Abstract
Visceral adiposity confers significant risk for developing metabolic disease in obesity whereas preferential expansion of subcutaneous white adipose tissue (WAT) appears protective. Unlike subcutaneous WAT, visceral WAT is resistant to adopting a protective thermogenic phenotype characterized by the accumulation of Ucp1+ beige/BRITE adipocytes (termed 'browning'). In this study, we investigated the physiological consequences of browning murine visceral WAT by selective genetic ablation of Zfp423, a transcriptional suppressor of the adipocyte thermogenic program. Zfp423 deletion in fetal visceral adipose precursors (Zfp423loxP/loxP; Wt1-Cre), or adult visceral white adipose precursors (PdgfrbrtTA; TRE-Cre; Zfp423loxP/loxP), results in the accumulation of beige-like thermogenic adipocytes within multiple visceral adipose depots. Thermogenic visceral WAT improves cold tolerance and prevents and reverses insulin resistance in obesity. These data indicate that beneficial visceral WAT browning can be engineered by directing visceral white adipocyte precursors to a thermogenic adipocyte fate, and suggest a novel strategy to combat insulin resistance in obesity.
Highlights
Adipocytes are critical regulators of energy balance and nutrient homeostasis
Selective ablation of Zfp423 in fetal visceral white adipocyte precursors leads to the formation of thermogenic visceral adipose depots
We hypothesized that the thermogenic capacity of visceral white adipose depots can be unlocked under physiological conditions through removal of Zfp423, and that engineered visceral thermogenic adipocytes can drive improvements in systemic metabolic health
Summary
White adipocytes serve as the principal site for energy storage in mammals. These cells are characterized by a large unilocular lipid droplet and have the capacity to store or release energy depending on metabolic demand. Eutherian mammals contain a second major class of adipocytes that function to catabolize stored lipids and produce heat. These thermogenic adipocytes, consisting of brown and beige/BRITE adipocytes, are characterized by their multilocular lipid droplet appearance, high mitochondrial content, and expression of uncoupling protein 1 (Ucp1) (Cohen and Spiegelman, 2015; Harms and Seale, 2013). Brown/beige adipocytes have promising therapeutic potential as their activation in the setting of obesity has a profound impact on metabolic health
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