Loss-Of-Function G6PD Variant Moderated High-Fat Diet-Induced Obesity, Adipocyte Hypertrophy, and Fatty Liver in Male Rats

Authors

Shun Matsumura, New York Medical College
Christina Signoretti, New York Medical College
Samuel Fatehi, New York Medical College
Bat Ider Tumenbayar, Jacobs School of Medicine and Biomedical Sciences
Catherine D'Addario, New York Medical College
Erik Nimmer, Department of Biomedical Engineering
Colin Thomas, Department of Biomedical Engineering
Trisha Viswanathan, New York Medical College
Alexandra Wolf, New York Medical College
Victor Garcia, New York Medical College
Petra Rocic, Sam Houston State University College of Osteopathic Medicine
Yongho Bae, Department of Biomedical Engineering
SM Shafiqul Alam, New York Medical College
Sachin A. Gupte, New York Medical College

Author Type(s)

Student, Faculty

DOI

10.1016/j.jbc.2024.107460

Journal Title

Journal of Biological Chemistry

Document Type

Article

Publication Date

7-1-2024

Department

Pharmacology

Keywords

chemokines, cytokines, fat tissue, inflammation, inter-organ communication, liver, metabolic reprogramming, vascular biology

Disciplines

Medicine and Health Sciences

Abstract

Obesity is a major risk factor for liver and cardiovascular diseases. However, obesity-driven mechanisms that contribute to the pathogenesis of multiple organ diseases are still obscure and treatment is inadequate. We hypothesized that increased, glucose-6-phosphate dehydrogenase (G6PD), the key rate-limiting enzyme in the pentose shunt, is critical in evoking metabolic reprogramming in multiple organs and is a significant contributor to the pathogenesis of liver and cardiovascular diseases. G6PD is induced by a carbohydrate-rich diet and insulin. Long-term (8 months) high-fat diet (HFD) feeding increased body weight and elicited metabolic reprogramming in visceral fat, liver, and aorta, of the wild-type rats. In addition, HFD increased inflammatory chemokines in visceral fat. Interestingly, CRISPR-edited loss-of-function Mediterranean G6PD variant (G6PD^S188F) rats, which mimic human polymorphism, moderated HFD-induced weight gain and metabolic reprogramming in visceral fat, liver, and aorta. The G6PD^S188F variant prevented HFD-induced CCL7 and adipocyte hypertrophy. Furthermore, the G6PD^S188F variant increased Magel2 – a gene encoding circadian clock-related protein that suppresses obesity associated with Prader-Willi syndrome – and reduced HFD-induced non-alcoholic fatty liver. Additionally, the G6PD^S188F variant reduced aging-induced aortic stiffening. Our findings suggest G6PD is a regulator of HFD-induced obesity, adipocyte hypertrophy, and fatty liver.

Recommended Citation

Matsumura, S., Signoretti, C., Fatehi, S., Tumenbayar, B., D'Addario, C., Nimmer, E., Thomas, C., Viswanathan, T., Wolf, A., Garcia, V., Rocic, P., Bae, Y., Alam, S., & Gupte, S. (2024). Loss-Of-Function G6PD Variant Moderated High-Fat Diet-Induced Obesity, Adipocyte Hypertrophy, and Fatty Liver in Male Rats. Journal of Biological Chemistry, 300 (7). https://doi.org/10.1016/j.jbc.2024.107460