UCP1 Mitigates Hepatic Steatosis and Fibrosis Independent of Cold Exposure

Haley, J. A.; Le, J.; Li, R.; Korobkina, E.; de Fatima Silva, F.; Gaughan, M.; Fitzgibbons, T. P.; Martinez, N.; Chen, Q.; Fluharty, S. M.; Li, H.; Lewis, C. A.; Harris, J. E.; Zhu, L. J.; Mullen, A. C.; Jang, C.; Guertin, D. A.

doi:10.1101/2025.08.05.666925

bioRxiv · 10.1101/2025.08.05.666925

UCP1 Mitigates Hepatic Steatosis and Fibrosis Independent of Cold Exposure

Haley, J. A.·Le, J.·Li, R.·Korobkina, E.·de Fatima Silva, F.·Gaughan, M.·Fitzgibbons, T. P.·Martinez, N.·Chen, Q.·Fluharty, S. M.·Li, H.·Lewis, C. A.·Harris, J. E.·Zhu, L. J.·Mullen, A. C.·Jang, C.·Guertin, D. A.

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Abstract

Non-shivering thermogenesis by brown adipose tissue (BAT) is a promising target for anti-obesity therapies, making its regulatory mechanisms of significant translational interest. While cold-induced BAT thermogenesis (CIT) is well characterized, certain high-calorie diets can also activate BAT in the absence of cold, a process known as diet-induced thermogenesis (DIT). Despite its potential relevance to modern human diets and lifestyles, the mechanisms and physiological relevance underlying DIT remain poorly understood. Here, we show that DIT reduces adiposity and protects against hepatic steatosis and fibrosis in males but not female mice. Moreover, adipose tissue-specific ablation of uncoupling protein 1 (UCP1) reveals that BAT is the primary mediator of DIT but that non-adipocyte UCP1 also contributes to body weight regulation. Transcriptome analysis suggests that DIT is triggered by intrinsic metabolic stress, distinguishing it from CIT, which is driven by sympathetic tone. Finally, BAT-specific arteriovenous metabolomics identifies glucose as the predominant circulating fuel for DIT. These findings uncover distinct molecular and metabolic features of DIT, highlighting opportunities to harness BAT activity for treating obesity and metabolic diseases without requiring cold exposure.

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Haley, J. A., Le, J., Li, R., Korobkina, E., de Fatima Silva, F., Gaughan, M., Fitzgibbons, T. P., Martinez, N., Chen, Q., Fluharty, S. M., Li, H., Lewis, C. A., Harris, J. E., Zhu, L. J., Mullen, A. C., Jang, C., Guertin, D. A.. 2025-08-07. UCP1 Mitigates Hepatic Steatosis and Fibrosis Independent of Cold Exposure. https://doi.org/10.1101/2025.08.05.666925

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