Jordan, O. | Search bioRxiv

bioRxiv2025

Whole body MondoA deletion protects against diet-induced obesity through uncontrolled multi-organ substrate utilization and futile cycling

ObjectiveDelineating the nodal control points that maintain whole-body energy homeostasis is critical for understanding potential treatments of obesity and cardiometabolic diseases. The nutrient-sensing transcription factor MondoA is a regulator of skeletal muscle fuel storage, where muscle-specific inhibition improves glucose tolerance and insulin sensitivity. However, the role of MondoA in whole body energy metabolic homeostasis is not understood. MethodsGeneralized MondoA knockout (gKO) mice were generated and assessed for glucose tolerance and insulin sensitivity, body composition, energy expenditure, cold tolerance, and tissue specific transcriptional changes in response to high fat diet. Complementary studies in cultured human adipocytes assessed the impact of MondoA deficiency on substrate utilization and lipolysis. ResultsgKO mice are protected from diet-induced obesity and insulin resistance, through increased whole body energy expenditure. gKO mice exhibit reduced brown and inguinal white adipose tissue mass, without evidence of beiging. The gKO mice are hyperlactatemic and isolated MondoA-deficient adipocytes have increased 2-deoxyglucose uptake and glycolytic function. Lastly, gKO mice and KO adipocytes display increased circulating glycerol relative to free fatty acids in response to adrenergic stimulus consistent with elevated re-esterification. However, this phenotype is not recapitulated in adipocyte-specific KO mice. ConclusionsMondoA deficiency alters cellular sensing of nutrient availability and storage/utilization mechanisms. In the whole-body setting, this results in increased energy expenditure, potentially related to increased glucose uptake and glycolytic flux driving glycerol synthesis to supply high rates of lipolysis and lipid re-esterification. These results suggest that MondoA functions to maintain fuel storage and when lost, inter-organ futile cycling ensues. O_FIG O_LINKSMALLFIG WIDTH=140 HEIGHT=200 SRC="FIGDIR/small/680559v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@1ccf42dorg.highwire.dtl.DTLVardef@b2da28org.highwire.dtl.DTLVardef@1081aforg.highwire.dtl.DTLVardef@1b2168d_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical Abstract.C_FLOATNO 1) Global MondoA deficiency drives 2) tissue glucose uptake which in skeletal muscle is 3) converted and excreted as lactate, while in adipose tissue 4) triglyceride re-esterification requires 5) de novo glycerol synthesis to feed into the futile cycle. C_FIG

physiology↗

bioRxiv2024

gplasCC: classification and reconstruction of plasmids from short-read sequencing data for any bacterial species

Plasmids play a pivotal role in the spread of antibiotic resistance genes. Accurately reconstructing plasmids often requires long-read sequencing, but bacterial genomic data in publicly accessible repositories has historically been derived from short-read sequencing technology. We recently presented an approach for reconstructing Escherichia coli antimicrobial resistance plasmids using Illumina short reads. This method consisted of combining a robust binary classification tool named plasmidEC with gplas2, which is a tool that makes use of features of the assembly graph to bin predicted plasmid contigs into individual plasmids. Here, we developed gplasCC, a plasmidEC-simplification, capable of classifying plasmid contigs using Centrifuge databases. We have developed seven plasmidCC databases in addition to the database for E. coli: six species-specific models (Acinetobacter baumannii, Enterococcus faecium, Enterococcus faecalis, Klebsiella pneumoniae, Staphylococcus aureus and Salmonella enterica) and one species-independent model for less frequently studied bacterial species. We combined these models with gplas2 (now, gplasCC) to reconstruct plasmids from more than 100 bacterial species. This approach allows comprehensive analysis of the wealth of bacterial short-read sequencing data available in public repositories and advance our understanding of microbial plasmids.

bioinformatics↗