MafB Is Critical for Glucagon Production and Secretion in Mouse Pancreatic <i>α</i> Cells <i>In Vivo</i>

Abstract

The MafB transcription factor is expressed in pancreatic α and β cells during development but becomes exclusive to α cells in adult rodents. <i>Mafb</i>-null (<i>Mafb^-/-</i> ) mice were reported to have reduced α- and β-cell numbers throughout embryonic development. To further analyze the postnatal function of MafB in the pancreas, we generated endocrine cell-specific (<i>Mafb^Δ</i>^<i>Endo</i> ) and tamoxifen-dependent (<i>Mafb^Δ</i>^<i>TAM</i> ) <i>Mafb</i> knockout mice. <i>Mafb^Δ</i>^<i>Endo</i> mice exhibited reduced populations of insulin-positive (insulin⁺) and glucagon⁺ cells at postnatal day 0, but the insulin⁺ cell population recovered by 8 weeks of age. In contrast, the Arx⁺ glucagon⁺ cell fraction and glucagon expression remained decreased even in adulthood. <i>Mafb^Δ</i>^<i>TAM</i> mice, with <i>Mafb</i> deleted after pancreas maturation, also demonstrated diminished glucagon⁺ cells and glucagon content without affecting β cells. A decreased Arx⁺ glucagon⁺ cell population in <i>Mafb^Δ</i>^<i>Endo</i> mice was compensated for by an increased Arx⁺ pancreatic polypeptide⁺ cell population. Furthermore, gene expression analyses from both <i>Mafb^Δ</i>^<i>Endo</i> and <i>Mafb^Δ</i>^<i>TAM</i> islets revealed that MafB is a key regulator of glucagon expression in α cells. Finally, both mutants failed to respond to arginine, likely due to impaired arginine transporter gene expression and glucagon production ability. Taken together, our findings reveal that MafB is critical for the functional maintenance of mouse α cells <i>in vivo</i>, including glucagon production and secretion, as well as in development.