Biology subjects

Paules, E. M.

Publications and source records attributed to Paules, E. M..

3 recordsLinked to original sources

bioRxiv2025

Urinary Signatures Predict Calorie Restriction-Mediated Weight Loss in Obese Diversity Outbred Mice

Predictive analytics encompassing metabolomic profiles are increasingly being used to forecast 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 predictive of 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 the common metabolites and sex-specific metabolites to reveal moderate (males) to robust (females, males plus females) prediction models 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.

physiology↗

bioRxiv2024

Tirzepatide attenuates mammary tumor progression in diet-induced obese mice

Obesity, an established risk and progression factor for at least 13 cancer types, is highly prevalent globally, and effective strategies to mitigate the burden of obesity-related cancer are urgently needed. We investigated whether tirzepatide, a widely used incretin-mimetic drug that induces substantial weight loss, offers anticancer benefits. Across 3 tumor models, we demonstrate that chronic tirzepatide treatment reverses diet-induced increases in body weight and fat mass, systemic metabolic perturbations, and tumor growth. We also showed that the anticancer activity of tirzepatide does not involve direct effects on the neoplastic cells used, which lack incretin receptor expression. The anticancer actions of tirzepatide require the reversal of both the metabolic dysregulation and hyporesponsiveness of CD8+ tumor infiltrating lymphocytes evident in obesity. Our findings establish tirzepatide as a promising compound for intercepting obesity-related cancers.

cancer biology↗

bioRxiv2021

Homocysteine-induced endoplasmic reticulum stress activates FGF21 via CREBH, resulting in browning and atrophy of white adipose tissue in Bhmt knockout mice.

Betaine-homocysteine methyltransferase (BHMT) catalyzes the transfer of methyl-groups from betaine to homocysteine (Hcy) producing methionine and dimethylgycine. In this work, we characterize Bhmt wildtype (WT) and knockout (KO) mice that were fully backcrossed to a C57Bl6/J background. Consistent with our previous findings, Bhmt KO mice had decreased body weight, fat mass and adipose tissue weight compared to WT. Histological analyses and gene expression profiling indicate that adipose browning was activated in KO mice and contributed to the adipose atrophy observed. BHMT is not expressed in adipose tissue but is abundant in liver, thus, a signal must be originating from the liver that modulates adipose tissue. We found that, in Bhmt KO mice, homocysteine-induced endoplasmic reticulum (ER) stress, with activation of hepatic transcription factor cyclin AMP response element binding protein (CREBH), mediated an increase in hepatic and plasma concentrations of fibroblast growth factor 21 (FGF21), which is known to induce adipose browning. CREBH binds to the promoter regions of FGF21 to activate its expression. Taken together, our data indicate that deletion of a single gene in one-carbon metabolism modifies adipose biology and energy metabolism. It would be interesting to determine whether people with functional polymorphisms in BHMT exhibit a similar adipose atrophy phenotype.

cell biology↗