Metabolic surgery remains the most effective treatment modality for severe obesity and its comorbidities, including type 2 diabetes. Roux-en-Y gastric bypass (RYGB) is a commonly performed type of metabolic surgery that reconfigures gastrointestinal anatomy and profoundly remodels the gut microbiota.

The second messenger cyclic nucleotides cAMP and cGMP are key effectors of thermogenesis in adipocytes in response to a diverse array of cues. Their intracellular levels are normally regulated by the hydrolytic action of phosphodiesterases (PDEs), a conserved superfamily of enzymes composed of 12 families in humans (PDE1‐12) with distinct substrate specificities and tissue distribution profiles. Phosphodiesterase inhibitors are thus promising drugs for the treatment of metabolic disease by promoting cyclic nucleotide‐mediated adipose tissue thermogenesis, but so far mainly those that elevate either cAMP or cGMP signaling alone have been studied. We previously showed that inhibition of the dual‐specificity phosphodiesterase type 10A (PDE10A) with the small molecule drug MP‐10 sufficiently induces a thermogenic gene expression program in differentiated human white pre‐adipocytes (HWP‐ds) to a similar degree as combined cAMP and cGMP treatment. Here, we asked (1) which PDE10A isoforms are expressed in HWP‐ds, (2) the downstream signaling pathways PDE10A controls, and (3) how PDE10A expression is influenced by inflammatory stimuli in this cell type. Immunoblot analysis revealed that both the cytosolic (PDE10A1) and membrane‐bound (PDE10A2) isoforms of PDE10A are highly expressed in HWP‐ds, predominantly in the former subcellular compartment. This was confirmed by fractionation and immunofluorescence analyses. Inhibition of PDE10A with MP‐10 dose‐dependently increased PKA and PKG signaling as revealed by phosphorylation of cyclic response element binding protein (CREB) and vasodilator‐stimulated phosphoprotein (VASP) at S133 and S239, respectively. Consistently, the stimulation of lipolysis by MP‐10 was fully prevented by combined pre‐incubation of HWP‐ds with selective PKA and PKG inhibitors. Finally, mimicking the adipose tissue microenvironment in obesity by applying pro‐inflammatory cytokines onto HWP‐ds caused an early (4‐hour) and sustained (24‐hour) increase in PDE10A mRNA expression. These results provide new insight into the molecular character, function, and regulation of PDE10A in human adipocytes and further justify the use of selective inhibitors for the treatment of metabolic disease through stimulating adipose tissue thermogenesis in a more efficient and targeted manner.

No abstract