Distinct Influence of Hypercaloric Diets Predominant with Fat or Fat and Sucrose on Adipose Tissue and Liver Inflammation in Mice.
ABSTRACT: Overfeeding of a hypercaloric diet leads to obesity, diabetes, chronic inflammation, and fatty liver disease. Although limiting fat or carbohydrate intake is the cornerstone for obesity management, whether lowering fat or reducing carbohydrate intake is more effective for health management remains controversial. This study used murine models to determine how dietary fat and carbohydrates may influence metabolic disease manifestation. Age-matched C57BL/6J mice were fed 2 hypercaloric diets with similar caloric content, one with very high fat and low carbohydrate content (VHF) and the other with moderately high fat levels with high sucrose content (HFHS) for 12 weeks. Both groups gained more weight and displayed hypercholesterolemia, hyperglycemia, hyperinsulinemia, and liver steatosis compared to mice fed a normal low-fat (LF) diet. Interestingly, the VHF-fed mice showed a more robust adipose tissue inflammation compared to HFHS-fed mice, whereas HFHS-fed mice showed liver fibrosis and inflammation that was not observed in VHF-fed mice. Taken together, these results indicate macronutrient-specific tissue inflammation with excess dietary fat provoking adipose tissue inflammation, whereas moderately high dietary fat with extra sucrose is necessary and sufficient for hepatosteatosis advancement to steatohepatitis. Hence, liver and adipose tissues respond to dietary fat and sucrose in opposite manners, yet both macronutrients are contributing factors to metabolic diseases.
Project description:Visceral adipose tissue (VAT) inflammation and metabolic dysregulation are key components of obesity-induced metabolic disease. Upregulated arginase, a ureahydrolase enzyme with two isoforms (A1-cytosolic and A2-mitochondrial), is implicated in pathologies associated with obesity and diabetes. This study examined A2 involvement in obesity-associated metabolic and vascular disorders. WT and globally deleted A2(-/-) or A1(+/-) mice were fed either a high fat/high sucrose (HFHS) diet or normal diet (ND) for 16 weeks. Increases in body and VAT weight of HFHS-fed WT mice were abrogated in A2-/-, but not A1+/-, mice. Additionally, A2-/- HFHS-fed mice exhibited higher energy expenditure, lower blood glucose, and insulin levels compared to WT HFHS mice. VAT and adipocytes from WT HFHS fed mice showed greater A2 expression and adipocyte size and reduced expression of PGC-1?, PPAR-?, and adiponectin. A2 deletion blunted these effects, increased levels of active AMPK-?, and upregulated genes involved in fatty acid metabolism. A2 deletion prevented HFHS-induced VAT collagen deposition and inflammation, which are involved in adipocyte metabolic dysfunction. Endothelium-dependent vasorelaxation, impaired by HFHS diet, was significantly preserved in A2-/- mice, but more prominently maintained in A1+/- mice. In summary, A2 is critically involved in HFHS-induced VAT inflammation and metabolic dysfunction.
Project description:Background:trans-10,cis-12 Conjugated linoleic acid (t10,c12-CLA) is a dietary supplement that promotes weight loss by increasing fat oxidation and energy expenditure. We previously reported that in the absence of t10,c12-CLA, mice forced to lose equivalent body weight by food restriction (FR) do not exhibit increases in fat oxidation or energy expenditure but have improved glucose metabolism, consistent with FR as a metabolically healthy weight-loss method. Objective:Because diet is a primary determinant of gut bacterial populations, we hypothesized that the disparate metabolic effects accompanying weight loss from t10,c12-CLA or FR could be related to altered intestinal microbiota. Methods:Ten-week-old male LDL receptor-deficient (Ldlr-/-) mice were fed a high-fat, high-sucrose diet (HFHS; 36% lard fat, 36.2% sucrose + 0.15% cholesterol) for 12 wk (baseline), then switched to the HFHS diet alone (obese control), HFHS + 1% c9,t11-CLA (obese fatty acid control), HFHS + 1% t10,c12-CLA (weight-loss-inducing fatty acid), or HFHS + FR (weight-loss control group with 75-85% ad libitum HFHS food intake) for a further 8 wk. Fecal microbial content, short-chain fatty acids (butyrate, acetate), tissue CLA concentrations, and intestinal nutrient transporter expression were quantified. Results:Mice fed t10,c12-CLA or assigned to FR lost 14.5% of baseline body weight. t10,c12-CLA-fed mice had elevated concentrations of fecal butyrate (2-fold) and plasma acetate (1.5-fold) compared with HFHS-fed controls. Fecal ? diversity decreased by 7.6-14% in all groups. Butyrivibrio and Roseburia, butyrate-producing microbes, were enriched over time by t10,c12-CLA. By comparing with each control group, we also identified bacterial genera significantly enriched in the t10,c12-CLA recipients, including Lactobacillus, Actinobacteria, and the newly identified Ileibacterium valens of the Allobaculum genus, whereas other taxa were enriched by FR, including Clostridiales and Bacteroides. Conclusion:Modalities resulting in equivalent weight loss but with divergent metabolic effects are associated with compositional differences in the mouse intestinal microbiota.
Project description:Longevity and aging are influenced by common intracellular signals of the insulin/insulin-like growth factor (IGF)-1 pathway. Abnormally high levels of bioactive IGF-1 increase the development of various cancers and may contribute to metabolic diseases such as insulin resistance. Enhanced availability of IGF-1 is promoted by cleavage of IGF binding proteins (IGFBPs) by proteases, including the pregnancy-associated plasma protein-A (PAPPA). In vitro, PAPP-A is regulated by pro-inflammatory cytokines (PICs) such as interleukin (IL)-6 and tumor necrosis factor (TNF). Mice born with deficiency of the Papp-a gene (PAPP-A knockout (KO) mice) live ~30-40 % longer than their normal littermates and have decreased bioactive IGF-1 on standard diets. Our objective was to elucidate how the effects of high-fat, high-sucrose diet (HFHS) promote obesity, induce metabolic dysfunction, and alter systemic cytokine expression in PAPP-A KO and normal mice. PAPP-A KO mice fed HFHS diet for 10 weeks were more glucose tolerant and had enhanced insulin sensitivity compared to normal mice fed HFHS diet. PAPP-A KO mice fed HFHS diet had lower levels of pro-inflammatory cytokines (IL-2, IL-6, and TNF-?) compared to normal mice fed the same diet. However, anti-inflammatory cytokine levels (IL-4 and adiponectin) were higher in PAPP-A KO mice fed HFHS diet compared to normal mice fed HFHS. Circulating PAPP-A levels were elevated in normal mice fed an HFHS diet compared to normal mice fed a standard, low-fat, low-sucrose (LFLS) diet. Indirect calorimetry showed, at 10 weeks of feeding HFHS diet, significantly increased oxygen consumption (VO2) in PAPP-A KO mice fed HFHS diet compared to normal mice fed the same diet. Furthermore, respiratory quotient (RQ) was significantly lower in PAPP-A KO mice fed HFHS diet compared to normal (N) mice fed HFHS diet indicating PAPP-A KO mice fed HFHS diet are able to rely on fat as their primary source of energy more so than normal controls. We conclude that PAPP-A KO mice are resistant to the HFHS diet induction of metabolic dysfunction associated with higher levels of anti-inflammatory cytokines and a remarkably metabolic flexible phenotype and that some of the effects of HFHS diet in normal animals may be due to increased levels of PAPP-A.
Project description:Several diseases are associated with excess of adipose tissue, and obesity is considered an independent risk factor for the development of cardiac remodeling and heart failure. Dietary aspects have been studied to elucidate the mechanisms involved in these processes. Thus, the purpose was the development and characterization of an obesity experimental model from hypercaloric diets, which resulted in cardiac remodeling and predisposition to heart failure. Thirty- day-old male Wistar rats (n = 52) were randomized into four groups: control (C), high sucrose (HS), high-fat (HF) and high-fat and sucrose (HFHS) for 20 weeks. General characteristics, comorbidities, weights of the heart, left (LV) and right ventricles, atrium, and relationships with the tibia length were evaluated. The LV myocyte cross sectional area and fraction of interstitial collagen were assayed. Cardiac function was determined by hemodynamic analysis and the contractility by cardiomyocyte contractile function. Heart failure was analyzed by pulmonary congestion, right ventricular hypertrophy, and hemodynamic parameters. HF and HFHS models led to obesity by increase in adiposity index (C = 8.3 ± 0.2% vs. HF = 10.9 ± 0.5%, HFHS = 10.2 ± 0.3%). There was no change in the morphological parameters and heart failure signals. HF and HFHS caused a reduction in times to 50% relaxation without cardiomyocyte contractile damage. The HS model presented cardiomyocyte contractile dysfunction visualized by lower shortening (C: 8.34 ± 0.32% vs. HS: 6.91 ± 0.28), as well as the Ca2+ transient amplitude was also increased when compared to HFHS. In conclusion, the experimental diets based on high amounts of sugar, lard or a combination of both did not promote cardiac remodeling with predisposition to heart failure under conditions of obesity or excess sucrose. Nevertheless, excess sucrose causes cardiomyocyte contractility dysfunction associated with alterations in the myocyte sensitivity to intracellular Ca2+.
Project description:Nonalcoholic fatty liver disease (NAFLD) is characterized by the development of steatosis, which can ultimately compromise liver function. Mitochondria are key players in obesity-induced metabolic disorders; however, the distinct role of hypercaloric diet constituents in hepatic cellular oxidative stress and metabolism is unknown. Male mice were fed either a high-fat (HF) diet, a high-sucrose (HS) diet or a combined HF plus HS (HFHS) diet for 16 weeks. This study shows that hypercaloric diets caused steatosis; however, the HFHS diet induced severe fibrotic phenotype. At the mitochondrial level, lipidomic analysis showed an increased cardiolipin content for all tested diets. Despite this, no alterations were found in the coupling efficiency of oxidative phosphorylation and neither in mitochondrial fatty acid oxidation (FAO). Consistent with unchanged mitochondrial function, no alterations in mitochondrial-induced reactive oxygen species (ROS) and antioxidant capacity were found. In contrast, the HF and HS diets caused lipid peroxidation and provoked altered antioxidant enzyme levels/activities in liver tissue. Our work provides evidence that hepatic oxidative damage may be caused by augmented levels of peroxisomes and consequently higher peroxisomal FAO-induced ROS in the early NAFLD stage. Hepatic damage is also associated with autophagic flux impairment, which was demonstrated to be diet-type dependent. The HS diet induced a reduction in autophagosomal formation, while the HF diet reduced levels of cathepsins. The accumulation of damaged organelles could instigate hepatocyte injuries and NAFLD progression.
Project description:BACKGROUND: Dietary interventions are critical in the prevention of metabolic diseases. Yet, the effects of fatty fish consumption on type 2 diabetes remain unclear. The aim of this study was to investigate whether a diet containing farmed salmon prevents or contributes to insulin resistance in mice. METHODOLOGY/PRINCIPAL FINDINGS: Adult male C57BL/6J mice were fed control diet (C), a very high-fat diet without or with farmed Atlantic salmon fillet (VHF and VHF/S, respectively), and Western diet without or with farmed Atlantic salmon fillet (WD and WD/S, respectively). Other mice were fed VHF containing farmed salmon fillet with reduced concentrations of persistent organic pollutants (VHF/S(-POPs)). We assessed body weight gain, fat mass, insulin sensitivity, glucose tolerance, ex vivo muscle glucose uptake, performed histology and immunohistochemistry analysis, and investigated gene and protein expression. In comparison with animals fed VHF and WD, consumption of both VHF/S and WD/S exaggerated insulin resistance, visceral obesity, and glucose intolerance. In addition, the ability of insulin to stimulate Akt phosphorylation and muscle glucose uptake was impaired in mice fed farmed salmon. Relative to VHF/S-fed mice, animals fed VHF/S(-POPs) had less body burdens of POPs, accumulated less visceral fat, and had reduced mRNA levels of TNF? as well as macrophage infiltration in adipose tissue. VHF/S(-POPs)-fed mice further exhibited better insulin sensitivity and glucose tolerance than mice fed VHF/S. CONCLUSIONS/SIGNIFICANCE: Our data indicate that intake of farmed salmon fillet contributes to several metabolic disorders linked to type 2 diabetes and obesity, and suggest a role of POPs in these deleterious effects. Overall, these findings may participate to improve nutritional strategies for the prevention and therapy of insulin resistance.
Project description:Responses to a high fat, high sucrose (HFHS) diet vary greatly among inbred strains of mice. We sought to examine the epigenetic (DNA methylation) changes underlying these differences as well as variation in weight loss when switched to a low-fat chow diet. We surveyed DNA methylation from livers of 45 inbred mouse strains fed a HFHS diet for 8 weeks using reduced-representation bisulfite sequencing (RRBS). We observed a total of 1,045,665 CpGs of which 83 candidate sites were significantly associated with HFHS diet. Many of these CpGs correlated strongly with gene expression or clinical traits such as body fat percentage and plasma glucose. Five inbred strains were then studied in the context of weight loss to test for evidence of epigenetic "memory." The mice were first fed a HFHS diet for 6 weeks followed by a low-fat chow diet for 4 weeks. Four of the five strains returned to initial levels of body fat while one strain, A/J, retained almost 50% of the fat gained. A total of 36 of the HFHS diet responsive CpGs exhibited evidence of persistent epigenetic modifications following weight normalization, including CpGs near the genes Scd1 and Cdk1. Our study identifies DNA methylation changes in response to a HFHS diet challenge that revert more slowly than overall body fat percentage in weight loss and provides evidence for epigenetic mediated "memory."
Project description:BACKGROUND: Polyunsaturated n-3 fatty acids (n-3 PUFAs) are reported to protect against high fat diet-induced obesity and inflammation in adipose tissue. Here we aimed to investigate if the amount of sucrose in the background diet influences the ability of n-3 PUFAs to protect against diet-induced obesity, adipose tissue inflammation and glucose intolerance. METHODOLOGY/PRINCIPAL FINDINGS: We fed C57BL/6J mice a protein- (casein) or sucrose-based high fat diet supplemented with fish oil or corn oil for 9 weeks. Irrespective of the fatty acid source, mice fed diets rich in sucrose became obese whereas mice fed high protein diets remained lean. Inclusion of sucrose in the diet also counteracted the well-known anti-inflammatory effect of fish oil in adipose tissue, but did not impair the ability of fish oil to prevent accumulation of fat in the liver. Calculation of HOMA-IR indicated that mice fed high levels of proteins remained insulin sensitive, whereas insulin sensitivity was reduced in the obese mice fed sucrose irrespectively of the fat source. We show that a high fat diet decreased glucose tolerance in the mice independently of both obesity and dietary levels of n-3 PUFAs and sucrose. Of note, increasing the protein?sucrose ratio in high fat diets decreased energy efficiency irrespective of fat source. This was accompanied by increased expression of Ppargc1a (peroxisome proliferator-activated receptor, gamma, coactivator 1 alpha) and increased gluconeogenesis in the fed state. CONCLUSIONS/SIGNIFICANCE: The background diet influence the ability of n-3 PUFAs to protect against development of obesity, glucose intolerance and adipose tissue inflammation. High levels of dietary sucrose counteract the anti-inflammatory effect of fish oil in adipose tissue and increases obesity development in mice.
Project description:OBJECTIVE:Previous studies have reported that polyphenol-rich extracts from various sources can prevent obesity and associated gastro-hepatic and metabolic disorders in diet-induced obese (DIO) mice. However, whether such extracts can reverse obesity-linked metabolic alterations remains unknown. In the present study, we aimed to investigate the potential of a polyphenol-rich extract from cranberry (CE) to reverse obesity and associated metabolic disorders in DIO-mice. METHODS:Mice were pre-fed either a Chow or a High Fat-High Sucrose (HFHS) diet for 13 weeks to induce obesity and then treated either with CE (200?mg/kg, Chow?+?CE, HFHS?+?CE) or vehicle (Chow, HFHS) for 8 additional weeks. RESULTS:CE did not reverse weight gain or fat mass accretion in Chow- or HFHS-fed mice. However, HFHS?+?CE fully reversed hepatic steatosis and this was linked to upregulation of genes involved in lipid catabolism (e.g., PPAR?) and downregulation of several pro-inflammatory genes (eg, COX2, TNF?) in the liver. These findings were associated with improved glucose tolerance and normalization of insulin sensitivity in HFHS?+?CE mice. The gut microbiota of HFHS?+?CE mice was characterized by lower Firmicutes to Bacteroidetes ratio and a drastic expansion of Akkermansia muciniphila and, to a lesser extent, of Barnesiella spp, as compared to HFHS controls. CONCLUSIONS:Taken together, our findings demonstrate that CE, without impacting body weight or adiposity, can fully reverse HFHS diet-induced insulin resistance and hepatic steatosis while triggering A. muciniphila blooming in the gut microbiota, thus underscoring the gut-liver axis as a primary target of cranberry polyphenols.
Project description:Background:Autophagy maintains metabolic homeostasis of muscles, and its impairment may cause muscle dysfunction. Exercise can improve muscle dysfunction induced by long-term high-fat diet. This study aimed to explore the association of autophagy with impaired muscle dysfunction in obese conditions and investigate its relationship with exercise-induced muscle function improvement. Methods:Male C57BL/6 mice (n=24) were randomly assigned to four groups: low-fat diet+plain water feeding sedentary (CON) group, low-fat diet+plain water feeding exercise (CON+EX) group, high-fat high-sucrose (HFHS) diet-fed sedentary group, and HFHS diet-fed exercise (HFHS+EX) group, and subjected to a single bout of exhaustive exercise. Results:HFHS diet resulted in shorter hanging time, reduced grip force, and lower exhaustion time and distance, and decreased lean mass per body weight. Moreover, in the soleus, which is chosen as a representative red (oxidative) muscle, LC3II/LC3I ratio, P62, and Bnip3 levels were altered following the HFHS diet, and were negatively correlated with muscle performance parameters; exercise significantly decreased the LC3II/LC3 ratio while P62 increased with HFHS diet. Autophagy-related protein changes were not found in the white (glycolytic) gastrocnemius. Conclusion:The study revealed that 20-week HFHS diet causes a significant increase in body weight and fat mass, along with a decrease in muscle function. Autophagy-related LC3 and P62 protein expression was negatively correlated with muscle function, and they were reduced when a single bout of exercise stimulated the soleus of obese mice. However, no change of autophagy-related proteins was seen in the gastrocnemius.