cAMP driven UCP1 induction in human adipocytes requires ATGL-catalyzed lipolysis

Area of Science:

• Cell Biology
• Metabolism
• Endocrinology

Background:

• Uncoupling protein 1 (UCP1) is key in brown/beige adipocyte thermogenesis, induced by cAMP signaling.
• PPARγ agonists like rosiglitazone (Rsg) also enhance UCP1, but its induction mechanism in existing adipocytes versus new differentiation is unclear.

Purpose of the Study:

• To investigate the acute effects of Rsg and forskolin (Fsk) on UCP1 expression in human adipocytes.
• To determine if Rsg-induced UCP1 upregulation involves de novo beige adipocyte differentiation or direct induction in mature adipocytes.

Main Methods:

• Human adipocytes differentiated from progenitor cells were treated with Fsk, Rsg, or both.
• Techniques included Bulk RNASeq, RNAScope, RT-PCR, CRISPR-Cas9 knockout of PNPLA2 (ATGL), oxygen consumption, and western blotting.

Main Results:

• Both Rsg and Fsk rapidly induced UCP1 mRNA, independent of new adipocyte differentiation.
• Fsk-induced UCP1 was significantly reduced by ATGL knockout, indicating lipolysis is crucial for cAMP-mediated UCP1 induction.
• Rsg treatment reversed the ATGL knockout-induced suppression of Fsk-stimulated UCP1, suggesting lipolysis generates natural PPARγ agonists.

Conclusions:

• UCP1 transcription is acutely induced by both cAMP-dependent pathways and PPARγ activation in human adipocytes.
• cAMP signaling synergistically enhances UCP1 expression via both pathways.
• ATGL-mediated lipolysis likely produces ligands that activate PPARγ, contributing to cAMP-induced UCP1 expression.