Abstract
20-Hydroxyeicosatetraenoic acid (20-HETE) has been shown to positively correlate with body mass index, hyperglycemia, and plasma insulin levels. This study seeks to identify a causal relationship between 20-HETE and obesity-driven insulin resistance. Cyp4a14–/– male mice, a model of 20-HETE overproduction, were fed a regular or high-fat diet (HFD) for 15 wk. 20-SOLA [2,5,8, 11,14,17-hexaoxanonadecan-19-yl 20-hydroxyeicosa-6(Z),15(Z)-dienoate], a 20-HETE antagonist, was administered from week 0 or week 7 of HFD. HFD-fed mice gained significant weight (16.7 ± 3.2 vs. 3.8 ± 0.35 g, P < 0.05) and developed hyperglycemia (157 ± 3 vs. 121 ± 7 mg/dl, P < 0.05) and hyperinsulinemia (2.3 ± 0.4 vs. 0.5 ± 0.1 ng/ml, P < 0.05) compared with regular diet-fed mice. 20-SOLA attenuated HFD-induced weight gain (9.4 ± 1 vs. 16.7 ± 3g, P < 0.05) and normalized the hyperglycemia (157 ± 7 vs. 102 ± 5 mg/dl, P < 0.05) and hyperinsulinemia (1.1 ± 0.1 vs. 2.3 ± 0.4 ng/ml, P < 0.05). The impaired glucose homeostasis and insulin resistance in HFD-fed mice evidenced by reduced insulin and glucose tolerance were also ameliorated by 20-SOLA. Circulatory and adipose tissue 20-HETE levels significantly increased in HFD-fed mice correlating with impaired insulin signaling, including reduction in insulin receptor tyrosine (Y972) phosphorylation and increased serine (S307) phosphorylation of the insulin receptor substrate-1 (IRS-1). 20-SOLA treatments prevented changes in insulin signaling. These findings indicate that 20-HETE contributes to HFD-induced obesity, insulin resistance, and impaired insulin signaling.
| Original language | English (US) |
|---|---|
| Pages (from-to) | R934-R944 |
| Journal | American Journal of Physiology - Regulatory Integrative and Comparative Physiology |
| Volume | 315 |
| Issue number | 5 |
| DOIs | |
| State | Published - Nov 1 2018 |
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Keywords
- Hyperglycemia
- Hyperinsulinemia
- Insulin resistance
- Obesity
ASJC Scopus subject areas
- Physiology
- Physiology (medical)
Cite this
High-fat diet-induced obesity and insulin resistance in CYP4A14–/– mice is mediated by 20-HETE. / Gilani, Ankit; Pandey, Varunkumar; Garcia, Victor; Agostinucci, Kevin; Singh, Shailendra P.; Schragenheim, Joseph; Bellner, Lars; Falck, J R; Paudyal, Mahesh P.; Capdevila, Jorge H.; Abraham, Nader G.; Laniado Schwartzman, Michal.
In: American Journal of Physiology - Regulatory Integrative and Comparative Physiology, Vol. 315, No. 5, 01.11.2018, p. R934-R944.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - High-fat diet-induced obesity and insulin resistance in CYP4A14–/– mice is mediated by 20-HETE
AU - Gilani, Ankit
AU - Pandey, Varunkumar
AU - Garcia, Victor
AU - Agostinucci, Kevin
AU - Singh, Shailendra P.
AU - Schragenheim, Joseph
AU - Bellner, Lars
AU - Falck, J R
AU - Paudyal, Mahesh P.
AU - Capdevila, Jorge H.
AU - Abraham, Nader G.
AU - Laniado Schwartzman, Michal
PY - 2018/11/1
Y1 - 2018/11/1
N2 - 20-Hydroxyeicosatetraenoic acid (20-HETE) has been shown to positively correlate with body mass index, hyperglycemia, and plasma insulin levels. This study seeks to identify a causal relationship between 20-HETE and obesity-driven insulin resistance. Cyp4a14–/– male mice, a model of 20-HETE overproduction, were fed a regular or high-fat diet (HFD) for 15 wk. 20-SOLA [2,5,8, 11,14,17-hexaoxanonadecan-19-yl 20-hydroxyeicosa-6(Z),15(Z)-dienoate], a 20-HETE antagonist, was administered from week 0 or week 7 of HFD. HFD-fed mice gained significant weight (16.7 ± 3.2 vs. 3.8 ± 0.35 g, P < 0.05) and developed hyperglycemia (157 ± 3 vs. 121 ± 7 mg/dl, P < 0.05) and hyperinsulinemia (2.3 ± 0.4 vs. 0.5 ± 0.1 ng/ml, P < 0.05) compared with regular diet-fed mice. 20-SOLA attenuated HFD-induced weight gain (9.4 ± 1 vs. 16.7 ± 3g, P < 0.05) and normalized the hyperglycemia (157 ± 7 vs. 102 ± 5 mg/dl, P < 0.05) and hyperinsulinemia (1.1 ± 0.1 vs. 2.3 ± 0.4 ng/ml, P < 0.05). The impaired glucose homeostasis and insulin resistance in HFD-fed mice evidenced by reduced insulin and glucose tolerance were also ameliorated by 20-SOLA. Circulatory and adipose tissue 20-HETE levels significantly increased in HFD-fed mice correlating with impaired insulin signaling, including reduction in insulin receptor tyrosine (Y972) phosphorylation and increased serine (S307) phosphorylation of the insulin receptor substrate-1 (IRS-1). 20-SOLA treatments prevented changes in insulin signaling. These findings indicate that 20-HETE contributes to HFD-induced obesity, insulin resistance, and impaired insulin signaling.
AB - 20-Hydroxyeicosatetraenoic acid (20-HETE) has been shown to positively correlate with body mass index, hyperglycemia, and plasma insulin levels. This study seeks to identify a causal relationship between 20-HETE and obesity-driven insulin resistance. Cyp4a14–/– male mice, a model of 20-HETE overproduction, were fed a regular or high-fat diet (HFD) for 15 wk. 20-SOLA [2,5,8, 11,14,17-hexaoxanonadecan-19-yl 20-hydroxyeicosa-6(Z),15(Z)-dienoate], a 20-HETE antagonist, was administered from week 0 or week 7 of HFD. HFD-fed mice gained significant weight (16.7 ± 3.2 vs. 3.8 ± 0.35 g, P < 0.05) and developed hyperglycemia (157 ± 3 vs. 121 ± 7 mg/dl, P < 0.05) and hyperinsulinemia (2.3 ± 0.4 vs. 0.5 ± 0.1 ng/ml, P < 0.05) compared with regular diet-fed mice. 20-SOLA attenuated HFD-induced weight gain (9.4 ± 1 vs. 16.7 ± 3g, P < 0.05) and normalized the hyperglycemia (157 ± 7 vs. 102 ± 5 mg/dl, P < 0.05) and hyperinsulinemia (1.1 ± 0.1 vs. 2.3 ± 0.4 ng/ml, P < 0.05). The impaired glucose homeostasis and insulin resistance in HFD-fed mice evidenced by reduced insulin and glucose tolerance were also ameliorated by 20-SOLA. Circulatory and adipose tissue 20-HETE levels significantly increased in HFD-fed mice correlating with impaired insulin signaling, including reduction in insulin receptor tyrosine (Y972) phosphorylation and increased serine (S307) phosphorylation of the insulin receptor substrate-1 (IRS-1). 20-SOLA treatments prevented changes in insulin signaling. These findings indicate that 20-HETE contributes to HFD-induced obesity, insulin resistance, and impaired insulin signaling.
KW - Hyperglycemia
KW - Hyperinsulinemia
KW - Insulin resistance
KW - Obesity
UR - http://www.scopus.com/inward/record.url?scp=85055971898&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85055971898&partnerID=8YFLogxK
U2 - 10.1152/ajpregu.00125.2018
DO - 10.1152/ajpregu.00125.2018
M3 - Article
VL - 315
SP - R934-R944
JO - American Journal of Physiology - Heart and Circulatory Physiology
JF - American Journal of Physiology - Heart and Circulatory Physiology
SN - 0363-6135
IS - 5
ER -