1. Maintenance of thermogenic adipose tissues despite loss of the H3K27 acetyltransferases p300 or CBP.
- Author
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Gamu D, Cameron MS, and Gibson WT
- Subjects
- Animals, Mice, Uncoupling Protein 1 metabolism, Uncoupling Protein 1 genetics, Male, Diet, High-Fat, E1A-Associated p300 Protein metabolism, E1A-Associated p300 Protein genetics, CREB-Binding Protein metabolism, CREB-Binding Protein genetics, Mice, Inbred C57BL, Adrenergic beta-3 Receptor Agonists pharmacology, Mice, Knockout, Adipose Tissue, White metabolism, Adipose Tissue, Beige metabolism, p300-CBP Transcription Factors metabolism, p300-CBP Transcription Factors genetics, Gene Knockdown Techniques, Dioxoles, Thermogenesis genetics, Adipose Tissue, Brown metabolism, Obesity metabolism, Obesity genetics
- Abstract
Brown and beige adipose tissues are specialized for thermogenesis and are important for energy balance in mice. Mounting evidence suggests that chromatin-modifying enzymes are integral for the development, maintenance, and functioning of thermogenic adipocytes. p300 and cAMP-response element binding protein (CREB)-binding protein (CBP) are histone acetyltransferases (HATs) responsible for writing the transcriptionally activating mark H3K27ac. Despite their homology, p300 and CBP do have unique tissue- and context-dependent roles, which have yet to be examined in brown and beige adipocytes specifically. We assessed the requirement of p300 or CBP in thermogenic fat using uncoupling protein 1 ( Ucp1 ) - Cre-mediated knockdown in mice to determine whether their loss impacted tissue development, susceptibility to diet-induced obesity, and response to pharmacological induction via β
3 -agonism. Despite successful knockdown, brown adipose tissue mass and expression of thermogenic markers were unaffected by loss of either HAT. As such, knockout mice developed a comparable degree of diet-induced obesity and glucose intolerance to that of floxed controls. Furthermore, "browning" of white adipose tissue by the β3 -adrenergic agonist CL-316,243 remained largely intact in knockout mice. Although p300 and CBP have nonoverlapping roles in other tissues, our results indicate that they are individually dispensable within thermogenic fats specifically, possibly due to functional compensation by one another. NEW & NOTEWORTHY The role of transcriptionally activating H3K27ac epigenetic mark has yet to be examined in mouse thermogenic fats specifically, which we achieved here via Ucp1 -Cre-driven knockdown of the histone acetyltransferases (HAT) p300 or CBP under several metabolic contexts. Despite successful knockdown of either HAT, brown adipose tissue was maintained at room temperature. As such, knockout mice were indistinguishable to controls when fed an obesogenic diet or when given a β3 -adrenergic receptor agonist to induce browning of white fat. Unlike other tissues, thermogenic fats are resilient to p300 or CBP ablation, likely due to sufficient functional overlap between them.- Published
- 2024
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