Endocrine Abstracts

JOINT447

AMP-activated protein kinase (AMPK) is a heterotrimeric serine/threonine kinase playing a key role in metabolic regulation. The γ subunit of AMPK is the regulatory subunit responsible for binding and sensing the adenine nucleotides and the most understudied subunit. We found the expression of AMPK γ2 subunit, encoded by Prkag2 gene, is abundantly expressed in the mature adipocytes and its expression was significantly downregulated in obesity while boosted by cold exposure. Adipocyte-selective deletion of Prkag2 exacerbates diet-induced obesity and compromises adipose tissue browning in mice. Notably AMPK γ2 contains a unique nuclear localization signal (NLS). Mutation of the NLS mitigates the nuclear localization of AMPK γ2 along with its biological function in potentiating adipose browning. WT but not mutant AMPK γ2 stimulates the transcription of Neuregulin 4 (Nrg4). Additionally, CUT&Tag analysis reveals a direct binding of AMPK γ2 on Nrg4 gene locus, suggesting AMPK γ2 acts as a transcriptional co-activator of Nrg4. Supplementation of NRG4 reverses the compromised adipose browning in Prkag2 AKO mice. In human, NRG4, and other adipokines are tightly correlated with adipose AMPK γ2 expression. Our findings unravel the previously unrecognized function of AMPK γ2 as a transcriptional co-regulator independent of AMPK kinase activity in adipocytes.