The role of palmitoleic acid in regulating hepatic gluconeogenesis through SIRT3 in obese mice

Authors: GUO, XIN - Shandong University; JIANG, XIAOFAN - Shandong University; CHEN, KEYUN - Children'S Nutrition Research Center (CNRC); LIANG, QIJIAN - Shandong University; ZHANG, SHIXIU - Shandong University; ZHENG, JUAN - Huazhong University Of Science And Technology; MA, XIAOMIN - Shandong University; JIANG, HONHMRI - Shandong University; WU, HAO - Shandong University; TONG, QIANG - Children'S Nutrition Research Center (CNRC)

Submitted to: Nutrients
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/29/2022
Publication Date: 4/1/2022
Citation: Guo, X., Jiang, X., Chen, K., Liang, Q., Zhang, S., Zheng, J., Ma, X., Jiang, H., Wu, H., Tong, Q. 2022. The role of palmitoleic acid in regulating hepatic gluconeogenesis through SIRT3 in obese mice. Nutrients. 14(7). Article 1482. https://doi.org/10.3390/nu14071482.
DOI: https://doi.org/10.3390/nu14071482

Interpretive Summary: The production of glucose by the liver plays a crucial role in maintaining glucose level during starvation. However, uncontrolled glucose production by the liver contributes to elevated blood glucose in diabetic patients. Palmitoleic acid is a mono-unsaturated fatty acid that is available from dietary sources. Palmitoleic acid exhibits health beneficial effects on diabetes, inflammation, and metabolic diseases. However, the mechanism by which palmitoleic acid reduces blood glucose is still unclear. SIRT3 is a key metabolism-regulating enzyme. It is known that fasting elevates the expression of SIRT3 in the liver and it regulates many aspects of liver's response to nutrient deprivation, such as burning of the fat. However, it is unknown whether SIRT3 also regulates liver glucose production. Our study revealed that palmitoleic acid reduced liver glucose production and the expression of SIRT3 in high-fat diet fed mice. Overexpression of SIRT3 in the liver or in liver cells enhanced glucose synthesis. Further study revealed that SIRT3 enhanced the activities of three key enzymes that are involved in the synthesis of glucose. Therefore, our study indicated that under a high-fat diet, palmitoleic acid decreased liver glucose production by down-regulating the expression of SIRT3 and hence the activity of glucose-producing enzymes. Our study uncover the role of SIRT3 in the regulation of liver glucose production. We also uncover SIRT3’s role in mediating the anti-diabetic effect of palmitoleic acid. These findings may help to identify novel treatment of diabetes by palmitoleic acid supplementation or by inhibiting SIRT3.

Technical Abstract: Hepatic gluconeogenesis is a crucial process to maintain glucose level during starvation. However, unabated glucose production in diabetic patients is a major contributor to hyperglycemia. Palmitoleic acid is a monounsaturated fatty acid (16:1n7) that is available from dietary sources. Palmitoleic acid exhibits health beneficial effects on diabetes, insulin resistance, inflammation, and metabolic syndrome. However, the mechanism by which palmitoleate reduces blood glucose is still unclear. SIRT3 is a key metabolism-regulating NAD+-dependent protein deacetylase. It is known that fasting elevates the expression of SIRT3 in the liver and it regulates many aspects of liver's response to nutrient deprivation, such as fatty acid oxidation and ketone body formation. However, it is unknown whether SIRT3 also regulates gluconeogenesis. Our study revealed that palmitoleic acid reduced hepatic gluconeogenesis and the expression of SIRT3 under high-fat diet conditions. Overexpression of SIRT3 in the liver and hepatocytes enhanced gluconeogenesis. Further study revealed that SIRT3 played a role in enhancing the activities of gluconeogenic enzymes, such as PEPCK, PC, and MDH2. Therefore, our study indicated that under a high-fat diet, palmitoleic acid decreased gluconeogenesis by reducing enzymatic activities of PEPCK, PC, and MDH2 by down-regulating the expression of SIRT3.