Dietary Succinate Impacts the Nutritional Metabolism, Protein Succinylation and Gut Microbiota of Zebrafish

Abstract

Succinate is widely used in the food and feed industry as an acidulant, flavoring additive, and antimicrobial agent. This study investigated the effects of dietary succinate on growth, energy budget, nutritional metabolism, protein succinylation, and gut microbiota composition of zebrafish. Zebrafish were fed a control-check (0% succinate) or four succinate-supplemented diets (0.05, 0.10, 0.15, and 0.2%) for 4 weeks. The results showed that dietary succinate at the 0.15% additive amount (S0.15) can optimally promote weight gain and feed intake. Whole body protein, fat, and energy deposition increased in the S0.15 group. Fasting plasma glucose level decreased in fish fed the S0.15 diet, along with improved glucose tolerance. Lipid synthesis in the intestine, liver, and muscle increased with S0.15 feeding. Diet with 0.15% succinate inhibited intestinal gluconeogenesis but promoted hepatic gluconeogenesis. Glycogen synthesis increased in the liver and muscle of S0.15-fed fish. Glycolysis was increased in the muscle of S0.15-fed fish. In addition, 0.15% succinate-supplemented diet inhibited protein degradation in the intestine, liver, and muscle. Interestingly, different protein succinylation patterns in the intestine and liver were observed in fish fed the S0.15 diet. Intestinal proteins with increased succinylation levels were enriched in the tricarboxylic acid cycle while proteins with decreased succinylation levels were enriched in pathways related to fatty acid and amino acid degradation. Hepatic proteins with increased succinylation levels were enriched in oxidative phosphorylation while proteins with decreased succinylation levels were enriched in the processes of protein processing and transport in the endoplasmic reticulum. Finally, fish fed the S0.15 diet had a higher abundance of Proteobacteria but a lower abundance of Fusobacteria and Cetobacterium. In conclusion, dietary succinate could promote growth and feed intake, promote lipid anabolism, improve glucose homeostasis, and spare protein. The effects of succinate on nutritional metabolism are associated with alterations in the levels of metabolic intermediates, transcriptional regulation, and protein succinylation levels. However, hepatic fat accumulation and gut microbiota dysbiosis induced by dietary succinate suggest potential risks of succinate application as a feed additive for fish. This study would be beneficial in understanding the application of succinate as an aquatic feed additive.

Effects of Succinate on Growth Performance, Meat Quality and Lipid Synthesis in Bama Miniature Pigs

“…Furthermore, we found that the addition of succinate promoted pig fat deposition, especially subcutaneous fat and intramuscular fat content. Consistent with our results, the addition of 0.15% succinate to the zebrafish diet promoted the increase in crude protein, crude fat, and energy and significantly altered the growth and development of zebrafish [20]. A study of succinate in rats found that feeding sodium succinate increased energy expenditure but did not affect dietary intake and that succinate could enter the body as a substrate [28].…”

“…SIRT5 knockout of brown adipose tissue in mice leads to hyper-succinylation of these proteins, which in turn leads to mitochondrial respiratory impairment, defective mitophagy, and lipid metabolic disorder [19]. Recent reports have revealed that dietary disodium succinate regulates lipid synthesis, gluconeogenesis, and glycogen synthesis in intestinal, liver, and muscle tissues, thereby inhibiting protein degradation in tissues, increasing fat deposition, and improving glucose tolerance [20]. Mechanistically, it works by regulating the levels of succinylation of the tricarboxylic acid cycle and fatty acid degradation-related proteins.…”

Type 2 diabetes and succinate: unmasking an age-old molecule

“…Consequently, further investigations will be imperative to explore the potential of succinate supplementation once the pathology is already established. In addition, studies on zebrafish, an appealing model for obesity and type 2 diabetes, have yielded deleterious outcomes concerning weight gain, hepatic fat accumulation and gut microbiota composition [ 75 ], which points to potential species differences.…”

Protein succinylation, hepatic metabolism, and liver diseases

“…Mechanisms for succinylation: On one hand, succinylation could be processed via non-enzymatic manners, which relies on succinyl-CoA or succinate from mitochondrial and peroxisome sources[ 4 , 5 , 10 - 14 ]. Succinylation would occur if provided with sufficient succinyl-CoA[ 10 ].…”

“…Succinate entering the cells could be converted to succinyl-CoA to enhance lysine succinylation[ 1 ]. A study has shown that dietary succinate increases the succinylation of intestinal and hepatic proteins with a molecular weight of 25-35 kD in zebrafish[ 14 ].…”