrowning of the whitened BAT i...
(A and B) Real-time PCR analysis of Vegfa and Kdr expression in BAT (A) and WAT (B) of mice after injection of ad-vegfa or control vector into BAT of mice fed NC or HFHS diets. ad-lacZ was used as a control (Con) (n = 5–8). (C) Immunofluorescent staining with Fluorescein Griffonia (Bandeiraea) Simplicifolia Lectin I (green) to detect vasculature and with Bodipy-TR (red) to detect lipid in BAT from NC- or HFHS-fed mice after the injection of ad-vegfa of the control adenoviral vector. Scale bar: 100 μm. (D) H&E staining of BAT from NC- and HFHS-fed mice prepared in A after the injection of ad-vegfa or a control adenoviral vector. Scale bar: 50 μm. (E) Quantitative analysis of the number of large lipid droplets/field in BAT under the different experimental conditions (×400, n = 4). (F) Real-time PCR analysis of the expression of ND5, Ucp1, Ndufa, and Ppargc1a in BAT of mice described in A (n = 3–10). (G) Acute CTT of the different experimental groups of mice (n = 3–7). (H) Glucose uptake by BAT was evaluated by measuring 2DG uptake (n = 4–6). (I) GTT and ITT in the different experimental groups of mice receiving ad-vegfa or control adenovirus (n = 4–8). Data were analyzed by ANOVA (A, B, and E–I). *P < 0.05; **P < 0.01. All values represent the mean ± SEM.