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Enhanced hexose-6-phosphate dehydrogenase expression in adipose tissue may contribute to diet-induced visceral adiposity

International Journal of Obesity volume 42, pages 1999–2011 (2018)Cite this article

Subjects

Abstract

Background

Visceral fat accumulation increases the risk of developing type 2 diabetes and metabolic syndrome, and is associated with excessive glucocorticoids (GCs). Fat depot-specific GC action is tightly controlled by 11ß-hydroxysteroid dehydrogenase (11ß-HSD1) coupled with the enzyme hexose-6-phosphate dehydrogenase (H6PDH). Mice with inactivation or activation of H6PDH genes show altered adipose 11ß-HSD1 activity and lipid storage. We hypothesized that adipose tissue H6PDH activation is a leading cause for the visceral obesity and insulin resistance. Here, we explored the role and possible mechanism of enhancing adipose H6PDH in the development of visceral adiposity in vivo.

Methods

We investigated the potential contribution of adipose H6PDH activation to the accumulation of visceral fat by characterization of visceral fat obese gene expression profiles, fat distribution, adipocyte metabolic molecules, and abdominal fat-specific GC signaling mechanisms underlying the diet-induced visceral obesity and insulin resistance in H6PDH transgenic mice fed a standard of high-fat diet (HFD).

Results

Transgenic H6PDH mice display increased abdominal fat accumulation, which is paralleled by elevated lipid synthesis associated with induction of lipogenic transcriptor C/EBPα and PPARγ mRNA levels within adipose tissue. Transgenic H6PDH mice fed a high-fat diet (HFD) gained more abdominal visceral fat mass coupled with activation of GSK3β and induction of XBP1/IRE1α, but reduced pThr308 Akt/PKB content and browning gene CD137 and GLUT4 mRNA levels within the visceral adipose tissue than WT controls. HFD-fed H6PDH transgenic mice also had impaired insulin sensitivity and exhibited elevated levels of intra-adipose GCs with induction of adipose 11ß-HSD1.

Conclusion

These data provide the first in vivo mechanistic evidence for the adverse metabolic effects of adipose H6PDH activation on visceral fat distribution, fat metabolism, and adipocyte function through enhancing 11ß-HSD1-driven intra-adipose GC action.

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Author contributions

LL, YW, and JW contributed to the design and performance of experiments. LL, YW, JW, YD, SC, XL, and YL acquired and analyzed the data. MJ generated aP2- H6PDH transgenic mouse line. YL drafted and writing of the manuscript and supervised this project. MJ, KL, TCF, and CH reviewed this manuscript. All authors discussed and agreed on the results, and gave final approval.

Funding

YL is supported by NIH grant SC1DK104821 and LSI grant F00333003007. TCF is supported by NIH grant 2R24DA017298. LL is supported by grants from the Project of National Natural Science Foundation of China (8147102 and 8127086) and the Shanghai Leading Talent (SLJ15055). YD is supported by AHA grant 12SDG8760-002.

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    Authors and Affiliations

    1. Division of Endocrinology, Metabolism & Molecular Medicine, Charles R. Drew University of Medicine & Sciences, David Geffen School of Medicine, University of California, 1731 E. 120th St, Los Angeles, CA, 90059, USA

      Limei Liu, Ying Wang, Jian Wang, Scarlett Chang, Xiwen Liu, Theodore C. Friedman & Yanjun Liu

    2. Department of Endocrinology & Metabolism, Shanghai Jiaotong University Affiliated Sixth People’s Hospital, Shanghai Diabetes Institute, Shanghai, People’s Republic of China

      Limei Liu & Kabirullah Lutfy

    3. Department of Neonatology, The First Hospital of Jilin University, Changchun, People’s Republic of China

      Jian Wang & Yanjun Liu

    4. Vascular Biology Program, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA

      Yunzhou Dong & Hong Chen

    5. College of Pharmacy, Western University of Health Sciences, Pomona, CA, USA

      Kabirullah Lutfy

    6. Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA

      Meisheng Jiang

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    These author contributed equally: L. Liu, Y.Wang and J. Wang

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    Liu, L., Wang, Y., Wang, J. et al. Enhanced hexose-6-phosphate dehydrogenase expression in adipose tissue may contribute to diet-induced visceral adiposity. Int J Obes 42, 1999–2011 (2018). https://doi.org/10.1038/s41366-018-0041-1

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