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.

Short-term Cold Acclimation Recruits Brown Adipose Tissue in Obese Humans

“…Although these observations need to be confirmed in larger groups of subjects, this may indicate that the capacity to recruit BAT at a young age is not hampered by obesity per se. This is also consistent with data from rodent studies showing BAT "whitening" upon intake of a high-fat diet (28) and evidence that such whitened adipocytes can again be interconverted into brown/beige adipocytes with a high thermogenic capacity upon cold stimulation (29).…”

Selective Impairment of Glucose but Not Fatty Acid or Oxidative Metabolism in Brown Adipose Tissue of Subjects With Type 2 Diabetes

“…This is explained, at least in part, by capillary rarefaction in WAT (31). A similar obesityinduced capillary rarefaction in BAT, leading to the development of a WAT-like phenotype with the BAT shifting functions toward lipid storage rather than thermogenesis, was observed in high fat-fed mice (32). The lower radiodensity of the BAT in the overweight age-matched control subjects and in the participants with type 2 diabetes could suggest a similar shift toward lipid storage or a lipolytic dysfunction.…”

“…Blunted lipolytic action of catecholamines in WAT is an early event in obesity in humans (40) and in BAT of obese Zucker rats (41) due to a reduction in b-adrenergic receptor density. Reduced b-adrenergic receptor density was also demonstrated in BAT of high fat-, high sucrose-fed mice (32). This may have an effect on total volume of BAT recruited but not necessarily on oxidative capacity of activated BAT regions.…”

Pathological Role of Adipose Tissue Dysfunction in Cardio-Metabolic Disorders

“…Over-nutrition was recently shown to promote hypoxia in BAT, causing it to "whiten" through dysfunction and loss of mitochondria, thus contributing to impairment of systemic glucose metabolism. 29) Suppression of the dysfunction of WAT and maintenance of BAT homeostasis may be new therapeutic targets for preventing diseases associated with age-related systemic metabolic dysfunction such as obesity, diabetes, and heart failure. In this review, we delineate the link between adipose tissue abnormalities and systemic metabolic dysfunction in patients with cardio-metabolic diseases.…”