Mild Maternal Undernutrition Results in a Premature Neonatal Leptin Surge that Promotes Resistance in Male Offspring to a High Fat Diet

Malnutrition alters leptin signaling, resulting in dysregulation of pituitary somatotropes that may be sex-specific. We reported sex differences in acute fasting responses with reductions in serum leptin in males, but not females (1). Maternal undernutrition can also alter the neonatal leptin surge by blunting with 50% food deprivation (2), causing a premature surge with 30% food deprivation (3), and resulting in metabolic dysfunction in adulthood (2,3). We developed a milder undernutrition model to relate more closely to society’s nutritional challenges and to test the hypothesis that a shift in the neonatal leptin surge would result in sex-specific metabolic changes. Compared to paired ad libitum (Fed) dams, we studied pups from undernourished dams that were calorically restricted by 20% (CR20) from embryonic day 15 until postnatal day (PND) 21. We tested 216 offspring from 11 Fed dams and 13 undernourished dams (CR20), detecting a leptin surge in control fed progeny at PND11. CR20 offspring of both sexes had an early surge (PND8) that was 62% (P<0.0001) higher compared to offspring of Fed dams and was maintained at high levels until PND11. Interestingly, GH levels at PND1 were 354% (P<0.0001) higher in the CR20 progeny compared to controls. By PND16, serum IGF-1 levels in underfed pups were lower than levels in control pups (111364±71 vs 244145±135 pg/ml; P=0.0277). CR20 male weights were 13.1% lower (P<0.0001) and lengths were 8.4% shorter (P=0.0002) than controls by 8 weeks of age and did not recover. CR20 female weights were lower by 11% (P=0.0013) and lengths were shorter up to 3 weeks of age. At 3 months of age, offspring were exposed to a 45% HFD for 16 weeks, testing 54 pups from 3 dams per nutrient status. Fed mice from both sexes responded to the HFD with an average weight gain of 12.3g (P<0.0001) in females and 12.6g (P<0.0001) in males. Females from CR20 dams also gained weight (8.74g, P<0.0001) on the HFD, but was significantly lower than females from Fed dams (P=0.0362). Surprisingly, male progeny from CR20 dams did not respond to weight gain by HF feeding when compared to control fed males, appearing to be protected from impact. Sex-specific changes in pituitary Gh, Ghrhr, and Ghsr mRNA levels were as follows. Among CR20 males exposed to HFD, Ghsr mRNA increased by 64% (P=0.0154) when compared to control fed males. Among CR20 females, Gh expression was unchanged with HFD but Ghrhr expression was blunted by 54.7% (P=0.0363). However, Gh mRNA was reduced by 34% (P= 0.0265) when compared to control females on the HFD. Collectively, these data show that mild undernutrition causes a prematurely high leptin surge and sex-specific differences in growth and responses to a HFD, including a potential resistance to a HFD in underfed males. References: (1) TK Miles et al., J Endocrinol. 2020 Sep 1; (2) F Delahaye et al., Endocrinology. 2008 Feb; 149(2):470. (3) S Yura et al., Cell metabolism. 2005 1(6):371.