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

Berger, J. H.; Lau, A. N.; James, L. C.; Taing, R.; Ahn, B.; Yin, X.; Sakamoto, T.; Batmanov, K.; Jordan, O.; Patel, J.; Zhou, J.; Finck, B. N.; Titchenell, P. M.; Tesz, G. J.; Kelly, D. P.

doi:10.1101/2025.10.06.680559

bioRxiv · 10.1101/2025.10.06.680559

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

Berger, J. H.·Lau, A. N.·James, L. C.·Taing, R.·Ahn, B.·Yin, X.·Sakamoto, T.·Batmanov, K.·Jordan, O.·Patel, J.·Zhou, J.·Finck, B. N.·Titchenell, P. M.·Tesz, G. J.·Kelly, D. P.

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Abstract

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

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Berger, J. H., Lau, A. N., James, L. C., Taing, R., Ahn, B., Yin, X., Sakamoto, T., Batmanov, K., Jordan, O., Patel, J., Zhou, J., Finck, B. N., Titchenell, P. M., Tesz, G. J., Kelly, D. P.. 2025-10-07. Whole body MondoA deletion protects against diet-induced obesity through uncontrolled multi-organ substrate utilization and futile cycling. https://doi.org/10.1101/2025.10.06.680559

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