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.
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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

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Figure 1

The whitening of BAT associated with capillary rarefaction in diet-induced obesity.

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The whitening of BAT associated with capillary rarefaction in diet-induc...
(A) H&E staining of BAT from mice fed NC or HFHS diet. Scale bar: 50 μm. Right graph shows the number of large lipid droplets/field in BAT (×400, n = 4). (B) Electron micrographs of BAT from mice fed NC or HFHS diet. Right graph shows the number of mitochondria/cell (n = 3). Scale bar: 10 μm. (C and D) Real-time PCR expression of the mitochondrial-encoded transcript ND5 and the nucleus-encoded transcripts Ucp1, Ndufa, Atp5a, and Ppargc1a in BAT from mice fed NC or HFHS diet (n = 3–6). (E) Acute CTT for mice fed NC or HFHS (n = 5–7). (F) Immunofluorescent staining to detect blood vessels with Fluorescein Griffonia (Bandeiraea) Simplicifolia Lectin I (green) and adipocytes with Bodipy-TR (red) in BAT and WAT from mice fed NC or HFHS diet. Scale bars: 100 μm. (G and H) Pimonidazole staining (G) and positive area (H) in BAT and WAT of mice fed NC or HFHS diet determined by hypoxyprobe-1 staining (n = 4–6). Scale bars: 50 μm. (I) Oxygen levels in adipose tissues (AT pO2 [mmHg]) (n = 5–6). (J) Real-time PCR expression of Vegfa and Kdr in BAT and WAT of mice fed NC or HFHS diet (n = 4–10). Data were analyzed by 2-tailed Student’s t test (A–D and H) or ANOVA (E, I, and J). *P < 0.05; **P < 0.01. All values represent the mean ± SEM.