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. 2013 Sep 2;2(4):457-67.
doi: 10.1016/j.molmet.2013.08.007. eCollection 2013.

Cholesteryl ester transfer protein protects against insulin resistance in obese female mice

David A Cappel  1 , Brian T Palmisano, Christopher H Emfinger, Melissa N Martinez, Owen P McGuinness, John M Stafford
Affiliations

Cholesteryl ester transfer protein protects against insulin resistance in obese female mice

David A Cappel et al. Mol Metab. .

Abstract

Cholesteryl ester transfer protein (CETP) shuttles lipids between lipoproteins, culminating in cholesteryl ester delivery to liver and increased secretion of cholesterol as bile. Since gut bile acids promote insulin sensitivity, we aimed to define if CETP improves insulin sensitivity with high-fat feeding. CETP and nontransgenic mice of both sexes became obese. Female but not male CETP mice had increased ileal bile acid levels versus nontransgenic littermates. CETP expression protected female mice from insulin resistance but had a minimal effect in males. In liver, female CETP mice showed activation of bile acid-sensitive pathways including Erk1/2 phosphorylation and Fxr and Shp gene expression. In muscle, CETP females showed increased glycolysis, increased mRNA for Dio2, and increased Akt phosphorylation, known effects of bile acid signaling. These results suggest that CETP can ameliorate insulin resistance associated with obesity in female mice, an effect that correlates with increased gut bile acids and known bile-signaling pathways.

Keywords: Bile; Cholesterol; Glucose; Insulin resistance; Obesity; Sex-differences.

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Figures

Figure 1
Figure 1
CETP expression alters serum cholesterol and ileal bile acids in obese mice. (A) CETP activity in WT littermates and CETP-transgenic males. (B) Adiposity before (−) and after (+) high-fat diet in male mice. (C) Serum cholesterol in male mice. (D) Total ileal bile acids in male mice. (E) CETP activity in WT littermates and CETP-transgenic females. (F) Adiposity before (−) and after (+) high-fat diet in female mice. (G) Serum cholesterol in female mice. (H) Total ileal bile acids in female mice. Data represent the mean±SEM from n=6–8 animals per group, *p<0.05.
Figure 2
Figure 2
CETP expression decreases fasting plasma insulin in female mice. (A) Fasting blood glucose in male mice. (B) Fasting plasma insulin in male mice. (C) Fasting blood glucose in female mice. (D) Fasting plasma insulin in female mice. Data represent the mean±SEM from n=6–8 animals per group, *p<0.05.
Figure 3
Figure 3
CETP expression protects female mice against diet-induced insulin resistance. (A) Hyperinsulinemic-euglycemic clamp study design. (B) Clamp blood glucose in HFD-fed males. (C) Glucose infusion rate (GIR) required to maintain euglycemia during hyperinsulinemic clamp in HFD-fed males. (D) Insulin sensitivity index based on steady-state GIR/insulin for HFD-fed males. (E) Clamp blood glucose in HFD-fed females. (F) GIR for HFD-fed females. (G) Insulin sensitivity index for HFD-fed females. (H) Blood glucose during clamp in chow-fed females. (I) GIR for chow-fed females. (J) Insulin sensitivity index for chow-fed females. Data represent the mean±SEM from n=6–8 animals per group, *p<0.05.
Figure 4
Figure 4
CETP expression alters hepatic insulin signaling and bile acid signal related gene expression. (A) Immunoblot analysis of Akt, P-Akt (S-473), Erk1/2, P-Erk1/2, and actin in liver whole-cell extract from fasted and clamped CETP and WT female mice on a high fat diet. (B) Quantification of P-Akt to Akt ratio. (C) Quantification of P-Erk1/2 to Erk1/2 ratio. (D) Gene expression for genes whose products control glucose metabolism, bile acid metabolism, and gene transcription determined by qRT-PCR from hepatic RNA. Data represents the mean±SEM from n=4 animals per group. Asterix (*) indicates p<0.05 for insulin-treated versus fasted, brackets (a) indicate statistical significance (p<0.05) for genotype effect by 2-way ANOVA.
Figure 5
Figure 5
CETP-expressing mice on a high-fat diet display improved muscle insulin signaling and altered glucose metabolism. (A) Immunoblot analysis of Akt, P-Akt (S-473), and actin in muscle whole-cell extract from fasted and clamped CETP and WT female mice. (B) Quantification of P-Akt to Akt ratio. (C) Metabolite analysis of glycolytic and TCA cycle intermediates in muscle of fasted CETP and WT female mice. (D) Schematic representation of changes in glycolytic and TCA cycle intermediates. (E) Gene expression for Dio2, Cpt1b, and Hk2 determined by qRT-PCR from muscle RNA extracts. (F) Respiratory quotient determined by indirect calorimetry for HFD fed CETP and WT female mice. Data represent the mean±SEM from n=4 animals per group, except for (F) which is n=3 animals per group. *p<0.05.
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