Warming Induces Significant Reprogramming of Beige, but Not Brown, Adipocyte Cellular Identity

Abstract

Beige and brown adipocytes generate heat in response to reductions in ambient temperature. When warmed, both beige and brown adipocytes exhibit morphological "whitening," but it is unknown whether or to what extent this represents a true shift in cellular identity. Using cell-type-specific profiling in vivo, we uncover a unique paradigm of temperature-dependent epigenomic plasticity of beige, but not brown, adipocytes, with conversion from a brown to a white chromatin state. Despite this profound shift in cellular identity, warm whitened beige adipocytes retain an epigenomic memory of prior cold exposure defined by an array of poised enhancers that prime thermogenic genes for rapid response during a second bout of cold exposure. We further show that a transcriptional cascade involving glucocorticoid receptor and Zfp423 can drive warm-induced whitening of beige adipocytes. These studies identify the epigenomic and transcriptional bases of an extraordinary example of cellular plasticity in response to environmental signals.

Epigenetics and Epigenomics: Implications for Diabetes and Obesity

“…Their studies demonstrate highly dynamic regulation of liver chromatin state and architecture during fasting/feeding transitions and in response to circadian rhythm. The Rosen laboratory examined chromatin state in brown, beige, and white adipocytes in response to cold and heat exposure and observed that beige adipocytes have unique plasticity not shared by interscapular brown adipocytes (30). Further, beige cells that have been "whitened" after warming retain certain epigenetic features of the cold state.…”

A new mouse model for noninvasive fluorescence‐based monitoring of mitochondrial UCP1 expression

“…It has been already reported that rewarming after cold exposure reduces UCP1 expression levels in BAT [42].…”

Brown adipocytes from induced pluripotent stem cells—how far have we come?

“…Interscapular BAT, like skeletal muscle, derives from paraxial mesoderm precursors positive for Myf5 , Pax7 , and Pax3 (reviewed in Refs. and ). The closely related origin of BAT and skeletal muscle is also reflected in the expression of genes, such as PRDM16, that can be manipulated genetically to functionally toggle the cell‐fate between muscle cells and brown adipocytes .…”

“…Functionally, one difference between brown and beige adipocytes is that beige adipocytes switch between brown‐ and white‐like states and lose UCP1 expression upon withdrawal of either cold or β‐adrenergic receptor stimuli . This appears to be due to several factors, including glucocorticoid receptor stimulation of Zfp423 expression, a known antibeige adipocyte transcription factor, as well as an autophagy‐mediated clearance pathway for mitochondria in beige cells that may be more limited in brown adipocytes . Furthermore, in mice, there exists heterogeneity in the function within the beige adipocyte lineage.…”

“…56 This appears to be due to several factors, including glucocorticoid receptor stimulation of Zfp423 expression, a known antibeige adipocyte transcription factor, as well as an autophagy-mediated clearance pathway for mitochondria in beige cells that may be more limited in brown adipocytes. 56,57 Furthermore, in mice, there exists heterogeneity in the function within the beige adipocyte lineage. A recent study has described a new type of beige adipocyte that is developmentally distinct in origin and function, and it can compensate in the absence of β-adrenergic signaling to provide energy homeostasis through enhanced glucose oxidation during cold adaptation.…”