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Glycerol-3-phosphate acyltransferase 1 deficiency in ob/ob mice diminishes hepatic steatosis but does not protect against insulin resistance or obesity.

Wendel AA, Li LO, Li Y, Cline GW, Shulman GI, Coleman RA - Diabetes (2010)

Bottom Line: Hepatic steatosis is strongly associated with insulin resistance, but a causal role has not been established.Despite the reduction in hepatic lipids, fasting glucose and insulin concentrations did not improve, and insulin tolerance remained impaired.These results suggest that decreasing hepatic steatosis alone does not improve insulin resistance, and that factors other than increased hepatic DAG and TAG contribute to hepatic insulin resistance in this genetically obese model.

View Article: PubMed Central - PubMed

Affiliation: Department of Nutrition, University of North Carolina, Chapel Hill, North Carolina, USA.

ABSTRACT

Objective: Hepatic steatosis is strongly associated with insulin resistance, but a causal role has not been established. In ob/ob mice, sterol regulatory element binding protein 1 (SREBP1) mediates the induction of steatosis by upregulating target genes, including glycerol-3-phosphate acyltransferase-1 (Gpat1), which catalyzes the first and committed step in the pathway of glycerolipid synthesis. We asked whether ob/ob mice lacking Gpat1 would have reduced hepatic steatosis and improved insulin sensitivity.

Research design and methods: Hepatic lipids, insulin sensitivity, and hepatic insulin signaling were compared in lean (Lep(+/?)), lean-Gpat1(-/-), ob/ob (Lep(ob/ob)), and ob/ob-Gpat1(-/-) mice. RESULTS Compared with ob/ob mice, the lack of Gpat1 in ob/ob mice reduced hepatic triacylglycerol (TAG) and diacylglycerol (DAG) content 59 and 74%, respectively, but increased acyl-CoA levels. Despite the reduction in hepatic lipids, fasting glucose and insulin concentrations did not improve, and insulin tolerance remained impaired. In both ob/ob and ob/ob-Gpat1(-/-) mice, insulin resistance was accompanied by elevated hepatic protein kinase C-epsilon activation and blunted insulin-stimulated Akt activation.

Conclusions: These results suggest that decreasing hepatic steatosis alone does not improve insulin resistance, and that factors other than increased hepatic DAG and TAG contribute to hepatic insulin resistance in this genetically obese model. They also show that the SREBP1-mediated induction of hepatic steatosis in ob/ob mice requires Gpat1.

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Obesity-induced hepatic steatosis, but not insulin resistance, was diminished in Gpat1−/− mice. A: Representative liver sections stained with hematoxylin-eosin from 16-week-old male mice. Images are at ×100 magnification with 100 μm indicated by the white bar in upper left panel. B: Hepatic triacylglycerol content (n = 9–10). Fasting (C) glucose and (D) insulin. Insulin tolerance tests were conducted in 15-week-old male mice. Lean mice (E; n = 6–8) were given 0.5 units insulin/kg body wt by intraperitoneal injection, and ob/ob mice (F; n = 7–9) were administered 1.5 units insulin/kg body wt. Glucose was measured from tail vein blood at times indicated and net areas of the curves (insets) were calculated as described in the “research design and methods” section. Lean (Lep+/?) and ob/ob (Lepob/ob). Data are expressed as LSM ± SE. Significant differences (P < 0.05) are denoted by different letters. (A high-quality digital representation of this figure is available in the online issue.)
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Figure 2: Obesity-induced hepatic steatosis, but not insulin resistance, was diminished in Gpat1−/− mice. A: Representative liver sections stained with hematoxylin-eosin from 16-week-old male mice. Images are at ×100 magnification with 100 μm indicated by the white bar in upper left panel. B: Hepatic triacylglycerol content (n = 9–10). Fasting (C) glucose and (D) insulin. Insulin tolerance tests were conducted in 15-week-old male mice. Lean mice (E; n = 6–8) were given 0.5 units insulin/kg body wt by intraperitoneal injection, and ob/ob mice (F; n = 7–9) were administered 1.5 units insulin/kg body wt. Glucose was measured from tail vein blood at times indicated and net areas of the curves (insets) were calculated as described in the “research design and methods” section. Lean (Lep+/?) and ob/ob (Lepob/ob). Data are expressed as LSM ± SE. Significant differences (P < 0.05) are denoted by different letters. (A high-quality digital representation of this figure is available in the online issue.)

Mentions: As previously reported (28), ob/ob mice developed grossly steatotic livers with macrosteatosis and microsteatosis that weighed four times more than livers from lean littermates (Table 1) and accumulated nearly five times as much TAG (Fig. 2A and B). In ob/ob-Gpat1−/− mice, the lack of Gpat1 reduced liver weight by 28% and hepatic TAG content by 59%, evidenced by the absence of large lipid droplets. In ob/ob livers, the lipogenic genes fatty acid synthase (Fasn) and stearoyl-CoA desaturase 1 (Scd1) were increased 4- and 6.4-fold, respectively. However, neither Fasn and Scd1 nor transcription factors that regulate lipogenesis, SREBP1 (Srebf1) and ChREBP (Mlxipl), were affected by the lack of Gpat1 (supplementary Fig. 2A). Similarly, protein expression of the mature form of SREBP1 was not affected by the absence of Gpat1 (supplementary Fig. 2B). The expression of genes related to β-oxidation was not altered (supplementary Fig. 2C). Combined, these data suggest that Gpat1 appeared to be a major SREBP1 target gene causing hepatic steatosis in ob/ob mice.


Glycerol-3-phosphate acyltransferase 1 deficiency in ob/ob mice diminishes hepatic steatosis but does not protect against insulin resistance or obesity.

Wendel AA, Li LO, Li Y, Cline GW, Shulman GI, Coleman RA - Diabetes (2010)

Obesity-induced hepatic steatosis, but not insulin resistance, was diminished in Gpat1−/− mice. A: Representative liver sections stained with hematoxylin-eosin from 16-week-old male mice. Images are at ×100 magnification with 100 μm indicated by the white bar in upper left panel. B: Hepatic triacylglycerol content (n = 9–10). Fasting (C) glucose and (D) insulin. Insulin tolerance tests were conducted in 15-week-old male mice. Lean mice (E; n = 6–8) were given 0.5 units insulin/kg body wt by intraperitoneal injection, and ob/ob mice (F; n = 7–9) were administered 1.5 units insulin/kg body wt. Glucose was measured from tail vein blood at times indicated and net areas of the curves (insets) were calculated as described in the “research design and methods” section. Lean (Lep+/?) and ob/ob (Lepob/ob). Data are expressed as LSM ± SE. Significant differences (P < 0.05) are denoted by different letters. (A high-quality digital representation of this figure is available in the online issue.)
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC2874692&req=5

Figure 2: Obesity-induced hepatic steatosis, but not insulin resistance, was diminished in Gpat1−/− mice. A: Representative liver sections stained with hematoxylin-eosin from 16-week-old male mice. Images are at ×100 magnification with 100 μm indicated by the white bar in upper left panel. B: Hepatic triacylglycerol content (n = 9–10). Fasting (C) glucose and (D) insulin. Insulin tolerance tests were conducted in 15-week-old male mice. Lean mice (E; n = 6–8) were given 0.5 units insulin/kg body wt by intraperitoneal injection, and ob/ob mice (F; n = 7–9) were administered 1.5 units insulin/kg body wt. Glucose was measured from tail vein blood at times indicated and net areas of the curves (insets) were calculated as described in the “research design and methods” section. Lean (Lep+/?) and ob/ob (Lepob/ob). Data are expressed as LSM ± SE. Significant differences (P < 0.05) are denoted by different letters. (A high-quality digital representation of this figure is available in the online issue.)
Mentions: As previously reported (28), ob/ob mice developed grossly steatotic livers with macrosteatosis and microsteatosis that weighed four times more than livers from lean littermates (Table 1) and accumulated nearly five times as much TAG (Fig. 2A and B). In ob/ob-Gpat1−/− mice, the lack of Gpat1 reduced liver weight by 28% and hepatic TAG content by 59%, evidenced by the absence of large lipid droplets. In ob/ob livers, the lipogenic genes fatty acid synthase (Fasn) and stearoyl-CoA desaturase 1 (Scd1) were increased 4- and 6.4-fold, respectively. However, neither Fasn and Scd1 nor transcription factors that regulate lipogenesis, SREBP1 (Srebf1) and ChREBP (Mlxipl), were affected by the lack of Gpat1 (supplementary Fig. 2A). Similarly, protein expression of the mature form of SREBP1 was not affected by the absence of Gpat1 (supplementary Fig. 2B). The expression of genes related to β-oxidation was not altered (supplementary Fig. 2C). Combined, these data suggest that Gpat1 appeared to be a major SREBP1 target gene causing hepatic steatosis in ob/ob mice.

Bottom Line: Hepatic steatosis is strongly associated with insulin resistance, but a causal role has not been established.Despite the reduction in hepatic lipids, fasting glucose and insulin concentrations did not improve, and insulin tolerance remained impaired.These results suggest that decreasing hepatic steatosis alone does not improve insulin resistance, and that factors other than increased hepatic DAG and TAG contribute to hepatic insulin resistance in this genetically obese model.

View Article: PubMed Central - PubMed

Affiliation: Department of Nutrition, University of North Carolina, Chapel Hill, North Carolina, USA.

ABSTRACT

Objective: Hepatic steatosis is strongly associated with insulin resistance, but a causal role has not been established. In ob/ob mice, sterol regulatory element binding protein 1 (SREBP1) mediates the induction of steatosis by upregulating target genes, including glycerol-3-phosphate acyltransferase-1 (Gpat1), which catalyzes the first and committed step in the pathway of glycerolipid synthesis. We asked whether ob/ob mice lacking Gpat1 would have reduced hepatic steatosis and improved insulin sensitivity.

Research design and methods: Hepatic lipids, insulin sensitivity, and hepatic insulin signaling were compared in lean (Lep(+/?)), lean-Gpat1(-/-), ob/ob (Lep(ob/ob)), and ob/ob-Gpat1(-/-) mice. RESULTS Compared with ob/ob mice, the lack of Gpat1 in ob/ob mice reduced hepatic triacylglycerol (TAG) and diacylglycerol (DAG) content 59 and 74%, respectively, but increased acyl-CoA levels. Despite the reduction in hepatic lipids, fasting glucose and insulin concentrations did not improve, and insulin tolerance remained impaired. In both ob/ob and ob/ob-Gpat1(-/-) mice, insulin resistance was accompanied by elevated hepatic protein kinase C-epsilon activation and blunted insulin-stimulated Akt activation.

Conclusions: These results suggest that decreasing hepatic steatosis alone does not improve insulin resistance, and that factors other than increased hepatic DAG and TAG contribute to hepatic insulin resistance in this genetically obese model. They also show that the SREBP1-mediated induction of hepatic steatosis in ob/ob mice requires Gpat1.

Show MeSH
Related in: MedlinePlus