Dataset Information

Loss-of-function G6PD variant moderated high-fat diet-induced obesity, adipocyte hypertrophy, and fatty liver in male rats.

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.

SUBMITTER: Matsumura S

PROVIDER: S-EPMC11328872 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Loss-of-function G6PD variant moderated high-fat diet-induced obesity, adipocyte hypertrophy, and fatty liver in male rats.

Matsumura Shun S Signoretti Christina C Fatehi Samuel S Tumenbayar Bat Ider BI D'Addario Catherine C Nimmer Erik E Thomas Colin C Viswanathan Trisha T Wolf Alexandra A Garcia Victor V Rocic Petra P Bae Yongho Y Alam Sm Shafiqul SS Gupte Sachin A SA

The Journal of biological chemistry 20240612 7

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. G6 ...[more]

PMID: 38876306

Similar Datasets

Project description:ObjectivesObesity, an emerging global health issue, involves numerous factors; understanding its underlying mechanisms for prevention and therapeutics is urgently needed. Cellular retinoic acid binding protein 1 (Crabp1) knockout (CKO) mice exhibit an obese phenotype under normal diet (ND) feedings, which prompted us to propose that Crabp1 could play a role in modulating adipose tissue development/homeostasis. Studies were designed to elucidate the underlying mechanism of Crabp1's action in reducing obesity.Subjects/methodsIn animal studies, 6 weeks old male wild type and CKO mice were fed with ND or high-fat diet (HFD) for 10 weeks. Body weight and food intake were regularly monitored. Glucose tolerance test and biological parameters of plasma (glucose and insulin levels) were measured after 10 weeks of ND vs. HFD feedings. Visceral adipose tissues were collected for histological and molecular analyses to determine affected signaling pathways. In cell culture studies, the 3T3L1 adipocyte differentiation model was used to examine and validate relevant signaling pathways.ResultsCKO mice, compared to WT mice, gained more body weight, exhibited more elevated fasting plasma glucose levels, and developed more severe impaired glucose tolerance under both ND and HFD. Histological examination revealed readily increased adipocyte hypertrophy and adipose tissue inflammation under HFD feedings. In 3T3L1 adipocytes, Crabp1 silencing enhanced extracellular signal-regulated kinase 1/2 (ERK1/2) activation, accompanied by elevated markers and signaling pathways of lipid accumulation and adipocyte hypertrophy.ConclusionsThis study identifies Crabp1's physiological role against the development of obesity. The protective function of CRABP1 is likely attributed to its classically proposed (canonical) activity as a trap for RA, which will reduce RA availability, thereby dampening RA-stimulated ERK1/2 activation and adipocyte hypertrophy. The results suggest Crabp1 as a potentially new therapeutic target in managing obesity and metabolic diseases.

Dataset Information

Loss-of-function G6PD variant moderated high-fat diet-induced obesity, adipocyte hypertrophy, and fatty liver in male rats.

Publications

Loss-of-function G6PD variant moderated high-fat diet-induced obesity, adipocyte hypertrophy, and fatty liver in male rats.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets