Thoumas, J.-L. | Search bioRxiv

bioRxiv2024

Protein restriction associated with high fat induces metabolic dysregulation without obesity in juvenile mice

Dysregulation of energy metabolism, including hyperglycemia, insulin resistance and fatty liver have been reported in a substantial proportion of lean children. However, non-obese murine models recapitulating these features are lacking to study the mechanisms underlying the development of metabolic dysregulations in lean children. Here, we develop a model of diet-induced metabolic dysfunction without obesity in juvenile mice by feeding male and female mice a diet reflecting Western nutritional intake combined with protein restriction (mWD) during 5 weeks after weaning. mWD-fed mice (33% fat, 8% protein) do not exhibit significant weight gain and have moderate increase in adiposity compared to control mice (16% fat, 20% protein). After 3 weeks of mWD, juvenile mice have impaired glucose metabolism including hyperglycemia, insulin resistance and glucose intolerance. mWD also triggers hepatic metabolism alterations, as shown by the development of simple liver steatosis. Both male and female mice fed with mWD displayed metabolic dysregulation, which a probiotic treatment with Lactiplantibacillus plantarum WJL failed to improve. Overall, mWD-fed mice appear to be a good preclinical model to study the development of diet-induced metabolic dysfunction without obesity in juveniles.

physiology↗

bioRxiv2024

Suboptimal refeeding compensates stunting in a mouse model of juvenile malnutrition

BackgroundEarly life, particularly after weaning, is the most rapid period of growth in mammals, and this growth is highly dependent on adequate nutrition. Protein-energy malnutrition (PEM) during this critical window can lead to stunting and wasting, which have long-term health consequences. ObjectiveThis study aimed to develop a mouse model of juvenile PEM to assess the effects of refeeding with various diets and interventions on growth recovery, including the impact of probiotic supplementation and suboptimal refeeding diets. MethodsJuvenile C57Bl/6J mice were fed a low-protein diet (LPD, 5% kcal from protein) starting at postnatal day 14 (P14) to induce malnutrition. Following weaning, both male and female mice were refed an optimal diet (Altromin 1310, 27% kcal from protein) at different times ranging from P28 to P56. In a second intervention, male mice were supplemented during refeeding with Lactiplantibacillus plantarum WJL (LpWJL), a probiotic known to stimulate growth in malnourished conditions. A final group of malnourished male mice were refed with a Western diet (WD, 34.5% kcal from fat; 15.3% kcal from protein) or a modified Western diet (MWD, 34.2% kcal from fat; 7.5% kcal from protein) to model suboptimal refeeding. ResultsRefeeding with an optimal diet fully restored growth in female mice, but male mice exhibited persistent stunting despite nutritional rehabilitation. LpWJL treatment during refeeding did not enhance systemic growth in males. In contrast, refeeding with WD or MWD restored body length but impaired glucose metabolism, particularly in mice refed MWD after PEM. LpWJL exacerbated glucose intolerance in the suboptimal refeeding groups. ConclusionSex-dependent differences exist in the recovery from early-life malnutrition, with males showing incomplete growth recovery despite optimal refeeding. Suboptimal diets, while compensating for stunting, impair glucose metabolism, especially when protein intake is insufficient. Probiotic supplementation with LpWJL did not improve growth outcomes.

physiology↗