NYMC Faculty Publications

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

Shun Matsumura, Department of Pharmacology, New York Medical College, Valhalla, New York, USA.
Christina Signoretti, Department of Pharmacology, New York Medical College, Valhalla, New York, USA.
Samuel Fatehi, Department of Pharmacology, New York Medical College, Valhalla, New York, USA.
Bat Ider Tumenbayar, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, New York, USA.
Catherine D'Addario, Department of Pharmacology, New York Medical College, Valhalla, New York, USA.
Erik Nimmer, Department of Biomedical Engineering, School of Engineering and Applied Sciences, University at Buffalo, State University of New York, Buffalo, New York, USA.
Colin Thomas, Department of Biomedical Engineering, School of Engineering and Applied Sciences, University at Buffalo, State University of New York, Buffalo, New York, USA.
Trisha Viswanathan, Department of Pharmacology, New York Medical College, Valhalla, New York, USA.
Alexandra Wolf, Department of Pharmacology, New York Medical College, Valhalla, New York, USA.
Victor Garcia, Department of Pharmacology, New York Medical College, Valhalla, New York, USA.
Petra Rocic, Department of Physiology & Pharmacology, SHSU College of Osteopathic Medicine, Conroe, Texas, USA.
Yongho Bae, Department of Biomedical Engineering, School of Engineering and Applied Sciences, University at Buffalo, State University of New York, Buffalo, New York, USA; Department of Pathology and Anatomical Sciences, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, New York, USA.
Sm Shafiqul Alam, Department of Pathology, Microbiology, and Immunology (PMI), New York Medical College, Valhalla, New York, USA.
Sachin A. Gupte, Department of Pharmacology, New York Medical College, Valhalla, New York, USA. Electronic address: s_gupte@nymc.edu.

Author Type(s)

Student, Faculty

DOI

10.1016/j.jbc.2024.107460

Journal Title

The Journal of Biological Chemistry

First Page

107460

Document Type

Article

Publication Date

7-1-2024

Department

Pharmacology

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) rats, which mimic human polymorphism, moderated HFD-induced weight gain and metabolic reprogramming in visceral fat, liver, and aorta. The G6PD variant prevented HFD-induced CCL7 and adipocyte hypertrophy. Furthermore, the G6PD 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 variant reduced aging-induced aortic stiffening. Our findings suggest G6PD is a regulator of HFD-induced obesity, adipocyte hypertrophy, and fatty liver.

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