Korean J Physiol Pharmacol.  2017 Sep;21(5):519-529. 10.4196/kjpp.2017.21.5.519.

Sodium butyrate has context-dependent actions on dipeptidyl peptidase-4 and other metabolic parameters

• Lee ES
• Lee DS
• Pandeya PR
• Kim YC
• Kang DG
• Lee HS
• Oh BC
• Lee DH

• KMID: 2388697
• DOI: http://doi.org/10.4196/kjpp.2017.21.5.519

Abstract

Sodium butyrate (SB) has various metabolic actions. However, its effect on dipeptidyl peptidase 4 (DPP-4) needs to be studied further. We aimed to evaluate the metabolic actions of SB, considering its physiologically relevant concentration. We evaluated the effect of SB on regulation of DPP-4 and its other metabolic actions, both in vitro (HepG2 cells and mouse mesangial cells) and in vivo (high fat diet [HFD]-induced obese mice). Ten-week HFD-induced obese C57BL/6J mice were subjected to SB treatment by adding SB to HFD which was maintained for an additional 16 weeks. In HepG2 cells, SB suppressed DPP-4 activity and expression at sub-molar concentrations, whereas it increased DPP-4 activity at a concentration of 1,000 µM. In HFD-induced obese mice, SB decreased blood glucose, serum levels of insulin and IL-1β, and DPP-4 activity, and suppressed the increase in body weight. On the contrary, various tissues including liver, kidney, and peripheral blood cells showed variable responses of DPP-4 to SB. Especially in the kidney, although DPP-4 activity was decreased by SB in HFD-induced obese mice, it caused an increase in mRNA expression of TNF-α, IL-6, and IL-1β. The pro-inflammatory actions of SB in the kidney of HFD-induced obese mice were recapitulated by cultured mesangial cell experiments, in which SB stimulated the secretion of several cytokines from cells. Our results showed that SB has differential actions according to its treatment dose and the type of cells and tissues. Thus, further studies are required to evaluate its therapeutic relevance in metabolic diseases including diabetes and obesity.

Keyword

Dipeptidyl peptidase 4; HepG2 cells; Mesangial cells; Obesity; Sodium butyrate

MeSH Terms

Animals
Blood Cells
Blood Glucose
Body Weight
Butyric Acid*
Cytokines
Diet
Dipeptidyl Peptidase 4
Hep G2 Cells
In Vitro Techniques
Insulin
Interleukin-6
Kidney
Liver
Mesangial Cells
Metabolic Diseases
Mice
Mice, Obese
Obesity
RNA, Messenger
Sodium*
Blood Glucose
Butyric Acid
Cytokines
Dipeptidyl Peptidase 4
Insulin
Interleukin-6
RNA, Messenger
Sodium

Figure

• 

  Fig. 1 The effects of SB on DPP-4 regulation (A~E) or acetyl-H3 and acetyl-H4 acetylation (F) in HepG2 cells.HepG2 cells were treated with SB (0, 1, 10, 100, 1,000 µM) for 72 h. DPP-4 activity was determined as described in the “Methods” section. Histone was extracted using a histone extraction kit. Data represent means±S.E. *p<0.05, **p<0.01, and ***p<0.001 vs. untreated cells.

• 

  Fig. 2 The effects of SB on DPP-4 regulation in HepG2 cells and culture medium under co-stimulation with normal or high glucose condition (A~F).HepG2 cells were treated with glucose (11 and 30 mM) for up to 8 days (A~C). HepG2 cells were treated with glucose (11 and 30 mM) for 2 days (D), 4 days (E), and 6 days (F). DPP-4 activity was determined as described in the “Methods” section. Data represent means±S.E. *p<0.05, **p<0.01 ***p<0.001 vs. glucose 11 mM treated cells. Figure

• 

  Fig. 3 The effects of SB on DPP-4 activity (A), body weight (B), blood glucose (C), and insulin secretion (D) in HFD-induced obese mice.C57BL/6J mice were fed NCD (Control, n=9) or 60% high-fat diet (HFD) for 10 weeks. Mice in the control group were fed NCD for the additional 16-week period (Control, n=9). HFD-induced obese mice were divided into two groups; the mice were kept on HFD with SB incorporated at 5% wt/wt (HFD+SB, n=9) or HFD only (HFD, n=9) for the additional 16-week period. Data represent means±S.E. *p<0.05, **p<0.01, and ***p<0.001 vs. Control group; #p<0.05, ##p<0.01, and ###p<0.001 vs. HFD group.

• 

  Fig. 4 The effects of SB on DPP-4 regulation (A, B), and TNF-α (C, G), IL1β (D, H), IL-6 (E, I), and MCP-1 (F) production in peripheral blood cells (PBCs) or serum of HFD-induced obese mice (as in Fig. 3).At 16 weeks after combination with SB in HFD-induced obese mice, the mice were sacrificed and the PBCs were collected (B~F). Data represent means±S.E. *p<0.05, **p<0.01, and ***p<0.001 vs. Control group; #p<0.05, ##p<0.01, and ###p<0.001 vs. HFD group.

• 

  Fig. 5 The effects of SB on DPP-4 regulation (A, B, G, H), and TNF-α (C, I), IL-1β (D, J), IL-6 (E, K), and MCP-1 (F, L) production in the liver or kidney tissues of HFD-induced obese mice (as in Fig. 3).Data represent means±S.E. *p<0.05, and **p<0.01 vs. Control group; #p<0.05, ##p<0.01, and ###p<0.001 vs. HFD group.

• 

  Fig. 6 The effects of SB on DPP-4 regulation (A, B), and TNF-α (C), IL-1β (D), IL-6 (E), and MCP-1 (F) production in mesangial cells.Mesangial cells were treated with SB (0, 1, 10, 100, 1,000 µM) for 72 h. Data represent means±S.E. *p<0.05, **p<0.01, and ***p<0.001 vs. untreated cells.

• 

  Fig. 7 The pathway scheme of the effects of SB on the regulation of DPP-4 as well as other differential actions in HepG2 cells, mouse mesangial cells, and HFD-induced obese mice in context-dependent manners.

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