Introduction and Objective: KAT8 (lysine acetyltransferase 8), also known as MOF or MYST1, acetylates diverse protein substrates to regulate multiple cellular processes. Although KAT8 is expressed in adipocytes and adipose tissue, its function in adipocytes is unknown. We previously generated a mouse model with adiponectin-expressing cell-specific deletion of KAT8 (KAT8AKO) and found that these mice develop lipoatrophy, insulin resistance, and marked remodeling of white and brown adipose tissue. Given the cellular heterogeneity of white adipose tissue, this study aimed to determine the cell-autonomous role of KAT8 in adipocytes.Methods: RNA silencing was performed to knockdown KAT8 in differentiated 3T3-L1 adipocytes. Insulin signaling, glucose uptake, and basal and adrenergic-stimulated lipolysis were assessed.Results: KAT8 knockdown caused a notable shift in the insulin dose curve, reflected by reduced insulin-stimulated AKT phosphorylation at Ser473, while ERK activation was unchanged. Consistent with impaired AKT signaling, insulin-stimulated glucose uptake was significantly impaired following KAT8 depletion. Despite reduced adipocyte number and lipid content observed in KAT8AKO mice in vivo, KAT8 knockdown did not alter basal or adrenergic-stimulated glycerol release in 3T3-L1 adipocytes.Conclusion: These findings demonstrate that adipocyte KAT8 is required for maintaining insulin sensitivity through selective regulation of AKT-dependent signaling pathways, without affecting ERK signaling or lipolysis. These data provide mechanistic insight into the metabolic dysfunction observed in KAT8AKO mice and identify KAT8 as a regulator of adipocyte insulin signaling.
D.A. Mendoza: None. A.J. Richard: None. T. Mendoza: None. J. Stephens: None.
COBRE P&F grant (P30 GM118430), National Institutes of Health (R01DK135266)
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