Endocrine Abstracts

Protein phosphatase 2A (PP2A) is a multimeric serine/threonine phosphatase which has multiple functions. However, the potential involvement of PP2A in insulin’s metabolic signaling pathway is presently unknown. Brain insulin resistant state is characterized by disturbances in transducing the signal from IR/IRS/AKT, changing feeding behaviour and body weight. We showed that diet induced obese rats (DIO) have a marked increase in PP2A protein expression in the hypothalamus. Thus, we generated a selective, transient reduction in PP2A by infusion of an antisense oligonucleotide designed to blunt the expression of PP2A in rat hypothalamic areas surrounding the third ventricle in control and obese rats. The selective decrease in hypothalamic PP2A resulted in decreased food intake, reduced body weight, reduced adiposity after high-fat feeding, improved insulin action and signaling in hypothalamus. Central insulin signaling was increased by phosphorylation of AKT in PP2A ASO treated rats. To assess the impact of hypothalamic PP2A down-regulation on the peripheral action of insulin, we performed hyperinsulinemic-euglycemic clamp studies. The insulin action on peripheral glucose uptake was increased. In conclusion, we have demonstrated an important role of hypothalamic PP2A in the modulation of energy balance, insulin action, and glucose metabolism. Thus, the reduction in hypothalamic PP2A should be sufficient to promote an appreciable weight reduction and access to the brain may also be necessary to optimally improve insulin sensitivity and glucose homeostasis.

Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.

Funding: This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.