Low Sodium Supply in Early Life Causes Growth Restriction and Programs Long‐Term Changes in Energy Homeostasis
Authors: Ziegler Alisha A. , Grobe Connie C. , Reho John J. , Grobe Justin L. , Segar Jeffrey L. 
Published: May 2022

Preterm birth is a risk factor for the development of a multitude of diseases later in life. Preterm infants are also at risk for growth failure following parturition, which further compounds the adverse effects of preterm birth. Previous studies have shown that prematurely born human infants’ kidneys are inefficient at retaining sodium, therefore putting these infants at high risk of sodium depletion. We have developed a “post‐wean” dietary manipulation to model early‐life sodium depletion. In this model, mice are fed variations of soy‐free 2920x diet (Teklad); low‐sodium (0.04% Na, n=6), or high/normal‐sodium (0.30% Na, n=8), from weaning at week three of life, until week six of life. At six weeks of age, all mice are switched back to the “standard” 2920x diet (0.15% Na). Food and water intake behaviors, physical activity, energy expenditure, and body composition of the mice were serially analyzed using a multiplexed phenotyping system (Promethion, Sable Systems International) and time‐domain nuclear magnetic resonance (NMR; Bruker LF110). Mice supplied low‐Na between 3‐6 weeks of age exhibited delayed growth during weeks 3‐6, then rapid “catch‐up growth” following return to “normal” diet in week 6, and similar growth kinetics to the high‐Na group thereafter (diet x age interaction p<0.01). The delay in body mass expansion in the low‐Na group was due to a decrease in fat‐free mass (diet x age interaction p<0.01). Mice fed low‐Na diet exhibited reduced food intake (diet p<0.01), due to slower eating speed (diet p<0.01) and meal size (diet p=0.01). The reduced food intake relative to body composition was sustained through 18 weeks of age (diet x age interaction p=0.93). Water intake was also increased in mice treated with low‐Na diet both during diet intervention and through 18 weeks of age (diet p<0.01), due to an increased number of drinking bouts (diet p<0.01) of comparable size (diet p=0.46). Total aerobic energy expenditure was increased in mice fed the low‐Na diet, even after correction for body composition (diet p<0.01). Mice treated with low‐Na diet in early life also exhibited an increase in energy expenditure that was maintained through 18 weeks of age (diet x age p>0.99), even after correction for body composition and for differences in food intake. Finally, mice treated with low‐Na diet demonstrate a reduction in calories that are unaccounted for by these methods (diet p<0.01, diet x age interaction p=0.68). In conclusion, post‐wean sodium depletion causes growth failure and changes in body composition that parallel premature human infant growth failure. Profoundly, this relatively simple 3‐week diet switch causes changes in intake behaviors and energy expenditure that are then “programmed” for at least another 12 weeks after switch back to a “normal” diet. These findings support our working hypothesis that early‐life sodium supply impacts energy homeostasis and growth kinetics and prompts reconsideration of current guidelines concerning sodium supplementation to prematurely born and low‐birthweight infants.