(C) Activation of ER stress pathways was determined as phosphorylation status of Elf2a (E74-like factor 2a), IRE1 (Inositol-requiring enzyme-1) and JNK (c-Jun N-terminal kinase), and protein content of ATF6 (activating transcription factor 6), GRP78 (78kDa glucose-regulated protein), Chop (C/EBP homologous protein) and HSP70 (heat shock protein 70). the divergent response of different mouse strains to dietary challenges. Obesity, insulin resistance and related metabolic health issues have escalated globally to epidemic levels. One of the major factors proposed to underpin this dramatic increase in the incidence of metabolic disease is excess caloric intake. While much of the focus in this area has been on increases in lipid intake, there is accumulating evidence that diets enriched in fructose (FR) also contribute to the risks of the metabolic syndrome1. Upon dietary intake, fructose is directly transported to the liver via the portal vein, where it is able to bypass several of the control actions of glucose metabolism (including phosphofructokinase), and therefore serves as an unregulated source of both glycerol 3-phosphate and acetyl-CoA2. The liver responds to flooding with acetyl-CoA by increasing lipogenic pathways and storing excess energy in form of triglycerides3. Ectopic lipid accumulation is further accelerated by elevated malonyl-CoA levels (the product of acetyl-CoA carboxylase), which inhibits CPT1, leading to reduced entry of fatty acids into mitochondria for oxidation4. Accordingly, excess hepatic lipid storage is a key characteristic observed in both rodents and humans after acute and long-term fructose intake2, Cytochalasin H 5, 6, 7. Elevated fructose consumption is also known to adversely impact whole Cytochalasin H body glucose tolerance and insulin sensitivity (summarised in8), however the mechanisms responsible for these effects are still not completely understood. While there are some discrepancies between different studies, livers from FRfed rodents frequently exhibit (1) diacylglycerol (DAG) accumulation9, 10, 11, (2) activation Cytochalasin H of inflammatory and stress signalling pathways, including activation of c-Jun N-terminal kinases (JNK) and endoplasmic reticulum stress markers12, 13, 14, 15, 16, 17and (3) inhibition of components of the insulin signalling cascade10, 15, 17, 18, 19. Mouse strains differ in their metabolic response to high calorie diets20, 21, 22, 23, 24, and we have recently shown that BALB/c mice are protected against high-fat diet-induced glucose intolerance and insulin resistance24. This favourable metabolic phenotype of BALB/c mice was strongly related ECT2 to a lack of hepatic lipid accumulation24. Given that excess lipid deposition in the liver is a major factor driving metabolic dysfunction in response to FR-enriched diets, our goals in this study were to examine if BALB/c mice were also refractory to the metabolic defects induced by FR feeding and to additionally investigate the potential mechanisms connecting hepatic lipid accumulation with impaired glucose metabolism in this model. == Results == == Body weight, adiposity and food intake == Body weight was unchanged in Cytochalasin H FR-fed BL6 and BALB/c mice when compared to chow diet (C)-fed Cytochalasin H control mice (Fig. 1A). Adiposity, indicated as percent fat mass (measured by EchoMRI) (Fig. 1B) and by the size of the epididymal, inguinal and retroperitoneal fat pads (Table 1), was increased in both mouse strains after FR-feeding. In contrast, liver and brown adipose tissue (BAT) weight was unchanged in FR-fed mice (Table 1). Food intake was measured weekly as an average of six cages with four mice per cage for each strain. Energy intake (in kcal/day/mouse) tended to be increased in both mouse strains on the FR-diet (+8. 9% in BL6 mice and +8. 6% in BALB/c mice), although this did not reach statistical significance. == Figure 1 . Metabolic characteristics in chow- and fructose-fed BL6 and BALB/c mice. == Shown are (A) body weight, (B) fat.