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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" pheno-type 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.
Introduction
Brown adipose tissue (BAT) is activated by the sympathetic ner- vous system (SNS) to generate heat rather than ATP through uncoupled oxidative phosphorylation (1). BAT is abundant in small rodents and newborn humans and was once thought to dis- appear in human adulthood. Recent studies, however, have shown that human adults also possess active BAT (2-4). In addition to its thermogenic function, it has been suggested that BAT contrib- utes to systemic metabolism because of its high oxidative capac- ity (5-7). Because BAT decreases with obesity and aging (4, 8), the decline in BAT function may be linked to impaired metabolism under these conditions. While it has been shown that increasing BAT mass through transplantation improves metabolism param- eters in a model of diet-induced obesity (9), most studies on BAT are associative and the molecular mechanisms that contribute to obesity-linked BAT dysfunction are largely unknown.
Recently, a number of studies have pointed to the importance of the microvasculature in controlling adipose tissue inflammation and overall metabolic function (10-12). Studies with obese patients and mice have documented that the white adipose tissues (WAT) of these organisms display capillary rarefaction and evidence of hypoxia, which correlate...