Biology subjects

McIntyre, R. L.

Publications and source records attributed to McIntyre, R. L..

3 recordsLinked to original sources

bioRxiv2026

Mitochondrial carrier SLC25A34 links clock, diet, and temperature control of interorganellar lipid cycling

Adipocyte lipid metabolism is coordinated by circadian rhythms, diet, and environmental temperature. Yet how these diverse signals are molecularly integrated remains unknown. Here we show that clock, diet, and temperature cues converge on the orphan mitochondrial transporter, SLC25A34, to orchestrate thermogenic cycling of lipid synthesis and oxidation. During sleep, the clock suppresses Slc25a34 transcription through REV-ERB. Waking, lipid-rich diets, or cold exposure abolish this repression, allowing lipolytic signals to stimulate Slc25a34 expression via PPAR. SLC25A34 then imports oxaloacetate into mitochondria to accelerate the export of substrates used for acetyl-CoA production in the cytosol. This feeds into cytosolic lipid synthesis and transcriptional induction of mitochondrial biogenesis, which collectively promote mitochondrial lipid oxidation. Thus, SLC25A34 confers circadian, dietary, and environmental control of thermogenic metabolism through interorganellar lipid cycling.

molecular biology↗

bioRxiv2025

Cold exposure induces the constitutively active thermogenic receptor, GPR3, via ERRα and ERRγ

ObjectivesDespite transformative advances in obesity pharmacotherapy, safely increasing energy expenditure remains a key unmet need. Exploiting thermogenic adipocytes represents a promising target given their capacity for significant catabolic activity. We previously showed that G protein-coupled receptor 3 (GPR3) can drive energy expenditure in brown and white mouse and human adipocytes. GPR3 is a unique GPCR because it displays high intrinsic activity and leads to constitutive cAMP signaling upon reaching the cell surface. Therefore, the transcriptional induction of GPR3 is analogous to ligand-binding activation of most GPCRs. Gpr3 expression is physiologically induced in thermogenic adipocytes by cold exposure and mimicking this event through overexpression in mice is fully sufficient to increase energy expenditure and counteract metabolic disease. Yet the factors mediating physiological Gpr3 expression remain unknown. MethodsHere, we apply ATAC-Seq to identify cold-induced promoter elements of Gpr3. We uncover a role for the estrogen-related receptors, ERR and ERR{gamma}, in the physiological transcriptional control of Gpr3 using adipose-specific double knock-out mice with and without adeno associated virus (AAV)-mediated rescue. ResultsWe show that ERR directly binds the cold-induced promoter element of Gpr3 and that adipocyte ERR and ERR{gamma} are required for the in vivo transcriptional induction of Gpr3 during cold exposure. Importantly, deficient Gpr3 cold-inducibility in adipose-specific ERR and ERR{gamma} KO mice is fully rescued by delivery of AAVs re-expressing either ERR or ERR{gamma} directly into brown adipose tissue. ConclusionsERR and ERR{gamma} are critical regulators of cold-induced transcription of Gpr3 and represent a targetable strategy for pharmacologically unlocking GPR3-induced energy expenditure.

molecular biology↗

bioRxiv2020

Inhibition of the neuromuscular acetylcholine receptor with atracurium activates FOXO/DAF-16-induced longevity

Transcriptome-based drug screening is emerging as a powerful tool to identify geroprotective compounds to intervene in age-related disease. We hypothesized that, by mimicking the transcriptional signature of the highly conserved longevity intervention of FOXO3 (daf-16 in worms) overexpression, we could identify and repurpose compounds with similar downstream effects to increase longevity. Our in silico screen, utilizing the LINCS transcriptome database of genetic and compound interventions, identified several FDA-approved compounds that activate FOXO downstream targets in mammalian cells. These included the neuromuscular blocker atracurium, which also robustly extends both lifespan and healthspan in C. elegans. This longevity is dependent on both daf-16 signaling and inhibition of the neuromuscular acetylcholine receptor. Other neuromuscular blockers tubocurarine and pancuronium caused similar healthspan benefits. We demonstrate nuclear localization of DAF-16 upon atracurium treatment, and, using RNAseq transcriptomics, identify activation of DAF-16 downstream effectors. Together, these data demonstrate the capacity to mimic genetic lifespan interventions with drugs, and in doing so, reveal that the neuromuscular acetylcholine receptor regulates the highly conserved FOXO/DAF-16 longevity pathway.

molecular biology↗