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Abstract Disclosure: T.K. Miles: None. V.G. Ortega: None. K.D. Carroll: None. A.K. Odle: None. S.D. Byrum: None. A.J. Gies: None. A.N. Lagasse: None. A.C. Haney: None. M.C. MacNicol: None. A.M. MacNicol: None. G.V. Childs: None. Leptin is involved in pituitary development and function and regulates the expression of Musashi (MSI), a translational regulator that inhibits Pou1f1 expression. The neonatal leptin surge, involved in anorexigenic neuron development, is altered by maternal nutrition. Our recently published work showed that a 20% maternal undernutrition model causes a premature neonatal leptin surge, and adult male offspring have a reduced response to diet induced weight gain. We hypothesize that a blunted neonatal leptin surge, due to maternal undernutrition, will alter neonatal MSI expression and target regulation, possibly persisiting into adulthood. To address this hypothesis, we developed a 30% maternal caloric restriction model (CR30) in FVB mice. At PND10, weight was reduced in male (-1.70g, p0.0001) and female CR30 offspring (-2.59g, p0.0001). In addition, CR30 offspring had blunted neonatal leptin surges (males: -7.34ng/mL, p=0.0487; females: -22.25ng/mL, p0.0001) compared to offspring of ad libitum fed dams (FED). Msi2 (-0.515, p=0.0004) and Pou1f1 (-0.834, p0.0001) transcripts were reduced in the pituitary of PND10 CR30 pups. Adult offspring (8 weeks) of FED dams given a 60% high fat diet (FED-HFD) for 25 weeks gained a significant amount of weight (male: +8.86g, p0.0001; female: +7.36g, p0.0001) compared to control fed (10% fat) animals. Female CR30 offspring weight gain on the HFD was not significantly different from FED-HFD females. Conversely, male CR30-HFD final weight gain compared to controls (+5.65g, p0.0001) was significantly lower than FED-HFD males final weight gain (-3.38g, p=0.0044). Serum leptin was significantly elevated in all HFD groups of both sexes and serum PAI-1 increased in FED-HFD groups. FED-HFD mice (both sexes) and CR30-HFD females (but not males) showed impaired glucose tolerance. The pituitary proteome of PND10 CR30 neonates revealed 15 upregulated and 7 downregulated proteins (logFC±1, adj. p0.055), of which 7 are known MSI targets. Pathway analysis predicts a positive z-score for the “COPII mediated vesicle transport” pathway and a negative z-score for “processing of capped intron-containing pre-mRNA” pathway. Interestingly, in the adult offspring, the CR30 along did not alter the proteome response, except after HFD stress. Some identified proteins were sex and condition specific, such as corticotropin-releasing factor-binding protein (CRHBP), which was uniquely decreased (LogFC = -4.1885, adj. p = 0.0175) in the CR30-HFD males. The data indicate that a blunted neonatal leptin surge, induced by maternal caloric restriction, alters the expression of Musashi and binding targets both in the neonate and the adult. Some of these targets are known regulators of pituitary development and/or function, such as Pou1f1. Thus, we show here a novel response by Musashi in the pituitary to nutritional signals in the neonatal mouse. Presentation: 6/3/2024
Miles et al. (Tue,) studied this question.