Direct comparison of metabolic health effects of the flavonoids quercetin,hesperetin, epicatechin,apigenin and anthocyanins in high-fat-diet-fed mice

Dietary flavonoid intake is associated with reduced risk of cardiovascular diseases, possibly by affecting metabolic health. The relative potency of different flavonoids in causing beneficial effects on energy and lipid metabolism has not been investigated. Effects of quercetin, hesperetin, epicatechin, apigenin and anthocyanins in mice fed a high-fat diet (HF) for 12 weeks were compared, relative to normal-fat diet. HF-induced body weight gain was significantly lowered by all flavonoids (17–29 %), but most by quercetin. Quercetin significantly lowered HF-induced hepatic lipid accumulation (71 %). Mesenteric adipose tissue weight and serum leptin levels were significantly lowered by quercetin, hesperetin and anthocyanins. Adipocyte cell size and adipose tissue inflammation were not affected. The effect on body weight and composition could not be explained by individual significant effects on energy intake, energy expenditure or activity. Lipid metabolism was not changed as measured by indirect calorimetry or expression of known lipid metabolic genes in liver and white adipose tissue. Hepatic expression of Cyp2b9 was strongly downregulated by all flavonoids. In conclusion, all flavonoids lowered parameters of HF-induced adiposity, with quercetin being most effective.

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Antihyperlipidemic potential of diosmin in Swiss Albino mice with high-fat diet induced hyperlipidemia

The aim of this study was to investigate the antihyperlipidemic potential of Diosmin (DS) in mice fed with a high-fat diet (HFD). Animals were divided in five groups (n = 6). The total duration of the study was 90 days split into two intervals. During the first 45-day interval, mice were administered with HFD, whereas during the second 45-day interval they were co-administered HFD plus DS or the standard drug atorvastatin. DS was administered at the dose of 100 and 200 mg/kg;p.o. DS treatment to HFD-induced hyperlipidemic mice caused significant decrements in the levels of total cholesterol, triglycerides, LDL-C and VLDL-C. Moreover, DS resulted in significant increase in the levels of HDL-C and improvements in total protein levels, whereas it caused remarkable decreases in SGOT, SGPT and ALP enzymatic activities in hyperlipidemic mice. Histopathological examination of hyperlipidemic mice revealed a disorganized hepatic tissue, fatty changes, and mononuclear cell infiltration, which were all ameliorated by DS administration. The results revealed that DS possesses potential ameliorating benefits again.st hyperlipidemia induced by HFD on lipid profile, liver function enzymes and hepatic histoarchitecture. Further investigations are highly recommended and clinical trials are warranted in order to assess the efficacy and to fully dissect the mode-of-action underpinning the observed antihyperlipidemic effect of DS.     

Sub-chronic administration of stable GIP analog in mice decreases serum LPL activity and body weight

GIP receptor knockout mice were shown to be protected from the development of obesity on a high fat diet, suggesting a role of GIP in the development of obesity. In our study we aimed to test the hypothesis if excess of GIP could accelerate development of obesity and to identify GIP gene targets in adipose tissue. Therefore, mice were kept on a chow or a high fat diet and during the last 2 weeks D-Ala²-GIP or PBS injections were performed. Afterwards, serum LPL activity and several biochemical parameters (TG, FFA, cholesterol, glucose, insulin, resistin, IL-6, IL-1β, TNFα, GIP) were measured. Fat tissue was isolated and QPCR was performed for a set of genes involved in energy metabolism and inflammation. A DNA-microarray was used to identify GIP gene targets in adipose tissue of the chow diet group. We found that the D-Ala²-GIP injections caused a significant decrease in both body weight and LPL activity compared to controls. Serum biochemical parameters were not affected by D-Ala²-GIP, with an exception for resistin and insulin. The set of inflammatory genes were significantly decreased in adipose tissue in the D-Ala²-GIP injected animals on a chow diet. A DNA-microarray revealed that APO-genes and CYP-genes were affected by D-Ala²-GIP treatment in adipose tissue. These results suggest that the body weight-reducing effect of D-Ala²-GIP may be explained by lower LPL activity and insulin serum level. Moreover, the identified GIP candidate gene targets in adipose tissue link GIP action to lipid metabolism exerted by APO and CYP genes.     

A high-fat diet and high-fat and high-cholesterol diet may affect glucose and lipid metabolism differentially through gut microbiota in mice

This study was conducted to investigate the effects of a high-fat diet (HFD) and high-fat and high-cholesterol diet (HFHCD) on glucose and lipid metabolism and on the intestinal microbiota of the host animal. A total of 30 four-week-old female C57BL/6 mice were randomly divided into three groups (n=10) and fed with a normal diet (ND), HFD, or HFHCD for 12 weeks, respectively. The HFD significantly increased body weight and visceral adipose accumulation and partly lowered oral glucose tolerance compared with the ND and HFHCD. The HFHCD increased liver weight, liver fat infiltration, liver triglycerides, and liver total cholesterol compared with the ND and HFD. Moreover, it increased serum high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and total cholesterol compared with the ND and HFD and upregulated alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase significantly. The HFHCD also significantly decreased the α-diversity of the fecal bacteria of the mice, to a greater extent than the HFD. The composition of fecal bacteria among the three groups was apparently different. Compared with the HFHCD-fed mice, the HFD-fed mice had more Oscillospira, Odoribacter, Bacteroides, and [Prevotella], but less [Ruminococcus] and Akkermansia. Cecal short-chain fatty acids were significantly decreased after the mice were fed the HFD or HFHCD for 12 weeks. Our findings indicate that an HFD and HFHCD can alter the glucose and lipid metabolism of the host animal differentially; modifications of intestinal microbiota and their metabolites may be an important underlying mechanism.     

Factors predicting nongenetic variability in body weight gain induced by a high-fat diet in inbred C57BL/6J mice

Inbred C57BL/6J mice displayed large individual variations in weight gain when fed a high-fat diet (HFD). The objective of this study was to examine whether this predominantly nongenetic variability could be predicted by relevant baseline features and to explore whether variations in these significant features were influenced during pregnancy and/or lactation. Fat mass (FM), fat-free mass (FFM), food intake (FI), resting metabolic rate (RMR), physical activity (PA), and body temperature (T(b)) were all evaluated at baseline in 60 mice (aged 10-12 weeks) before HFD feeding. Regression analyses showed that baseline FM was a strong positive predictor of weight gain between 4 and 16 weeks of HFD. Baseline PA was negatively associated with weight gain at week 8, 12, and 16, and baseline FFM had a positive effect at week 12 and 16. In a second experiment, 40 female mice were mated and litter sizes (LS) were manipulated on day 3 of lactation. Weaning weight and postweaning growth rate (GR) had positive impacts on FM and FFM at age 9 weeks (FM, P = 0.001; FFM, P < 0.001: n = 97). Lactation LS had a negative effect on weaning weight and a positive effect on postweaning GR. In conclusion, our results show that obesity induced by HFD was associated with a higher baseline FM, a higher baseline FFM and a lower baseline PA level before the exposure of HFD. Two of these traits (FM and FFM) were influenced by lactation LS via weaning weight and postweaning GR.     

Deficiency of MGAT2 increases energy expenditure without high-fat feeding and protects genetically obese mice from excessive weight gain

Acyl CoA:monoacylglycerol acyltransferase 2 (MGAT2) is thought to be crucial for dietary fat absorption. Indeed, mice lacking the enzyme (Mogat2(-/-)) are resistant to obesity and other metabolic disorders induced by high-fat feeding. However, these mice absorb normal quantities of fat. To explore whether a high level of dietary fat is an essential part of the underlying mechanism(s), we examined metabolic responses of Mogat2(-/-) mice to diets containing varying levels of fat. Mogat2(-/-) mice exhibited 10-15% increases in energy expenditure compared with wild-type littermates; although high levels of dietary fat exacerbated the effect, this phenotype was expressed even on a fat-free diet. When deprived of food, Mogat2(-/-) mice expended energy and lost weight like wild-type controls. To determine whether MGAT2 deficiency protects against obesity in the absence of high-fat feeding, we crossed Mogat2(-/-) mice with genetically obese Agouti mice. MGAT2 deficiency increased energy expenditure and prevented these mice from gaining excess weight. Our results suggest that MGAT2 modulates energy expenditure through multiple mechanisms, including one independent of dietary fat; these findings also raise the prospect of inhibiting MGAT2 as a strategy for combating obesity and related metabolic disorders resulting from excessive calorie intake.     

Mulberry leaves (Morus alba L.) ameliorate obesity-induced hepatic lipogenesis,fibrosis, and oxidative stress in high-fat diet-fed mice

Obesity is associated with chronic diseases such as fatty liver, type 2 diabetes, cardiovascular disease, and severe metabolic syndrome. Obesity causes metabolic impairment including excessive lipid accumulation and fibrosis in the hepatic tissue as well as the increase in oxidative stress. In order to investigate the effect of mulberry leaf (Morus alba L.) extract (MLE) on obesity-induced oxidative stress, lipogenesis, and fibrosis in liver, MLE has been gavaged for 12 weeks in high-fat diet (HFD)-induced obese mice. MLE treatment significantly ameliorated LXRα-mediated lipogenesis and hepatic fibrosis markers such as α-smooth muscle actin, while MLE up-regulated lipolysis-associated markers such as lipoprotein lipase in the HFD-fed mice. Moreover, MLE normalized the activities of antioxidant enzymes including heme oxygenase-1 and glutathione peroxidase in accordance with protein levels of 4-hydroxynonenal in the HFD-fed mice. MLE has beneficial effects on obesity-related fatty liver disease by regulation of hepatic lipid metabolism, fibrosis, and antioxidant defense system. MLE supplementation might be a potential therapeutic approach for obesity-related disease including non-alcoholic fatty liver disease.     

Genetic disruption of protein phosphatase 5 in mice prevents high-fat diet feeding-induced weight gain

The role of serine/threonine protein phosphatase 5 (PP5) in the development of obesity and insulin resistance associated with high-fat diet-feeding (HFD) was examined using PP5-deficient mice (Ppp5c^−/−). Despite similar caloric intake, Ppp5c^−/− mice on HFD gained markedly less weight and did not accumulate visceral fat compared to wild-type littermates (Ppp5c^+/+). On a control diet, Ppp5c^−/− mice had markedly improved glucose control compared to Ppp5c^+/+ mice, an effect diminished by HFD. However, even after 10 weeks of HFD glucose control in Ppp5c^−/− mice was similar to that observed in Ppp5c^+/+ mice on the control diet. Thus, PP5 deficiency confers protection against HFD-induced weight gain in mice.     

Administration of a maple syrup extract to mitigate their hepatic inflammation induced by a high-fat diet: a transcriptome analysis

Effects of the administration of maple syrup extract (MSX) on hepatic gene expression were investigated in mice fed a high-fat diet. Gene annotation enrichment analysis based on gene ontology revealed some changes in the expression of genes related to lipid metabolism and the immune response in MSX-fed mice. Detailed analysis of these data indicated that MSX ingestion mitigates hepatic inflammation.     

A high-fat diet suppresses de novo lipogenesis and desaturation but not elongation and triglyceride synthesis in mice

Intracellular lipids and their synthesis contribute to the mechanisms and complications of obesity-associated diseases. We describe an NMR approach that provides an abbreviated lipidomic analysis with concurrent lipid biosynthetic fluxes. Following deuterated water administration, positional isotopomer analysis by deuterium NMR of specific lipid species was used to examine flux through de novo lipogenesis (DNL), FA elongation, desaturation, and TG-glycerol synthesis. The NMR method obviated certain assumptions regarding sites of enrichment and exchangeable hydrogens required by mass isotope methods. The approach was responsive to genetic and pharmacological gain or loss of function of DNL, elongation, desaturation, and glyceride synthesis. BDF1 mice consuming a high-fat diet (HFD) or matched low-fat diet for 35 weeks were examined across feeding periods to determine how flux through these pathways contributes to diet induced fatty liver and obesity. HFD mice had increased rates of FA elongation and glyceride synthesis. However DNL was markedly suppressed despite insulin resistance and obesity. We conclude that most hepatic TGs in the liver of HFD mice were formed from the reesterification of existing or ingested lipids, not DNL.     

Mechanisms of hepatic steatosis in mice fed a lipogenic methionine choline-deficient diet

The methionine choline-deficient (MCD) diet results in liver injury similar to human nonalcoholic steatohepatitis (NASH). The aims of this study were to define mechanisms of MCD-induced steatosis in insulin-resistant db/db and insulin-sensitive db/m mice. MCD-fed db/db mice developed more hepatic steatosis and retained more insulin resistance than MCD-fed db/m mice. Both subcutaneous and gonadal fat were reduced by MCD feeding: gonadal fat decreased by 23% in db/db mice and by 90% in db/m mice. Weight loss was attenuated in the db/db mice, being only 13% compared with 35% in MCD-fed db/db and db/m mice, respectively. Both strains had upregulation of hepatic fatty acid transport proteins as well as increased hepatic uptake of [14C]oleic acid: 3-fold in db/m mice (P < 0.001) and 2-fold in db/db mice (P < 0.01) after 4 weeks of MCD feeding. In both murine strains, the MCD diet reduced triglyceride secretion and downregulated genes involved in triglyceride synthesis. Therefore, increased fatty acid uptake and decreased VLDL secretion represent two important mechanisms by which the MCD diet promotes intrahepatic lipid accumulation in this model. Feeding the MCD diet to diabetic rodents broadens the applicability of this model for the study of human NASH.     

Suppression by licorice flavonoids of abdominal fat accumulation and body weight gain in high-fat diet-induced obese C57BL/6J mice

We applied licorice flavonoid oil (LFO) to high-fat diet-induced obese C57BL/6J mice and investigated its effect. LFO contains hydrophobic flavonoids obtained from licorice by extraction with ethanol. The oil is a mixture of medium-chain triglycerides, having glabridin, a major flavonoid of licorice, concentrated to 1.2% (w/w). Obese mice were fed on a high-fat diet containing LFO at 0 (control), 0.5%, 1.0%, or 2.0% for 8 weeks. Compared with mice in the control group, those in the 1% and 2% LFO groups efficiently reduced the weight of abdominal white adipose tissues and body weight gain. A histological examination revealed that the adipocytes became smaller and the fatty degenerative state of the hepatocytes was improved in the 2% LFO group. A DNA microarray analysis of the liver showed up-regulation of those genes for beta-oxidation and down-regulation of those for fatty acid synthesis in the 2% LFO group. These findings suggest that LFO prevented and ameliorated diet-induced obesity via the regulation of lipid metabolism-related gene expression in the liver.     

Heterologous expression of AtClo1, a plant oil body protein, induces lipid accumulation in yeast

Proteomic approaches on lipid bodies have led to the identification of proteins associated with this compartment, showing that, rather than the inert fat depot, lipid droplets appear as complex dynamic organelles with roles in metabolism control and cell signaling. We focused our investigations on caleosin [ Arabidopsis thaliana caleosin 1 (AtClo1)], a minor protein of the Arabidopsis thaliana seed lipid body. AtClo1 shares an original triblock structure, which confers to the protein the capacity to insert at the lipid body surface. In addition, AtClo1 possesses a calcium-binding domain. The study of plants deficient in caleosin revealed its involvement in storage lipid degradation during seed germination. Using Saccharomyces cerevisiae as a heterologous expression system, we investigated the potential role of AtClo1 in lipid body biogenesis and filling. The green fluorescent protein-tagged protein was correctly targeted to lipid bodies. We observed an increase in the number and size of lipid bodies. Moreover, transformed yeasts accumulated more fatty acids (+46.6%). We confirmed that this excess of fatty acids was due to overaccumulation of lipid body neutral lipids, triacylglycerols and steryl esters. We showed that the original intrinsic properties of AtClo1 protein were sufficient to generate a functional lipid body membrane and to promote overaccumulation of storage lipids in yeast oil bodies.     

Beneficial effects of alpha linolenic acid rich flaxseed oil on growth performance and hepatic cholesterol metabolism in high fat diet fed rats

The purpose of the study was to investigate the effect of flaxseed oil (FO), rich in alpha-linolenic acid (ALA) (18:3 n-3) on growth parameters and lipid metabolism of rats fed with high fat diet. High fat diet (HFD) resulted in significant alterations in hepatic lipids, increase in body weight gain and negative effect on lipoprotein metabolism. FO supplementation significantly lowered the increase in body weight gain, liver weight, plasma cholesterol, triglycerides, phospholipids, free fatty acids, high-density lipoprotein (HDL), low-density lipoprotein-cholesterol (LDL-C), very low-density lipoprotein (VLDL), LDL/HDL and TC/HDL ratio in HFD fed rats. FO significantly reduced the hepatic and plasma lipid levels indicating its hypolipidemic activity. On the other hand, oral administration of FO exhibited lower plasma lipoprotein profile as compared to HFD rats. Hepatic protection by FO is further substantiated by the normal liver histological findings in HFD fed rats. These data suggest that FO participate in the normal regulation of plasma lipid concentration and cholesterol metabolism in liver. No adverse effect of FO on growth parameters and plasma lipids in rats fed with fat-free diet. The results of the present study demonstrate that FO may be developed as a useful therapy for hyperlipidemia through reducing hepatic lipids, thereby proving its hypolipidemic activity.     

Effects of diet and exercise on metabolic disturbances in high-fat diet-fed mice

Consumption of a high-fat diet (HFD) is associated with white adipose tissue (WAT) inflammation, which contributes to key components of the metabolic syndrome, including insulin resistance (IR) and hepatic steatosis (HS). To determine the differential effects of exercise training (EX), low-fat diet (LFD), and their combination on WAT inflammation, Balb/cByJ male mice (n = 34) were fed an HFD for 12 wks before they were randomized into one of four intervention groups: HFD-EX, LFD-EX, HFD-sedentary (SED), or LFD-SED. EX mice performed 12 wks of exercise training on a motorized treadmill (1 h/d, 5 d/wk, 12 m/min, 5% grade, 65% VO₂ max), while SED mice remained sedentary in their home cages. WAT gene expression of adipokines was assessed using rt-PCR. IR was measured using HOMA-IR, and HS via hepatic triglyceride content. EX significantly reduced (53%) WAT gene expression of MCP-1, and LFD significantly reduced (50%) WAT gene expression of the macrophage specific marker, F4/80 as well as the adipocytokine IL-1ra (25%). EX independently improved IR, while both EX and LFD improved HS. These findings suggest that both diet and exercise have unique beneficial effects on WAT inflammatory markers and the mechanism by which each treatment improves metabolic complications associated with chronic consumption of an HFD may be different.