Myeloid monoamine oxidase A protects against glucose intolerance, insulin resistance and weight gain in high-fat diet-fed mice by preventing the hyperactivation of macrophages

The aim of this study was to determine the role of myeloid monoamine oxidase A (Mao A) in diet-induced obesity (DIO). Ten-week-old male and female LysMCre^tg/tg (CTL) and LysMCre^tg/tgMaoA^fl/fl (Mao A_Myeloid^-/-) mice were fed a high-fat diet for 20 week. Male but not female mice with myeloid Mao A deficiency showed increased weight gain, increased visceral adipose tissue (AT) weight as well as elevated fasting blood glucose and leptin levels. However, both male and female Mao A_Myeloid^-/- mice showed increased insulin resistance of the AT and glucose intolerance. Mao A mRNA levels were reduced by 90% and 94% in bone marrow-derived macrophages (BMDM) from male and female Mao A_Myeloid^-/- mice, respectively, but neither Mao A mRNA expression nor protein levels or Mao A activity in AT were altered by myeloid Mao A deficiency. Targeted gene profiling of M_TNFα+IFNγ and M_IL-4-polarized BMDM from Mao A KO mice and 129S1 strain-matched control mice revealed that Mao A deficiency amplifies the expression of polarization state-specific marker genes in BMDM from male mice but affects only a few selected marker genes in female polarized BMDM. Myeloid Mao A protects male but not female mice from AT inflammation, AT expansion and DIO, possibly by suppressing the polarization of monocyte-derived macrophages recruited into the AT. However, myeloid Mao A deficiency promoted insulin resistance in AT and glucose intolerance in both male and female mice suggesting that macrophage Mao A in other tissues contributes to the maintenance of glucose tolerance and homeostasis.