Urinary signatures are associated with calorie restriction-mediated weight loss in obese Diversity Outbred mice - PubMed (original) (raw)

. 2025 Dec 9;20(12):e0329422.

doi: 10.1371/journal.pone.0329422. eCollection 2025.

Isis Trujillo-Gonzalez 1 2, Melissa VerHague 2, Jody Albright 2, Delisha Stewart 3, Susan J Sumner 1 2, Susan L McRitchie 2, David Kirchner 2, Michael F Coleman 1, Brian J Bennett 4 5, Annie Green Howard 6, Penny Gordon-Larsen 1, John E French 1 2, Stephen D Hursting 1 2 7

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Urinary signatures are associated with calorie restriction-mediated weight loss in obese Diversity Outbred mice

Evan M Paules et al. PLoS One. 2025.

Abstract

Metabolomic profiles are increasingly being used to identify responders to dietary interventions. Advances using this approach are particularly needed to personalize and enhance the effectiveness of dietary weight loss interventions. Using obese Diversity Outbred (DO) mice that model genetic and phenotypic heterogeneity of human populations, we aimed to identify urinary metabolite signatures associated with responsiveness to calorie restriction (CR)-mediated weight loss. DO mice (150 males, 150 females) were fed a high-fat diet for 12 weeks to induce obesity, then urine was collected and an 8-week CR regimen (30% decrease in energy intake) initiated. At study completion, mice were rank-ordered according to their percent body weight change, with mice in the extreme quartiles deemed CR responders (n = 67) versus nonresponders (n = 67). Targeted semi-quantitative metabolomics identified elevated glutamic acid and hydroxyproline as key urinary metabolites that distinguish CR responders from CR nonresponders, independent of sex. Three urinary metabolites (glutamic acid, hydroxyproline, and putrescine) distinguished male CR responders from nonresponders. Six metabolites (glutamic acid, hydroxyproline, dopamine, histamine, lysine, and spermine) distinguished female CR responders from nonresponders. Multivariate receiver operating characteristic analyses integrated these metabolites to reveal potential sex specific and sex-independent associations of CR-mediated weight loss. Further, pathway analysis identified several metabolic pathways, including arginine and proline metabolism, and alanine, aspartate, and glutamate biosynthesis, that distinguished CR responders from nonresponders and could be indicative of metabolic reprogramming to enhance insulin sensitivity and energy metabolism.

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Conflict of interest statement

Evan M. Paules, PhD. is a Balchem postdoctoral fellow. Balchem had no role in the study design, data collection, analysis, or preparation of the manuscript. The other authors declare no competing interests.

Figures

Fig 1

Fig 1. Timeline of the high-fat diet, urine collection, and calorie restriction.

Fig 2

Fig 2. OPLS-DA scores plots of CR responder and CR nonresponder urinary metabolites.

Scores plots of (A) all CR responders (blue circles) and nonresponders (red circles), (B) male CR responders and CR nonresponders, and (C) female CR responders and CR nonresponders.

Fig 3

Fig 3. Multivariate ROC curves that distinguish CR responders and CR nonresponders.

Receiver operating characteristic (ROC) curves of (A) all CR responders and nonresponders (AUC: 0.76, confidence interval (CI): 0.68-0.85), (B) male CR responders and CR nonresponders (AUC: 0.71, CI: 0.51-0.85), and (C) female CR responders and CR nonresponders (AUC: 0.84, CI: 0.69-0.96).

Fig 4

Fig 4. Pathway analysis differentiating CR responders and CR nonresponders urinary profiles.

Bubble chart of KEGG pathway analysis for (A) all, (B) male, and (C) female CR responders vs CR nonresponders. Top pathways with p < 0.05 and pathway score > 0.3 are labeled accordingly. Pathway impact values are on the x-axis while -log(p) values are on the y-axis.

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