2146-P: Offspring Exposed to Maternal High-Fat Diet Exhibits Decreased REG3G, Pancreatic Islet Dysfunction, and Systemic Inflammation

Offspring exposed to in-utero overnutritive state, such as hyperglycemia and hyperlipidemia, are more likely to develop altered immune response and pancreatic islet dysfunction. Recently, we reported that fetal rats exposed to in-utero hyperglycemia had decreased fetal β-cell REG3G, and then developed lower β-cell mass and insulin secretion at adulthood. We hypothesize that exposure to maternal high fat diet not only suppresses offspring β-cell REG3G, but also increases inflammation thereby instigating offspring islet dysfunction. Female mice were fed 42% high fat diet (HFD) 4 weeks before pregnancy until weaning, and offspring were evaluated at different ages. P0 mice born to HFD mothers had lower pancreatic islet REG3G expression (n=3/group*). On postnatal day 21 (P21), HFD weanlings had impaired glucose [GTT AUC: male HFD 37± 3%* higher: 8-11/group; female HFD 22 ± 3%* higher: 3-9/group]. Glucose intolerance persisted in 8-week-old male from HFD mothers (n=5-9/group*), with decreased pancreatic islets glucose induced calcium response measured using Fura-2AM calcium imaging (F1/F0: Con:2.00 ± 0.06, HFD2w: 1.69±0.12*, HFD4w: 0.71±0.09*, n =3-6/group). Since members of the Reg3 subclass are reported to mediate macrophage polarization and chemotaxis in pancreatic cancer and heart, we assessed bone marrow derived macrophages response at P21 and at 8 weeks. Compared to controls, HFD P21 weanling had increased in M1 macrophages polarization, as well as an increase in macrophage IL-1b secretion when stimulated with LPS(3/group*). We also found that, at 8 weeks of age, HFD male offspring had increased activation markers of splenic dendritic cells (3/group*) indicating development of systemic inflammation early in life. Taken together, our findings suggest that mice offspring from HFD mothers have decreased REG3G expression early, followed by pancreatic dysfunction and a heightened inflammatory response. [*p<0.05 when compared to control].