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High-fat diet-induced adiposity, adipose inflammation, hepatic steatosis and hyperinsulinemia in outbred CD-1 mice.

Gao M, Ma Y, Liu D - PLoS ONE (2015)

Bottom Line: Increased fat accumulation in white adipose tissue subsequently led to ectopic fat deposition in brown adipose tissue, giving rise to whitening of brown adipose tissue without altering plasma level of triglyceride.Ectopic fat deposition was also observed in the liver, which was associated with elevated expression of key genes involved in hepatic lipid sequestration, including Ppar-γ2, Cd36 and Mgat1.Notably, adipose chronic inflammation and ectopic lipid deposition in the liver and brown fat were accompanied by glucose intolerance and insulin resistance, which was correlated with hyperinsulinemia and pancreatic islet hypertrophy.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, Georgia, United States of America.

ABSTRACT
High-fat diet (HFD) has been applied to a variety of inbred mouse strains to induce obesity and obesity related metabolic complications. In this study, we determined HFD induced development of metabolic disorders on outbred female CD-1 mice in a time dependent manner. Compared to mice on regular chow, HFD-fed CD-1 mice gradually gained more fat mass and consequently exhibited accelerated body weight gain, which was associated with adipocyte hypertrophy and up-regulated expression of adipose inflammatory chemokines and cytokines such as Mcp-1 and Tnf-α. Increased fat accumulation in white adipose tissue subsequently led to ectopic fat deposition in brown adipose tissue, giving rise to whitening of brown adipose tissue without altering plasma level of triglyceride. Ectopic fat deposition was also observed in the liver, which was associated with elevated expression of key genes involved in hepatic lipid sequestration, including Ppar-γ2, Cd36 and Mgat1. Notably, adipose chronic inflammation and ectopic lipid deposition in the liver and brown fat were accompanied by glucose intolerance and insulin resistance, which was correlated with hyperinsulinemia and pancreatic islet hypertrophy. Collectively, these results demonstrate sequentially the events that HFD induces physiological changes leading to metabolic disorders in an outbred mouse model more closely resembling heterogeneity of the human population.

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HFD induced hepatic steatosis.(A) Representative images of liver histological examinations. (B) Liver triglyceride determination. (C) Blood aspartate aminotransferase. (D) Blood alanine aminotransferase. Values in (B), (C) and (D) represent average ± SD (n = 4). ** P < 0.01 compared with mice on chow.
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pone.0119784.g005: HFD induced hepatic steatosis.(A) Representative images of liver histological examinations. (B) Liver triglyceride determination. (C) Blood aspartate aminotransferase. (D) Blood alanine aminotransferase. Values in (B), (C) and (D) represent average ± SD (n = 4). ** P < 0.01 compared with mice on chow.

Mentions: Obesity is usually correlated with ectopic fat deposition in the liver. To examine whether HFD caused hepatic steatosis in female CD-1 mice, we performed H&E staining and Oil-red O staining on liver sections. Fig. 5A shows HFD induced progressively enlarged vacuoles in the liver, suggesting hepatic fat deposition. This is confirmed by Oil-red O staining showing red dots in liver sections of mice fed an HFD (Fig. 5A). Biochemical determination revealed that HFD markedly elevated hepatic triglyceride by ∼3.2-fold at end of experiment (Fig. 5B). Neither AST nor ALT levels were significantly elevated by HFD feeding (Fig. 5C-D). Gene expression analysis showed that several key genes involved in hepatic lipid sequestration including Ppar-γ2, Cd36 and Mgat-1 were gradually up-regulated by an HFD (Fig. 6A-C). In addition, an elevated hepatic Fgf21 expression was observed in mice on the HFD for 12 weeks (Fig. 6D). Additionally, we determined hepatic levels of a panel of inflammatory markers, including F4/80, Cd11b, Tnfα, and Il6, and found no significant difference between mice on HFD and those on regular chow (S3 Fig.). Collectively, these results suggest that HFD induces hepatic steatosis, which is associated with elevated expression of key genes for lipid deposition.


High-fat diet-induced adiposity, adipose inflammation, hepatic steatosis and hyperinsulinemia in outbred CD-1 mice.

Gao M, Ma Y, Liu D - PLoS ONE (2015)

HFD induced hepatic steatosis.(A) Representative images of liver histological examinations. (B) Liver triglyceride determination. (C) Blood aspartate aminotransferase. (D) Blood alanine aminotransferase. Values in (B), (C) and (D) represent average ± SD (n = 4). ** P < 0.01 compared with mice on chow.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4358885&req=5

pone.0119784.g005: HFD induced hepatic steatosis.(A) Representative images of liver histological examinations. (B) Liver triglyceride determination. (C) Blood aspartate aminotransferase. (D) Blood alanine aminotransferase. Values in (B), (C) and (D) represent average ± SD (n = 4). ** P < 0.01 compared with mice on chow.
Mentions: Obesity is usually correlated with ectopic fat deposition in the liver. To examine whether HFD caused hepatic steatosis in female CD-1 mice, we performed H&E staining and Oil-red O staining on liver sections. Fig. 5A shows HFD induced progressively enlarged vacuoles in the liver, suggesting hepatic fat deposition. This is confirmed by Oil-red O staining showing red dots in liver sections of mice fed an HFD (Fig. 5A). Biochemical determination revealed that HFD markedly elevated hepatic triglyceride by ∼3.2-fold at end of experiment (Fig. 5B). Neither AST nor ALT levels were significantly elevated by HFD feeding (Fig. 5C-D). Gene expression analysis showed that several key genes involved in hepatic lipid sequestration including Ppar-γ2, Cd36 and Mgat-1 were gradually up-regulated by an HFD (Fig. 6A-C). In addition, an elevated hepatic Fgf21 expression was observed in mice on the HFD for 12 weeks (Fig. 6D). Additionally, we determined hepatic levels of a panel of inflammatory markers, including F4/80, Cd11b, Tnfα, and Il6, and found no significant difference between mice on HFD and those on regular chow (S3 Fig.). Collectively, these results suggest that HFD induces hepatic steatosis, which is associated with elevated expression of key genes for lipid deposition.

Bottom Line: Increased fat accumulation in white adipose tissue subsequently led to ectopic fat deposition in brown adipose tissue, giving rise to whitening of brown adipose tissue without altering plasma level of triglyceride.Ectopic fat deposition was also observed in the liver, which was associated with elevated expression of key genes involved in hepatic lipid sequestration, including Ppar-γ2, Cd36 and Mgat1.Notably, adipose chronic inflammation and ectopic lipid deposition in the liver and brown fat were accompanied by glucose intolerance and insulin resistance, which was correlated with hyperinsulinemia and pancreatic islet hypertrophy.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, Georgia, United States of America.

ABSTRACT
High-fat diet (HFD) has been applied to a variety of inbred mouse strains to induce obesity and obesity related metabolic complications. In this study, we determined HFD induced development of metabolic disorders on outbred female CD-1 mice in a time dependent manner. Compared to mice on regular chow, HFD-fed CD-1 mice gradually gained more fat mass and consequently exhibited accelerated body weight gain, which was associated with adipocyte hypertrophy and up-regulated expression of adipose inflammatory chemokines and cytokines such as Mcp-1 and Tnf-α. Increased fat accumulation in white adipose tissue subsequently led to ectopic fat deposition in brown adipose tissue, giving rise to whitening of brown adipose tissue without altering plasma level of triglyceride. Ectopic fat deposition was also observed in the liver, which was associated with elevated expression of key genes involved in hepatic lipid sequestration, including Ppar-γ2, Cd36 and Mgat1. Notably, adipose chronic inflammation and ectopic lipid deposition in the liver and brown fat were accompanied by glucose intolerance and insulin resistance, which was correlated with hyperinsulinemia and pancreatic islet hypertrophy. Collectively, these results demonstrate sequentially the events that HFD induces physiological changes leading to metabolic disorders in an outbred mouse model more closely resembling heterogeneity of the human population.

Show MeSH
Related in: MedlinePlus