Protein restriction in the pregnant mouse modifies fetal growth and pulmonary development: role of fetal exposure to β-hydroxybutyrate

Abstract

Maternal undernutrition during sensitive periods of pregnancy results in offspring predisposed towards the development of a number of diseases of adulthood, including hypertension and diabetes. In order to determine the nature of any gross alterations in fetal growth during early organogenesis, we supplied timed-mated pregnant mice with diets containing 6% protein (6%P), 9% protein (9%P) or 18% protein (18%P; control) from day 0 of pregnancy. At embryonic days 11 (E11), 12 (E12) and 13 (E13), females were killed and fetuses removed. Gross morphological analysis revealed that fetal limb growth was impaired between E11 and E12 in 6%P animals, but this recovered by E13. Likewise, fetal liver growth and lung branching morphogenesis were seen to exhibit an initial growth impairment at E12 followed by a rapid recovery by E13. Coincident with the observed changes in fetal growth, we noted an elevation in maternal hepatic triglyceride content, expression of the ketogenic 3-hydroxy-3-methylglutarylCoA synthase 2 (Hmgcs2) and circulating plasma β-hydroxybutyrate (BOHB). In addition, fetal liver Hmgcs2 expression was switched on by E13 in both 6%P-and 9%P-exposed animals. Exogenous BOHB did not influence branching morphogenesis in fetal lung explant cultures; however, we cannot rule out the possibility that this may occur in vivo. In conclusion, we find that disturbance of fetal growth by maternal dietary protein restriction is associated and therefore potentially indicated by changes in maternal and fetal ketone body metabolism.

Maternal protein restriction induces alterations in hepatic tumor necrosis factor-α/CYP7A1 signaling and disorders regulation of cholesterol metabolism in the adult rat offspring

“…This effect is partly mediated through affecting the epigenetic modification of genes that regulate metabolism and transportation of glucose and lipid. (16–18) Our laboratory also developed an IUGR model in rats by maternal protein restriction, whereas the animals showed disturbed hepatic metabolism, in line with other studies. (19) …”

Excess Maternal Salt Intake Produces Sex-Specific Hypertension in Offspring: Putative Roles for Kidney and Gastrointestinal Sodium Handling

“…Western blotting was carried out as previously described [24]. Briefly, tissues were disrupted in 5 volumes of ice-cold homogenisation buffer (150 mM NaCl, 50 mM HEPES, 2.5 mM EDTA, 10% glycerol, 1% Triton, 1 mM Na 3 VO 4 , 10 mM NaF) containing a protease inhibitor cocktail (Roche Diagnostics, West Sussex, UK).…”

Renal programming: cause for concern?

“…Early studies of renal programming models induced by maternal low-protein diet, malnutrition, or dexamethasone exposure demonstrated marked increases in systolic blood pressure of as much as 30 mmHg in animals as young as 4 wk of age when measured by tail cuff (28,82). However, with greater use of radiotelemetry techniques it has become increasingly apparent that resting blood pressure in these animals is often not different from control animals or only moderately elevated even when followed into old age (8,44,81,144). Some of these studies even show low blood pressures compared with control offspring (14,81,109).…”

“…However, with greater use of radiotelemetry techniques it has become increasingly apparent that resting blood pressure in these animals is often not different from control animals or only moderately elevated even when followed into old age (8,44,81,144). Some of these studies even show low blood pressures compared with control offspring (14,81,109). These radiotelemetry studies have reinforced that it is the presence of secondary stressors, whether this be in the form of physical/psychological stress (e.g., restraint stress associated with tail cuff), physiological stress (e.g., dietary salt intake), or presence of coexisting disease (e.g., diabetes) that may be crucial for the translation of renal programming events into adult hypertension (Fig.…”