Directing visceral white adipocyte precursors to a thermogenic adipocyte fate improves insulin sensitivity in obese mice.

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 <i>Zfp423</i>, a transcriptional suppressor of the adipocyte thermogenic program. <i>Zfp423</i> deletion in fetal visceral adipose precursors (<i>Zfp423^l</i>^oxP/loxP; <i>Wt1-Cre</i>), or adult visceral white adipose precursors (<i>Pdgfrb</i>^rtTA; <i>TRE-Cre; Zfp423^l</i>^oxP/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.