Abstract
Diets enriched in fructose (FR) increase lipogenesis in the liver, leading to hepatic lipid accumulation and the development of insulin resistance. Previously, we have shown that in contrast to other mouse strains, BALB/c mice are resistant to high fat diet-induced metabolic deterioration, potentially due to a lack of ectopic lipid accumulation in the liver. In this study we have compared the metabolic response of BALB/c and C57BL/6 (BL6) mice to a fructose-enriched diet. Both strains of mice increased adiposity in response to FR-feeding, while only BL6 mice displayed elevated hepatic triglyceride (TAG) accumulation and glucose intolerance. The lack of hepatic TAG accumulation in BALB/c mice appeared to be linked to an altered balance between lipogenic and lipolytic pathways, while the protection from fructose-induced glucose intolerance in this strain was likely related to low levels of ER stress, a slight elevation in insulin levels and an altered profile of diacylglycerol species in the liver. Collectively these findings highlight the multifactorial nature of metabolic defects that develop in response to changes in the intake of specific nutrients and the divergent response of different mouse strains to dietary challenges.
Highlights
The results suggest that the lack of excess TAG storage in BALB/c mice in response to FR-feeding is partially explained by an altered balance between lipogenesis and lipolysis, as well as potentially reduced incorporation of exogenous FA into their hepatic lipid pool
There is a large body of literature demonstrating that dietary intake of high amounts of fructose leads to fatty liver and the development of glucose intolerance and insulin resistance
The improved glucose clearance in FR-fed BALB/c mice was associated with a reduction in hepatic Endoplasmic reticulum (ER) stress markers and a mild elevation in circulating insulin levels during the glucose tolerance test (GTT)
Summary
The results suggest that the lack of excess TAG storage in BALB/c mice in response to FR-feeding is partially explained by an altered balance between lipogenesis and lipolysis, as well as potentially reduced incorporation of exogenous FA into their hepatic lipid pool This is interesting, as both mouse strains exhibit a moderate increase in the protein levels of some fatty acid uptake proteins, including fatty acid transport protein 2 (FATP2) and FATP4 (Fig. 3A). Markers of lipid metabolism and oxidative capacity were assessed to determine the potential causes of TAG accumulation In both strains there was a substantial increase in total ACC2 content after FR-feeding, while markers of fatty acid entry into muscle (measured as protein content of the fatty acid transport proteins CD36, FATP2 and FATP4) were reduced (Fig. 6A). In BL6 mice ER stress markers (phosphorylation of IRE1 and Elf2α , as well as HSP70) were significantly increased with FR-feeding, while in BALB/c mice only phosphorylation of IRE1 exhibited an increase when compared to controls (Fig. 7B)
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