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HIV-1 Viral Protein R Couples Metabolic inflexibility with White Adipose Tissue Thermogenesis

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posted on 07.07.2021, 21:06 by Neeti Agarwal, Dinakar Iyer, Pradip Saha, Aaron R. Cox, Yan Xia, Netanya S. Utay, Anoma Somasundaram, Ulrich Schubert, Jordan E. Lake, Sean M. Hartig, Ashok Balasubramanyam
Persons living with HIV (PLWH) manifest chronic disorders of brown and white adipose tissues that lead to diabetes and metabolic syndrome. The mechanisms that link viral factors to defective adipose tissue function and abnormal energy balance in PLWH remain incompletely understood. Here, we explored how the HIV accessory protein viral protein R (Vpr) contributes to adaptive thermogenesis in two mouse models and human adipose tissues. Uncoupling protein 1 (UCP1) gene expression was strongly increased in subcutaneous white adipose tissue (WAT) biopsies from PLWH and in subcutaneous WAT of the Vpr mice, with near-equivalent mRNA copy number. Histology and functional studies confirmed beige transformation in subcutaneous but not visceral WAT in the Vpr mice. Measurements of energy balance indicated Vpr mice displayed metabolic inflexibility and could not shift efficiently from carbohydrate to fat metabolism during day-night cycles. Furthermore, Vpr mice showed a marked inability to defend body temperature when exposed to 4oC. Importantly, Vpr couples higher tissue catecholamine levels with UCP1 expression independent of β-adrenergic receptors. Our data reveal surprising deficits of adaptive thermogenesis that drive metabolic inefficiency in HIV-1 Vpr mouse models, providing an expanded role for viral factors in the pathogenesis of metabolic disorders in PLWH.

Funding

This work was funded by the Rutherford Diabetes Research Fund (to A.B.); and American Diabetes Association grant #1-18-IBS-105 and R01DK114356 (to S.M.H.). The study was also funded in part by an award from the Baylor College of Medicine Nutrition and Obesity Pilot and Feasibility Fund and the Nancy Chang, PhD Award for Research Excellence.

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