(P18-002-25) Myeloid Monoamine Oxidase A Deficiency Promotes Insulin Resistance and Glucose Intolerance in High-Calorie Diet-Fed Mice But Accelerates Weight Gain Only in Male Mice

Objectives: The aim of this study was to determine the role of myeloid monoamine oxidase A (Mao A) in diet-induced obesity (DIO).

Methods: After a one-week run-in period on a defined, phytochemical-free low-fat maintenance diet, 10-week-old male and female LysMCre^tg/tg and LysMCre^tg/tgMaoA^fl/fl (Mao A _myeloid^-/-) mice were switched to a high-calorie diet for 20 weeks. Mice were weighed weekly and food intake was assessed. After week 20, mice were fasted for 6 h, and glucose tolerance was assessed. Mice were then fasted overnight, blood was collected by cardiac puncture.Perigonadal white adipose tissues (WAT) were collected and prepared for Western blot analyses and qPCR. Plasma was used to quantify leptin, insulin, triglycerides, cholesterol, and non-esterified fatty acid levels. Bone marrow-derived macrophages were generated and mRNA was collected for gene profiling by qPCR.

Results: Male adibut not female mice with myeloid Mao A deficiency showed increased weight gain, increased visceral AT weight as well as elevated fasting blood glucose and leptin levels. However, both male and female Mao A _myeloid^-/- mice showed increased glucose intolerance and insulin resistance of the AT as indicate by elevated pAKT/AKT ratios in the AT. Importantly, Mao A mRNA levels were reduced by 90% and 94% in bone marrow-derived macrophages from male and female Mao A _myeloid^-/-mice, respectively, but Mao A protein expression levels in AT were not altered by myeloid Mao A deficiency. Targeted gene profiling by qRT-PCR in BMDM isolated from male and female Mao A _myeloid^-/- mice revealed no compensatory induction of Mao B. We also observed no statistically significant changes in the expression of Nox1 and Nox4, Nrf2 or Nrf2-dependent genes, nor in glucose transporter expression Glut1, Glut3 or Glut 4 in BMDM isolated from male and female Mao A _myeloid^-/- mice.

Conclusions: Our findings show that myeloid Mao A protects male but not female mice from DIO though an unknown mechanism. However, myeloid Mao A deficiency induced insulin resistance in AT and glucose intolerance in both male and female mice suggesting that Mao A in AT macrophages may play an important role in regulating glucose sensing and metabolism.

Funding Sources: This study was supported by R01 HL153120 and a Wake Forest School of Medicine CTSI Pilot Grant.