Mouse model in Castration/Fructose group
The combination of low testosterone and high fructose intake revealed changes in gut microbiota and increased fat on the liver.
Image Credit: Osaka Metropolitan University
Scientific Frontline: Extended "At a Glance" Summary: Synergistic Effects of Low Testosterone and High Fructose on Hepatic Steatosis
The Core Concept: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a progressive liver condition initiated by fatty liver, which is significantly worsened by the combined presence of low testosterone levels and high dietary fructose intake.
Key Distinction/Mechanism: While obesity, diabetes, and diet independently affect liver health, the concurrent combination of testosterone deficiency and excessive fructose actively alters the gut microbiota composition. This synergistic interaction elevates intestinal pyruvate levels, which directly promotes neutral lipid accumulation within hepatocytes (liver cells) more severely than either factor alone.
Major Frameworks/Components:
- In Vivo Mouse Models: Utilization of castrated and sham-operated male mice subjected to controlled fructose diets to isolate the variables of testosterone deficiency and sugar intake.
- Microbiome Analysis: Identification of altered gut microbiota composition and increased cecal pyruvate levels as the primary drivers of lipid accumulation.
- Antibiotic Intervention: The application of antibiotics to demonstrate that mitigating gut microbiota changes successfully prevents the abnormal increase in liver weight and fat.
- Hepatocyte Targeting: Laboratory experiments using primary hepatocytes confirming that pyruvate acts synergistically with fructose to drive neutral lipid accumulation.
- Branch of Science: Endocrinology, Metabolism, Hepatology, and Nutritional Science.
Future Application: The findings provide a foundational framework for developing targeted therapeutic drugs and establishing evidence-based dietary interventions aimed at mitigating gut microbiota alterations and managing pyruvate levels to prevent or reverse fatty liver progression.
Why It Matters: With approximately 40% of adult men worldwide currently suffering from MASLD, identifying the specific molecular and microbial pathways triggered by common lifestyle and hormonal factors is critical for addressing a rapidly growing global metabolic health crisis.
Low testosterone in itself can cause a variety of health problems, but the addition of a poor diet can exacerbate certain conditions. Metabolic dysfunction-associated steatotic liver disease (MASLD) is one example that approximately 40% of adult men worldwide currently suffer from and has become a global problem. Fatty liver, the initial stage of MASLD, is associated with risk factors such as obesity, type 2 diabetes, decreased testosterone, and high fructose intake from beverages and processed foods. However, the relationship and combined effects of these on the liver have yet to be fully understood.
Focusing on the two distinct factors, decreased testosterone and high fructose intake, a Graduate School of Agriculture research group led by graduate student Hiroki Takahashi and Associate Professor Naoki Harada conducted a study to observe their effects on the liver. Eight-week-old male mice were castrated or sham-operated and divided into six groups, Sham/Control, Sham/ Fructose, Sham/Fructose + Antibiotics, Castration/Control, Castration/Fructose, and Castration/Fructose + Antibiotics. Analyses of liver cells, tissue, plasma, cecal organic acids, and gut microbiota samples were conducted to evaluate the effects and differences between each group.
Results revealed that liver weight increased in castrated mice with fructose intake but lessened in those treated with antibiotics. Each factor alone caused a slight change in liver triglyceride levels, but when the two factors combined, they synergistically contributed to fat accumulation on the liver and worsened fatty liver. Further, the castration and fructose intake group showed signs of altered gut microbiota composition, liver gene expression, and increased levels of cecal pyruvate.
“Upon examining this mechanism, we found that changes in the gut microbiota led to increased levels of pyruvate within the intestine. Furthermore, experiments using mouse-derived primary hepatocytes revealed that pyruvate acts synergistically with fructose to promote neutral lipid accumulation in hepatocytes,” explained Takahashi.
“Going forward, we hope to clarify the mechanism by which pyruvate promotes triglyceride accumulation to pioneer the development of therapeutic drugs and establishment of preventive methods through dietary interventions,” added Professor Harada.
Funding: This work was supported by the Japan Society for the Promotion of Science KAKENHI (Grant Nos. 22H02289 and 25K01971 to N.H.) and Thomas J. Beatson Jr. Foundation Grant (No. 2022-006 to E.Y.), National Institute of Diabetes and Digestive and Kidney Diseases (Grant No. R01DK136888 to E.Y.), and Juvenile Diabetes Research Foundation (JDRF) (Grant No. 5-CDA-2022-1178-A-N to E.Y.).
Published in journal: American Journal of Physiology-Endocrinology and Metabolism
Authors: Hiroki Takahashi, Naoki Harada, Yohei Hayamizu, Erdenetsogt Dungubat, Masami Nakazawa, Tomoya Kitakaze, Keiichiro Sugimoto, Hiroshi Inui, Eiji Yoshihara, Yoshihisa Takahashi, and Ryoichi Yamaji
Source/Credit: Osaka Metropolitan University
Reference Number: med031126_02
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