AZIN2-dependent polyamine metabolism determines adipocyte progenitor fate and protects against obesity and dysmetabolism

Abstract

Adipose tissue homeostasis plays a critical role in metabolic disease but the metabolic circuitry regulating adipose tissue dynamics remains unclear. In this study, polyamine metabolism emerges as an important regulator of adipose tissue pathophysiology. We identify AZIN2 (Antizyme inhibitor 2), a protein promoting polyamine synthesis and acetylation, as a major regulator of total acetyl-CoA in adipocyte progenitors (APs). AZIN2 deficient APs demonstrate increased H3K27 acetylation marks in genes related to lipid metabolism, cell cycle arrest and cellular senescence, and enhanced adipogenesis compared to wild-type counterparts. Upon high-fat diet (HFD)-induced obesity, global AZIN2 deficiency in mice provokes adipose tissue hypertrophy, AP senescence, lipid storage perturbations, inflammation and insulin resistance. IL4 promotes Azin2 expression in APs but not mature adipocytes due to diminished IL4 receptor expression in the latter. In human visceral and subcutaneous adipose tissue, AZIN2 expression positively correlates with expression of early progenitor markers and genes associated with protection against insulin resistance, while it negatively correlates with markers of lipogenesis. In sum, AZIN2-driven polyamine metabolism preserves adipose tissue health, a finding that could be therapeutically harnessed for the management of obesity-associated metabolic disease.