Brown adipocytes hold the potential to mitigate body fat accumulation and type 2 diabetes (T2D) via their specialized function in dissipating energy as heat, a process known as thermogenesis. To fuel their function, brown adipocytes release the bond energy of fat through lipolysis and β-oxidation; then, uncoupling cellular respiration releases this energy as physical heat. In addition to their energy-dissipating function, brown adipocytes can release factors, such as lipids, metabolites, peptides, or microRNA, to regulate metabolism. Signaling lipids have demonstrated roles in regulating thermogenesis in brown adipocytes by regulating lipid uptake and utilization. To further explore these pathways, we performed signaling lipidomics analysis in in vitro differentiated human brown adipocytes and found 15-keto-PGF2α was increased when treated with forskolin, an adenylyl cyclase activator that mimics adrenergic stimulation. Previous studies have shown PGF2α, the parent molecule of 15-keto-PGF2α, inhibits maturation, or adipogenesis, in white adipocyte cell lines by preventing the expression of key adipogenesis genes, such as PPARγ and C/EBPα. Similarly, PGF2α inhibits thermogenic gene expression in brown adipocyte cells. To explore and compare the functional activities of PGF2α and 15-keto-PGF2α, we characterized the dose-response relationship of these lipids on thermogenic gene and protein expression. We found that 15-keto-PGF2α is not as potent as PGF2α at inhibiting both thermogenic gene and protein expression. This suggests the conversion of PGF2α to 15-keto-PGF2α represents a significant signaling event to promote thermogenesis in brown adipocytes. Interestingly, carbonyl reductase 1, an enzyme that catalyzes this conversion, is regulated by treatment with the adrenergic agonist, norepinephrine, in vitro and by cold exposure in vivo. Targeting this conversion may be an attractive approach towards activating thermogenesis to mitigate obesity and T2D.
E.Fadumiye: None. S.Kodani: None. M.Kiebish: None. V.Bussberg: None. Y.Tseng: Consultant; Cellarity.
National Institutes of Health (R01DK122808)