The Role of Palmitoleic Acid in Regulating Hepatic Gluconeogenesis through SIRT3 in Obese Mice

Xin Guo, Xiaofan Jiang, Keyun Chen, Qijian Liang, Shixiu Zhang, Juan Zheng, Xiaomin Ma, Hongmei Jiang, Hao Wu, Qiang Tong, Xin Guo, Xiaofan Jiang, Keyun Chen, Qijian Liang, Shixiu Zhang, Juan Zheng, Xiaomin Ma, Hongmei Jiang, Hao Wu, Qiang Tong

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.

Keywords: SIRT3; gluconeogenesis; high-fat diet; palmitoleic acid.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Palmitoleic acid increases systemic glucose clearance and reduces hepatic gluconeogenesis in obese mice. C57BL/6N male mice of 5–6 weeks of age were fed with LFD (low-fat diet) or HFD (high-fat diet) for 12 weeks. At the 13th week, BSA (bovine serum albumin), oleic acid, or palmitoleic acid was administered intragastrically. At the15th, 16th, and 17th weeks, GTT (Glucose tolerance tests), ITT (insulin tolerance tests) and PTT (pyruvate tolerance) were performed, respectively. (A) GTT for LFD group. (B) Area under curve of GTT in LFD group. (C) GTT for HFD group. (D) Area under curve of GTT in HFD group. (E) ITT for LFD group. (F) Area under curve of ITT in LFD group. (G) ITT for HFD group. (H) Area under curve of ITT in HFD group. (I) PTT for LFD group. (J) Area under curve of PTT in LFD group. (K) PTT for HFD group. (L) Area under curve of PTT in HFD group. Above data: n = 6–13 mice per group. (M) HOMA-IR in LFD group. (N) HOMA-IR in HFD group. Calculated based on fasting glucose level (mmol/L) and fasting insulin level (microU/mL). For HOMA-IR: n = 4–8 mice per group. The data are mean ± s.e. (error bars). *, p < 0.05, **, p < 0.01, ***, p < 0.001, BSA vs. palmitoleic acid; †, p< 0.05, ††, p < 0.01, †††, p < 0.001, oleic acid vs. palmitoleic acid; ‡, p < 0.05, ‡‡, p < 0.01, BSA vs. oleic acid.
Figure 1
Figure 1
Palmitoleic acid increases systemic glucose clearance and reduces hepatic gluconeogenesis in obese mice. C57BL/6N male mice of 5–6 weeks of age were fed with LFD (low-fat diet) or HFD (high-fat diet) for 12 weeks. At the 13th week, BSA (bovine serum albumin), oleic acid, or palmitoleic acid was administered intragastrically. At the15th, 16th, and 17th weeks, GTT (Glucose tolerance tests), ITT (insulin tolerance tests) and PTT (pyruvate tolerance) were performed, respectively. (A) GTT for LFD group. (B) Area under curve of GTT in LFD group. (C) GTT for HFD group. (D) Area under curve of GTT in HFD group. (E) ITT for LFD group. (F) Area under curve of ITT in LFD group. (G) ITT for HFD group. (H) Area under curve of ITT in HFD group. (I) PTT for LFD group. (J) Area under curve of PTT in LFD group. (K) PTT for HFD group. (L) Area under curve of PTT in HFD group. Above data: n = 6–13 mice per group. (M) HOMA-IR in LFD group. (N) HOMA-IR in HFD group. Calculated based on fasting glucose level (mmol/L) and fasting insulin level (microU/mL). For HOMA-IR: n = 4–8 mice per group. The data are mean ± s.e. (error bars). *, p < 0.05, **, p < 0.01, ***, p < 0.001, BSA vs. palmitoleic acid; †, p< 0.05, ††, p < 0.01, †††, p < 0.001, oleic acid vs. palmitoleic acid; ‡, p < 0.05, ‡‡, p < 0.01, BSA vs. oleic acid.
Figure 2
Figure 2
Palmitoleic acid did not alter SIRT3 expression in the liver of mice under LFD. C57BL/6N male mice of 5–6 weeks of age were fed with LFD for 12 weeks. At the 13th week, BSA, oleic acid, or palmitoleic acid was administered intragastrically. At the 18th week, mice were euthanized, and liver tissue was collected. (A) Expression of SIRT3 was detected using Western blot analysis. (B) Quantification of SIRT3 expression. AU, arbitrary units. The data are mean ± s.e. (error bars). n = 5 mice per group.
Figure 3
Figure 3
Palmitoleic acid reduced the expression of SIRT3 and MDH2 but did not change the protein levels of PC, PEPCK, and SIRT1 in the liver of mice under HFD. C57BL/6N male mice of 5–6 weeks of age were fed with HFD for 12 weeks. At the 13th week, BSA, oleic acid, or palmitoleic acid were administered intragastrically. At the 18th week, mice were euthanized, and liver tissues were collected. (A) Expression of SIRT3, SIRT1, and gluconeogenic enzymes in the liver of mice under HFD. Protein expression was detected using Western blot analysis. (B) Quantification of SIRT3 protein level. (C) Quantification of PC protein level. (D) Quantification of PEPCK protein level. (E) Quantification of MDH2 protein level. (F) Quantification of SIRT1 protein level. AU, arbitrary units. The data are mean ± s.e. (error bars). n = 4–6 mice per group. *, p < 0.05, **, p < 0.01, HFD BSA vs. HFD palmitoleic acid; †, p < 0.05, oleic acid vs. palmitoleic acid.
Figure 4
Figure 4
Palmitoleic acid reduces enzymatic activities of MDH2, PC, and PEPCK under HFD. C57BL/6N male mice of 5–6 weeks of age were fed with LFD or HFD for 12 weeks. At the 13th week, BSA, oleic acid, or palmitoleic acid was administered intragastrically. At the 18th week, mice were sacrificed, and liver tissue was collected. The enzyme activities of MDH2, PC, and PEPCK in the liver were measured. (A) Enzymatic activity of MDH2 in the liver of HFD-fed mice. (B) Enzymatic activity of PC in the liver of HFD-fed mice. (C) Enzymatic activity of PEPCK in the liver of HFD-fed mice. The data are mean ± s.e. (error bars). n = 4–7 mice per group. *, p < 0.05, **, p < 0.01, HFD BSA vs. HFD palmitoleic acid; ††, p < 0.01, †††, p < 0.001, HFD oleic acid vs. HFD palmitoleic acid.
Figure 5
Figure 5
Liver-specific SIRT3 overexpression increases gluconeogenesis. C57BL/6N male mice of 5–6 weeks of age were injected with AAV-GFP or AAV-SIRT3 via a tail vein and fed with LFD or HFD for 12 weeks, respectively. At the 13th week, PTT was performed. At the 14th week of feeding, mice were euthanized, and liver tissues were collected. (A) Protein level of SIRT3 in liver. (B) RNA level of SIRT3 in liver. (C) Protein level of SIRT3 in adipose tissue. (D) Quantification of SIRT3 protein level in adipose tissue. (E) Protein level of SIRT3 in muscle. (F) Quantification of SIRT3 protein level in muscle. The data are mean ± s.e. (error bars). n = 6 mice per group. **, p < 0.01, AAV-GFP vs. AAV-SIRT3. (G) PTT. Mice were fasted overnight and intraperitoneally injected with pyruvate (2 g/kg). Blood glucose levels were measured before injection and 15, 30, 60, and 120 min after injection. (H) Area under curve of PTT. The data are mean ± s.e. (error bars). n = 6–9 mice per group. §, p < 0.05, LFD AAV-SIRT3 vs. HFD AAV-SIRT3; *, p < 0.05, **, p < 0.01, ***, p < 0.001, LFD AAV-GFP vs. HFD AAV-GFP; ‡, p < 0.05, ‡‡‡, p < 0.001, LFD AAV-GFP vs. LFD AAV-SIRT3; †, p < 0.05, ††, p < 0.01, HFD AAV-GFP vs. HFD AAV-SIRT3.
Figure 6
Figure 6
Liver-specific SIRT3 overexpression increases MDH2 protein levels in mice. C57BL/6N male mice of 5–6 weeks of age were injected with AAV-GFP or AAV-SIRT3 via a tail vein and fed with LFD or HFD for 12 weeks. At the 14th week of feeding, mice were euthanized, and the liver tissues were collected. (A) Expression of SIRT3 and the levels of gluconeogenic-related enzymes in the liver. (B) Quantitative the expression of PEPCK protein level. (C) Quantitative the expression of PC protein level. (D) Quantification the expression of MDH2 protein level. AU, arbitrary units. The data are mean ± s.e. (error bars). n = 6 mice per group. *, p < 0.05, LFD AAV-GFP vs. HFD AAV-GFP; ‡, p < 0.05, LFD AAV-GFP vs. LFD AAV-SIRT3.
Figure 7
Figure 7
SIRT3 overexpression increases the activities of gluconeogenic enzymes. C57BL/6N male mice of 5–6 weeks of age were injected with AAV-GFP or AAV-SIRT3 via a tail vein and fed with LFD or HFD for 12 weeks. At the 14th week of feeding, mice were euthanized, and the liver tissues were collected. (A) Enzymatic activity of MDH2. (B) Enzymatic activity of PC. (C) Enzymatic activity of PEPCK. The data are mean ± s.e. (error bars). n = 4–7 mice per group *, p < 0.05, LFD AAV-GFP vs. HFD AAV-GFP; ‡, p < 0.05, ‡‡, p < 0.01, LFD AAV-GFP vs. LFD AAV-SIRT3; †, p < 0.05, ††, p < 0.01, HFD AAV-GFP vs. HFD AAV-SIRT3.
Figure 8
Figure 8
SIRT3 overexpression increases glucose production and the protein level of MDH2 in primary hepatocytes. Primary hepatocytes from HFD or LFD mice were isolated and infected with Ad-GFP or Ad-SIRT3 adenovirus. (A) Infection status after 48 h as fluorescent detection of GFP. (B) Glucose production from primary hepatocytes. In the presence of substrates (20 mM lactic acid and 2 mM pyruvate), the primary hepatocytes were stimulated with 100 nM glucagon for 3 h with or without 50 uM 3-TYP treatment for 24 h. a, p < 0.05, LFD Ad-GFP vs. LFD Ad-GFP+3-TYP; b, p < 0.05, LFD Ad-GFP vs. LFD Ad-SIRT3; c, p < 0.05, LFD Ad-GFP+3-TYP vs. LFD Ad-SIRT3; d, p <0.05, LFD Ad-GFP vs. HFD Ad-GFP; e, p < 0.05, HFD Ad-GFP vs. HFD Ad-GFP+3-TYP; f, p < 0.05, HFD Ad-GFP vs. HFD Ad-SIRT3; g, p < 0.01, HFD Ad-GFP+3-TYP vs. HFD Ad-SIRT3. (C) SIRT3, PC and MDH2 protein levels. Primary hepatocytes infected with adenovirus were treated with DMSO or 3-TYP for 24 h and 100 nM glucagon for 1 h. Cells were collected for protein extraction. Western blot analysis was used to detect the expression of SIRT3, PC, and MDH2. *, p < 0.05, LFD Ad-GFP vs. LFD Ad-SIRT3; ††, p < 0.01 HFD Ad-GFP vs. HFD Ad-SIRT3. The data are mean ± s.e. (error bars). n = 5 from three independent experiments.
Figure 9
Figure 9
Palmitoleic acid reverses the increase in gluconeogenesis caused by SIRT3 overexpression in primary hepatocytes. Primary hepatocytes from mice fed with HFD were isolated and infected with Ad-GFP or Ad-SIRT3 adenovirus. Ad-SIRT3-infected hepatocytes were also treated with palmitoleic acid for 48 h. (A) Glucose production from primary hepatocytes. In the presence of substrates (20 mM lactic acid and 2 mM pyruvate), the primary hepatocytes were stimulated with 100 nM glucagon for 3 h to detect the content of glucose in the medium. (B) SIRT3, PC, and MDH2 protein levels were detected using Western blot analysis. The data are mean ± s.e. (error bars). n = 6 from three independent experiments. *, p < 0.05, HFD Ad-GFP vs. HFD Ad-SIRT3; †, p < 0.05 HFD Ad-SIRT3 vs. HFD Ad-SIRT3+PO (palmitoleic acid).

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Source: PubMed

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