Biology subjects

Mullen, G. P.

Publications and source records attributed to Mullen, G. P..

3 recordsLinked to original sources

bioRxiv2025

Maternal exercise during lactation reprograms obesity-related changes in mammary metabolism to optimize milk fatty acids and offspring energy expenditure

Maternal obesity alters breast milk composition in ways that may predispose infants to excess adiposity. While maternal exercise during lactation has been associated with favorable shifts in milk metabolites in humans, the mechanisms by which exercise remodels the mammary gland and milk lipid profile to influence offspring metabolism remain unclear. We developed a mouse model incorporating daily moderate treadmill exercise during lactation, indirect calorimetry, stable isotope tracer respirometry, and mammary epithelial cell (MEC) proteomics in lean (LN) and diet-induced obese (OB) dams. Maternal obesity broadly remodeled the MEC proteome, reducing enzymes of de novo fatty acid synthesis and altering lipid transport and oxidative pathways. These molecular adaptations corresponded to higher milk triglyceride content and shifts in fatty acid composition, including an elevated omega-6 to omega-3 fatty acid ratio. The exercise (EX) intervention during lactation reset MEC protein networks, enhancing translational and vesicle transport pathways while reducing fatty acid desaturation, relative to the sedentary (SED) group. In OB dams, exercise increased milk medium-chain fatty acid (MCFA) levels and partially corrected the n6/n3 FA ratio. Offspring nursed by OB-EX dams exhibited higher whole-body energy expenditure, increased fatty acid oxidation, and improved metabolic flexibility compared to litters consuming OB-SED milk. Together, maternal exercise during lactation remodels mammary metabolism and milk fatty acid composition in obese dams, enhancing neonatal lipid oxidation and energy expenditure. These findings highlight lactation as a modifiable window, wherein maternal activity influences milk composition and infant metabolic health. New and noteworthyMaternal obesity alters milk fatty acid composition, with consequences for infant metabolism. Exercise during lactation in obese dams remodeled the mammary epithelial cell proteome, increasing medium-chain fatty acids in milk and enhancing lipid oxidation and energy expenditure in offspring.

physiology↗

bioRxiv2024

NR2F2 Reactivation in Early-life Adipocyte Stem-like Cells Rescues Adipocyte Mitochondrial Oxidation

In humans, perinatal exposure to an elevated omega-6 (n6) relative to omega-3 (n3) Fatty Acid (FA) ratio is associated with the likelihood of childhood obesity. In mice, we show perinatal exposure to excessive n6-FA programs neonatal Adipocyte Stem-like cells (ASCs) to differentiate into adipocytes with lower mitochondrial nutrient oxidation and a propensity for nutrient storage. Omega-6 FA exposure reduced fatty acid oxidation (FAO) capacity, coinciding with impaired induction of beige adipocyte regulatory factors PPAR{gamma}, PGC1, PRDM16, and UCP1. ASCs from n6-FA exposed pups formed adipocytes with increased lipogenic genes in vitro, consistent with an in vivo accelerated adipocyte hypertrophy, greater triacylglyceride accumulation, and increased % body fat. Conversely, n6-FA exposed pups had impaired whole animal 13C-palmitate oxidation. The metabolic nuclear receptor, NR2F2, was suppressed in ASCs by excess n6-FA intake preceding adipogenesis. ASC deletion of NR2F2, prior to adipogenesis, mimicked the reduced FAO capacity observed in ASCs from n6-FA exposed pups, suggesting that NR2F2 is required in ASCs for robust beige regulator expression and downstream nutrient oxidation in adipocytes. Transiently re-activating NR2F2 with ligand prior to differentiation in ASCs from n6-FA exposed pups, restored their FAO capacity as adipocytes by increasing the PPAR{gamma}-PGC1 axis, mitochondrial FA transporter CPT1A, ATP5 family synthases, and NDUF family Complex I proteins. Our findings suggest that excessive n6-FA exposure early in life dampens an NR2F2-mediated induction of beige adipocyte regulators, resulting in metabolic programming that is shifted towards nutrient storage.

physiology↗

bioRxiv2019

Systematic phenomics analysis of ASD-associated genes reveals shared functions and parallel networks underlying reversible impairments in habituation learning

A major challenge facing the genetics of Autism Spectrum Disorders (ASD) is the large and growing number of candidate risk genes and gene variants of unknown functional significance. Here, we used Caenorhabditis elegans to systematically functionally characterize ASD-associated genes in vivo. Using our custom machine vision system we quantified 26 phenotypes spanning morphology, locomotion, tactile sensitivity, and habituation learning in 87 strains each carrying a mutation in an ortholog of an ASD-associated gene. We identified hundreds of novel genotype-phenotype relationships ranging from severe developmental delays and uncoordinated movement to subtle deficits in sensory and learning behaviors. We clustered genes by similarity in phenomic profiles and used epistasis analysis to discover parallel networks centered on CHD8*chd-7 and NLGN3*nlg-1 that underlie mechanosensory hyper-responsivity and impaired habituation learning. We then leveraged our data for in vivo functional assays to gauge missense variant effect. Expression of wild-type NLG-1 in nlg-1 mutant C. elegans rescued their sensory and learning impairments. Testing the rescuing ability of all conserved ASD-associated neuroligin variants revealed varied partial loss-of-function despite proper subcellular localization. Finally, we used CRISPR-Cas9 auxin inducible degradation to determine that phenotypic abnormalities caused by developmental loss of NLG-1 can be reversed by adult expression. This work charts the phenotypic landscape of ASD-associated genes, offers novel in vivo variant functional assays, and potential therapeutic targets for ASD.

neuroscience↗