High Dietary Fat Exacerbates Weight Gain and Obesity in Female Liver Fatty Acid Binding Protein Gene-Ablated Mice

Since liver fatty acid binding protein (L-FABP) facilitates uptake/oxidation of long-chain fatty acids in cultured transfected cells and primary hepatocytes, loss of L-FABP was expected to exacerbate weight gain and/or obesity in response to high dietary fat. Male and female wild-type (WT) and L-FABP gene-ablated mice, pair-fed a defined isocaloric control or high fat diet for 12 weeks, consumed equal amounts of food by weight and kcal. Male WT mice gained weight faster than their female WT counterparts regardless of diet. L-FABP gene ablation enhanced weight gain more in female than male mice—an effect exacerbated by high fat diet. Dual emission X-ray absorptiometry revealed high-fat fed male and female WT mice gained mostly fat tissue mass (FTM). L-FABP gene ablation increased FTM in female, but not male, mice—an effect also exacerbated by high fat diet. Concomitantly, L-FABP gene ablation decreased serum β-hydroxybutyrate in male and female mice fed the control diet and, even more so, on the high-fat diet. Thus, L-FABP gene ablation decreased fat oxidation and sensitized all mice to weight gain as whole body FTM and LTM—with the most gain observed in FTM of control vs high-fat fed female L-FABP null mice. Taken together, these results indicate loss of L-FABP exacerbates weight gain and/or obesity in response to high dietary fat.     

Effect of <Emphasis Type="Italic">Fabp1/Scp</Emphasis>-<Emphasis Type="Italic">2/Scp</Emphasis>-<Emphasis Type="Italic">x</Emphasis> Ablation on Whole Body and Hepatic Phenotype of Phytol-Fed Male Mice

Liver fatty acid binding protein (Fabp1) and sterol carrier protein‐2/sterol carrier protein‐x (SCP‐2/SCP‐x) genes encode proteins that enhance hepatic uptake, cytosolic transport, and peroxisomal oxidation of toxic branched‐chain fatty acids derived from dietary phytol. Since male wild‐type (WT) mice express markedly higher levels of these proteins than females, the impact of ablating both genes (TKO) was examined in phytol‐fed males. In WT males, high phytol diet alone had little impact on whole body weight and did not alter the proportion of lean tissue mass (LTM) versus fat tissue mass (FTM). TKO conferred on dietary phytol the ability to induce weight loss as well as reduce liver weight, FTM, and even more so LTM. Concomitantly TKO induced hepatic lipid accumulation, preferentially threefold increased phospholipid (PL) at the expense of decreased triacylglycerol (TG) and total cholesterol. Increased PL was associated with upregulation of membrane fatty acid transport/translocase proteins (FATP 2,4), cytosolic fatty acid/fatty acyl‐CoA binding proteins (FABP2, ACBP), and the rate limiting enzyme in PL synthesis (Gpam). Decreased TG and cholesterol levels were not attributable to altered levels in respective synthetic enzymes or nuclear receptors. These data suggest that the higher level of Fabp1 and Scp2/Scpx gene products in WT males was protective against deleterious effects of dietary phytol, but TKO significantly exacerbated phytol effects in males.     

High Glucose and Liver Fatty Acid Binding Protein Gene Ablation Differentially Impact Whole Body and Liver Phenotype in High-Fat Pair-Fed Mice

Ad libitum-fed diets high in fat and carbohydrate (especially fructose) induce weight gain, obesity, and nonalcoholic fatty liver disease (NAFLD) in humans and animal models. However, interpretation is complicated since ad libitum feeding of such diets induces hyperphagia and upregulates expression of liver fatty acid binding protein (L-FABP)—a protein intimately involved in fatty acid and glucose regulation of lipid metabolism. Wild-type (WT) and L-fabp gene ablated (LKO) mice were pair-fed either high-fat diet (HFD) or high-fat/high-glucose diet (HFGD) wherein total carbohydrate was maintained constant but the proportion of glucose was increased at the expense of fructose. In LKO mice, the pair-fed HFD increased body weight and lean tissue mass (LTM) but had no effect on fat tissue mass (FTM) or hepatic fatty vacuolation as compared to pair-fed WT counterparts. These LKO mice exhibited upregulation of hepatic proteins in fatty acid uptake and cytosolic transport (caveolin and sterol carrier protein-2), but lower hepatic fatty acid oxidation (decreased serum β-hydroxybutyrate). LKO mice pair-fed HFGD also exhibited increased body weight; however, these mice had increased FTM, not LTM, and increased hepatic fatty vacuolation as compared to pair-fed WT counterparts. These LKO mice also exhibited upregulation of hepatic proteins in fatty acid uptake and cytosolic transport (caveolin and acyl-CoA binding protein, but not sterol carrier protein-2), but there was no change in hepatic fatty acid oxidation (serum β-hydroxybutyrate) as compared to pair-fed WT counterparts.     

Pristanic acid is activator of peroxisome proliferator activated receptor alpha

lsoprenoid phytanic acid (3,7,11,15‐tetramethylhexadecanoic acid) is degraded in peroxisomes by α‐oxidation to pristanic acid (2,6,10,14‐tetramethylpentadecanoic acid) and then via β‐oxidation. Branched‐chain phytanic acid is an activator of the peroxisome proliferator activated receptor α (PPAR ) which in liver cells regulates expression of genes encoding peroxisomal and mitochondrial β‐oxidative enzymes as well as cytosolic/nuclear liver‐type fatty acid binding protein (L‐FABP). In this report we address the question whether pristanic acid also acts as activator of PPARα and thus mediates the expression of its catabolizing enzymes. In a first in vivo approach we fed pristanic acid for 14 days to wildtype mice and to mice lacking sterol carrier protein 2/sterol carrier protein x which Ieads to a phenotype having high concentrations of branched‐chain fatty acids. In either genotype, feeding pristanic acid was associated with a strong induction of peroxisomal β‐oxidation enzymes tested (acyl‐CoA oxidase, bifunctional enzyme, thiolase) as well as of L‐FABP. The link between pristanic acid and protein expression observed was established by carrying out assays for transactivation of PPARα in transfected HepG2 cells. In comparison to hypolipidemic drugs and to straight‐chain fatty acids known to be PPARα agonists, branched‐chain phytanic and pristanic acids were substantially stronger activators, pristanic acid being even superior to phytanic acid.     

Metformin Reduces Lipogenesis Markers in Obese Mice Fed a Low-Carbohydrate and High-Fat Diet

Lipogenesis is the process by which fatty acids are synthesized. In metabolic syndrome, an insulin resistant state along with high plasma levels of free fatty acids (FFA) and hyperglycemia may contribute to the lipogenic process. The aim of the present study was to investigate the effects of oral administration of metformin on the expression of lipogenic genes and glycemic profile in mice fed with low‐carbohydrate high‐fat diet by evaluating their metabolic profile. SWISS male mice were divided into 4 groups (N = 7) that were fed with standard (ST), standard plus metformin (ST + MET), low‐carbohydrate high‐fat diet (LCHFD) and low‐carbohydrate high‐fat diet plus metformin (LCHFD + MET) (100 mg kg^?1 diet) diets respectively. Food intake, body weight and blood parameters, such as glucose tolerance, insulin sensitivity, glucose, HDL‐c, total cholesterol, triglycerides, ASL and ALT levels were assessed. Histological analyses were performed on hematoxylin and eosin‐stained epididymal adipose tissue histological specimens. The expression levels of peroxisome proliferator‐activated receptor (PPARγ), sterol regulatory element‐binding protein 1 (SREBP1), fatty acid synthase (FAS) and acetyl‐CoA carboxylase (ACC), were assessed by RT‐PCR. This study showed that metformin decreased adipocyte area, body weight and food consumption in obese animals when compared to the standard group. Furthermore, the expression of lipogenic markers in adipose tissue were diminished in obese animals treated with metformin. This data showed that oral administration of metformin improved glucose and lipid metabolic parameters in white adipose tissue by reducing the expression of lipogenesis markers, suggesting an important clinical application of MET in treating obesity‐related diseases in metabolic syndrome.     

Black Raspberry Seed Oil Improves Lipid Metabolism by Inhibiting Lipogenesis and Promoting Fatty‐Acid Oxidation in High‐Fat Diet‐Induced Obese Mice and db/db Mice

The objective of this study was to evaluate the beneficial effect of α‐linolenic acid‐rich black raspberry seed (BRS) oil on lipid metabolism in high‐fat diet (HFD)‐induced obese and db/db mice. Five‐week‐old C57BL/6 mice were fed diets consisting of 50% calories from lard, 5% from soybean, and 5% from corn oil (HFD), or 50% calories from lard and 10% from BRS oil (HFD + BRS oil diet) for 12 weeks. Six‐week‐old C57BL/KsJ‐db/db mice were fed diets consisting of 16% calories from soybean oil (standard diet), 8% from soybean, and 8% from BRS oil, or 16% from BRS oil for 10 weeks. The BRS oil diets lowered the levels of triacylglycerol, nonesterified fatty acids, and total cholesterol in serum and liver of both of the obese and db/db mice as compared with the HFD and standard diet, respectively. mRNA levels of lipogenesis markers including cluster of differentiation 36, fatty‐acid‐binding protein 1, sterol regulatory element binding protein 1c, fatty‐acid synthase, and solute carrier family 25 member 1 in the liver of the BRS oil groups were lower than those in the liver of the HFD and standard groups in the obese and db/db mice, respectively. On the other hand, fatty‐acid oxidation markers including carnitine palmitoyltransferase 1A, acyl‐CoA dehydrogenase, hydroxylacyl‐CoA dehydrogenase α, and acyl‐CoA oxidase in the liver of the BRS oil groups were higher than those in the liver of the HFD and standard groups in the obese and db/db mice, respectively. Peroxisome proliferator‐activated receptor α mRNA and protein levels increased in the liver and epididymal adipose tissue of the obese and db/db mice fed BRS oil compared with HFD and standard diet, respectively. BRS oil might improve lipid metabolism by inhibiting lipogenesis and promoting fatty‐acid oxidation in HFD‐induced obese and db/db mice.     

Calories,fat and cancer

The experiments reported are part of our effort to dissociate the tumor-enhancing effects of dietary fat and high caloric intake. Rats either were fed ad libitum diets containing 4% corn oil or their calories were restricted by 40% and their diets contained 13.1% corn oil. Incidence of 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary tumors was 80% in rats fed ad libitum and 20% in those fed the calorie-restricted diets. Incidence of 1,2-dimethylhydrazine (DMH)-induced colon tumors was 100% in rats fed ad libitum and 53% in those whose caloric intake was restricted by 40%. The tumor yield (tumors per tumor-bearing rat) was significantly lower in rats on caloric restriction. In another series, rats were fed diets containing 5, 15 or 20% corn oil ad libitum or were fed calorie-restricted (by 25%) diets which provided 20 or 26.6% corn oil (therefore, the same absolute amount of fat was consumed in each of the pair-fed groups). Tumor incidence and tumor yield in the two calorie-restricted groups were similar to those seen in the rats fed 5% fat ad lititum; tumor burden (total g of tumor) was 45–65% lower in the calorie-restricted rats. The data suggest that caloric intake is a more stringent determinant of tumor growth than fat intake.     

Effects of different dietary fat levels in cage‐fed Atlantic mackerel (Scomber scombrus)

In wild Atlantic mackerel, Scomber scombrus, the lipid content of the lateral muscle varies according to the season from around 30% in autumn to less than 5% in spring. To be able to offer mackerel with optimal quality on the market during spring or early summer after overwintering, it is necessary that the muscle lipid content is close to 30%, which is favoured by the customers. Wild caught mackerel were kept in salmon cages fed a high energy (300 g fat kg^{– 1} ) salmon diet rich in n‐3 polyunsaturated fatty acids from October 1997 to April 1998. Fish were submerged at 20—40 m at a temperature above 5 °C from January until April. Then the fish were brought to the surface and randomly divided into three duplicate groups, i.e., non‐fed, 150 g fat kg ^{– 1}, and 300 g fat kg ^{– 1} and kept until August 1998. The mortality was very low and the body weight doubled concomitant with an increased muscle lipid content from 19.5% to 30.9% during the first six months. Both groups receiving feed further increased the body weight and muscle lipid content at the same magnitude towards the end of the experiment. During the first six months the cross sectional area (CSA) of red muscle fibres increased 3.3fold and this size was maintained throughout the experiment. In contrast, in non‐fed mackerel the increase in CSA of red muscle fibres was 1.5fold. White muscle fibres revealed a much weaker response in fed mackerel and were not affected in mackerel deprived of feed. In wild mackerel the fatty acid oxidation (β‐oxidation) capacity dominated in the red part of the lateral muscle. During the winter an increased β‐oxidation capacity was found in heart and liver, whereas both red and white part of the lateral muscle showed a low fatty acid catabolism. In contrast, during summer red and white part of the lateral muscle possessed high β‐oxidation capacities, particularly in high energy‐fed and non‐fed mackerel. It is concluded that it is possible to feed captive mackerel during the winter and produce mackerel with a high quality for the market in early spring.     

Influence of diet on the kinetic behavior of hepatic carnitine palmitoyltransferase I toward different acyl CoA esters

The influence of diet on the kinetics of the overt form of rat liver mitochondrial carnitine palmitoyltransferase (CPT I; EC 2.3.1.21) was studied using rats fed either a low-fat diet (3% w/w fat), or diets which were supplemented with either olive oil (OO), safflower oil (SO) or menhaden (fish) oil (MO) to 20% w/w of fat (high fat diets). When animals were fed each of these four diets for 10 days, the order of the apparent maximal activity (V_max) of CPT I toward various individual fatty acyl CoA, when measured under a fixed molar ratio of acyl CoA/albumin, was 16∶1n−7>18∶1n−9>18∶2n−6>16∶0>22∶6n−3, and was thus not affected by the fat composition of the diet. However, in all but one case, the SO and MO diets elicited a higher V_max for each substrate than either the LF diet or the high fat OO diet. The apparent K _0.5 for the different acyl CoA esters was generally lowest in LF-fed animals, and highest in those fed the high-fat SO diet. Moreover, when compared with the situation of animals fed high-fat diets, the K _0.5 values of CPT I in LF-fed animals for palmitoyl CoA and oleoyl CoA were low. This possession by CPT I of a high “affinity” toward these nonessential fatty acyl CoAs, but a lower “affinity” toward linoleoyl CoA, the ester of an essential fatty acid, may enable this latter fatty acid to be spared from oxidation when its concentration in the diet is low. The data also emphasize that palmitoleoyl CoA, if available in the diet, is likely to be utilized by CPT I at a high rate.     

Absorption difference between diacylglycerol oil and butter blend containing diacylglycerol oil

This study aims at investigating whether the intake of butter blends containing diacylglycerol (DAG) oil may result in reduced fat accumulation, in similarity to DAG oil, and the potential metabolic differences between butter blends and DAG oil. Four experimental diets containing either 10 wt% DAG butter blend (BDAG), triacylglycerol (TAG) butter blend (BTAG), DAG oil (ODAG) or TAG oil (OTAG) were prepared, and each was fed to a group of 8 male Wistar rats. The design of the experiment was a combined balance and feeding experiment. The rats fed the BTAG and ODAG‐diets had a significantly higher protein content than rats fed the BDAG and OTAG‐diets, and the fat content was significantly lower in rats fed the ODAG‐diet as compared to rats fed the OTAG and BDAG‐diets. A significantly higher content of ash was observed in rats fed the two TAG diets. The ratio of abdominal fat weight/body weight was significantly higher for rats fed the BDAG‐diet than for rats fed the BTAG and ODAG‐diets. To conclude, the beneficial effects of DAG oil in reducing body fat accumulation cannot be observed in DAG oil containing butter blends, and the effect of DAG on bone health requires further investigation.     

Role of brown adipose tissue in thermogenesis induced by overfeeding a diet containing medium chain triglyceride

The role of brown adipose tissue in the mechanism of medium chain triglyceride (MCT)-induced thermogenesis was investigated. Under anesthesia, the interscapular brown adipose tissue (IBAT) was excised in male Sprague-Dawley rats, and the animals were fitted with gastrostomy tubes. After a 10-day recovery period, the animals were divided into two groups: one group received a diet containing MCT as 50% of calories, and the other group received an isocaloric diet containing long chain triglyceride (LCT). The diets were fed for 6 wk at a level of calorie intake that was 150% of the ad libitum intake of a parallel control group. During the last week of the study, resting and norepinephrine (NE)-stimulated O₂ consumption and CO₂ production were measured in a Noyons diaferometer. At the end of 6 wk, the animals were weighed and killed. The individual fat pads were dissected and weighed, and an aliquot of the right retroperitoneal fat pad was used to measure adipocyte size and number. The results showed that body weight and adipocyte size (but not adipocyte number) were significantly smaller in the MCT-fed compared to the LCT-fed animals. Resting as well as maximal NE-stimulated oxygen consumption values were significantly higher in the MCT-fed than the LCT-fed rats. It is concluded that the enhanced thermogenesis induced by MCT persists despite the absence of IBAT and that the phenomenon is likely related to more extensive oxidation of MCT-in contrast to LCT-derived fatty acids, thus leading to increased oxygen consumption, enhanced dissipation of energy as heat and diminished efficiency of weight gain and deposition of body fat. Presented at the symposium on “Specialty Lipids and Their Biofunctionality” at the annual meeting of the American Oil Chemists' Society, Philadelphia, May 1985.     

Interaction Between Marginal Zinc and High Fat Supply on Lipid Metabolism and Growth of Weanling Rats

The impact of a moderate Zn deficiency on growth and plasma and liver lipids was investigated in two 4-week experiments with male weanling rats fed fat-enriched diets. Semisynthetic, approximately isocaloric diets containing 3% soybean oil were supplemented with either 7 or 100 mg Zn/kg diet and with 22% beef tallow (BT) or sunflower oil (SF). In Experiment 1, which compared the dietary fat level and the fat source in a factorial design of treatments, all diets were fed ad libitum to 6 × 8 animals, whereas intake of the high-Zn BT and SF diets was restricted in Experiment 2 (5 × 6 rats) to the level of intake of the respective low-Zn diets. The low-Zn SF diet consistently depressed food intake and final live weights of the animals to a greater extent than the other low-Zn diets, while intake and growth were comparable among the animals fed the high-Zn diets. The marginal Zn deficit per se did not alter plasma triglyceride and cholesterol concentrations nor hepatic concentrations of triglyceride, cholesterol and phospholipids. The fatty acid pattern of liver phospholipids did not indicate that chain elongation and desaturation of fatty acids was impaired by a lack of zinc. It was concluded that dietary energy and fat intake, and fat source have a greater effect on plasma and liver lipids than a moderate Zn deficiency. Marginally Zn-deficient diets enriched with sunflower oil as a major energy source cause a greater growth retardation than diets rich in carbohydrates or beef tallow.     

Effect of diet composition and fasting on lipogenesis in lean and polygenic obese mice

A line of mice was developed which exhibited spontaneous obesity when fed commercial laboratory ration low in fat content. Obese mice were compared to a nonobese related line to determine whether energy source in the diet would affect onset of obesity. Experimental diets-beef tallow (38% of calories as beef fat and 2% as corn oil), corn oil (40% corn oil) or low-fat (2% corn oil)-were instituted ad libitum at the time of weaning. When the mice reached 6 months of age, lipogenesis was investigated by injecting intravenously³H₂O and glucose-U-¹⁴C.³H₂O and glucose-U-¹⁴C incorporation into fatty acids of fed mice was greater for obese than for lean mice. Fatty acid synthesis was inhibited by high-fat diets compared to low-fat diet in both lines. Of the 2 high-fat diets, the corn oil diet inhibited fatty acid synthesis about twice as much as beef tallow diet. There was no line effect on tritium incorporation into cholesterol. Cholesterol synthesis from glucose-U-¹⁴C was greater in obese than lean mice. Diets had no effect on tritium and glucose-U-¹⁴C incorporation into cholesterol. Fasting reduced fatty acid synthesis in all mice, but total body fatty acid synthesis was not affected by lines or dietary treatment under fasted conditions. These data suggest that degree of lipogenesis, in part, explains obesity. A failure of inhibition of lipogenesis or an enhanced efficiency in fat deposition by feeding beef tallow compared to corn oil diet may explain the fact that lean mice fed the beef tallow diet tended to be more obese that lean mice fed corn oil or low-fat diets.     

Bioactivity and emerging role of short and medium chain fatty acids

Cardiovascular disease (CVD) and insulin resistance are directly linked to overweight and obesity. Thus, any dietary strategy capable of causing weight reduction will lower CVD and diabetes risk. Oils rich in medium‐chain saturated fatty acids (MCFA) are among several dietary components that may have potential in the treatment of obesity. MCFA are less energy dense and highly ketogenic compared to long‐chain saturated and unsaturated fatty acids (LCFA). MCFA also differ from LCFA in their digestive and metabolic pathways, since they are easily oxidized and utilized as energy, with little tendency to deposit as body fat. The dietary intake of short (SCFA) and medium‐chain saturated fatty acids from natural food sources is approximately 2.4 g/day and accounts for about 9% of the total saturated fatty acid (SFA) intake. Although early clinical studies with high levels of MCFA resulted in increased levels of plasma triacylglycerols (TAG) and low‐density lipoprotein cholesterol (LDL‐C), and reduced levels of high‐density lipoprotein cholesterol (HDL‐C) compared to diets enriched in unsaturated LCFA, these adverse effects have not been observed in more recent studies with smaller more realistic amounts of MCFA. The lower caloric value of SCFA and MCFA and their unique metabolic features form the basis for their clinical use in enteral and parenteral nutrition and for novel reduced calorie lipids for use in conventional food products.     

Variablity of the intestinal uptake of lipids is genetically determined in mice

The response of the plasma cholesterol concentration to changes in dietary lipids varies widely in humans and animals. There are variations in the in vivo absorption of cholesterol between different strains of mice. This study was undertaken in three strains of inbred mice to test the hypotheses that: (i) there are strain differences in the in vitro uptake of fatty acids and cholesterol and (ii) the adaptability of the intestine to respond to variations in dietary lipids is genetically determined. An in vitro intestinal ring technique was used to assess the uptake of medium- and long-chain fatty acids and cholesterol into jejunum and ileum of adult DBA/2, C57BL6, and C57L/J mice. The jejunal uptake of cholesterol was similar in C57L/J, DBA/2, or C57BL6 fed ad libitum a low-fat (5.7% fat, no cholesterol) chow diet. This is in contrast to a previous demonstration that in vivo cholesterol absorption was lower in C57L/J than in the other murine strains. The jejunal uptake of several long-chain fatty acids was greater in DBA/2 fed for 4 wk the high-fat (15.8% fat and 1.25% cholesterol) as compared with the low-fat diet. Furthermore, on the high-fat diet, the uptake of many long-chain fatty acids was higher in DBA/2 than in C57BL6 or C57L/J. The differences in cholesterol and fatty acid uptake were not explained by variations in food uptake, body weight gain, or the weight of the intestine. In summary: (i) there are strain differences in the in vitro intestinal uptake of fatty acids but not of cholesterol; (ii) a high-fat diet enhances the uptake of long-chain fatty acids in only one of the three strains examined in this study; and (iii) the pattern of strain- and diet-associated alterations in the in vivo absorption of cholesterol differs from the pattern of changes observed in vitro. We speculate that genetic differences in cholesterol and fatty acid uptake are explained by variations in the expression of protein-mediated components of lipid uptake.     

Two-Week Isocaloric Time-Restricted Feeding Decreases Liver Inflammation without Significant Weight Loss in Obese Mice with Non-Alcoholic Fatty Liver Disease

Prolonged, isocaloric, time-restricted feeding (TRF) protocols can promote weight loss, improve metabolic dysregulation, and mitigate non-alcoholic fatty liver disease (NAFLD). In addition, 3-day, severe caloric restriction can improve liver metabolism and glucose homeostasis prior to significant weight loss. Thus, we hypothesized that short-term, isocaloric TRF would improve NAFLD and characteristics of metabolic syndrome in diet-induced obese male mice. After 26 weeks of ad libitum access to western diet, mice either continued feeding ad libitum or were provided with access to the same quantity of western diet for 8 h daily, over the course of two weeks. Remarkably, this short-term TRF protocol modestly decreased liver tissue inflammation in the absence of changes in body weight or epidydimal fat mass. There were no changes in hepatic lipid accumulation or other characteristics of NAFLD. We observed no changes in liver lipid metabolism-related gene expression, despite increased plasma free fatty acids and decreased plasma triglycerides in the TRF group. However, liver Grp78 and Txnip expression were decreased with TRF suggesting hepatic endoplasmic reticulum (ER) stress and activation of inflammatory pathways may have been diminished. We conclude that two-week, isocaloric TRF can potentially decrease liver inflammation, without significant weight loss or reductions in hepatic steatosis, in obese mice with NAFLD.     

Cardiac Lipid Metabolism Is Modulated by Casimiroa edulis and Crataegus pubescens Aqueous Extracts in High Fat and Fructose (HFF) Diet‐Fed Obese Rats

This study aim to evaluate the effect of Casimiroa edulis and Crataegus pubescens aqueous extracts on cardiac lipotoxicity in obese rats. Both extracts decrease cardiac hypertrophy and steatosis in high fat and fructose (HFF)‐diet‐fed obese rats. C. pubescens decreases the cardiac content of 16 and 18 carbon‐length fatty acids, whereas C. edulis extract does not alter the fatty acid profile. Regarding lipotoxic compounds, C. pubescens reduces the cardiac content of 16 and 18 carbon‐length ceramides and diacylglycerols, whereas C. edulis extract reduces ≥20 carbon‐length lipotoxic compounds. Both extracts down‐regulate fatty acid synthase (Fasn) and acetyl‐CoA carboxylase (Acaca) (lipogenesis), glyceril‐3‐phosphate acyltransferase (Gpat) (diacylglycerol synthesis) and serine palmitoyltransferase 1 (Spt1) (ceramide synthesis), and up‐regulate carnitine palmitoyltransferase 1 (Cpt1) and acyl‐CoA dehydrogenase (Acadm) (β‐oxidation), and the greatest effect is observed with C. pubescens. In addition, C. edulis exerts the greatest cardiac anti‐inflammatory activity, whereas C. pubescens shows the highest cardiac antioxidant activity. The cardioprotective effect of C. pubescens may be associated with its content of (?)‐epigallocatechin gallate, (+)‐catechin, chlorogenic acid, caffeic acid, and β‐campesterol, whereas the beneficial effect of C. edulis may be related to its high content of steroidal saponins and alkaloids. Therefore, these results demonstrate that both herbal aqueous extracts ameliorate cardiac lipotoxicity in HFF‐diet‐fed rats, and C. pubescens exerts a greater beneficial effect. Practical Applications: This study proposes the characterization of fatty acids and lipotoxic compounds (ceramides and diacylglycerols) of cardiac tissue in combination with the determination of the expression of specific genes related to lipid metabolism to identify the mechanisms associated with the cardioprotective effects of herbal extracts. The results obtained in this study demonstrate the cardioprotective potential of Casimiroa edulis and Crataegus pubescens aqueous extracts through the modulation of cardiac lipid metabolism in high fat and fructose diet fed obese rats. Therefore, these herbs can be used for the development of functional beverages or the extraction of bioactive compounds with cardioprotective effect.     

Acetoacetate metabolism of rats fed high fat or restricted calorie diets

Ethyl-¹⁴C-acetoacetate was used to trace oxidation and metabolism of acetoacetate when rats were fed a high fat diet (80% of total calories from beef tallow or corn oil, carbohydrate free), a high carbohydrate diet (2% corn oil) or a high carbohydrate diet with restriction of calories to one half of ad lib. consumption for two weeks. The rate of expiration of¹⁴CO₂ in all groups of animals did not differ significantly and was not related to plasma concentration of acetoacetate. The high fat diets slightly enhanced the oxidation of acetoacetate to¹⁴CO₂ over a 3 hr period compared to other diets. Incorporation of acetoacetate into fatty acids did not differ significantly among groups. Rats fed the high carbohydrate diet ad lib. incorporated into liver cholesterol more acetoacetate than did any other group, but dietary unsaturated fat resulted in greater incorporation of acetoacetate into cholesterol than saturated fat. High calorie and high beef tallow groups were ketonemic but the low concentration of plasma acetoacetate in rats fed a high corn oil diet indicates that unsaturated fatty acids are not ketogenic. The data show that utilization of acetoacetate is not significantly reduced in a ketonemic condition and support the premise that overproduction of ketone bodies is the cause of ketonemia. Rats appeared to be normal during the two-week period when no carbohydrate was included in the diet. Presented at the AOCS Meeting, Chicago, October, 1967.     

Dietary Omega-3 Fatty Acids Prevented Adipocyte Hypertrophy by Downregulating DGAT-2 and FABP-4 in a Sex-Dependent Fashion

Obesity is characterized by an increase in fat mass primarily as a result of adipocyte hypertrophy. Diets enriched in omega (n)‐3 polyunsaturated fatty acids (PUFA) are suggested to reduce obesity, however, the mechanisms are not well understood. We investigated the effect of n‐3 PUFA on adipocyte hypertrophy and the key genes involved in adipocyte hypertrophy. Female C57BL/6 mice were fed semi‐purified diets (20 % w/w fat) containing high n‐3 PUFA before mating, during pregnancy, and until weaning. Male and female offspring were continued on high n‐3 PUFA (10 % w/w), medium n‐3 PUFA (4 % w/w), or low n‐3 PUFA (2 % w/w) diet for 16 weeks postweaning. Adipocyte area was quantified using microscopy, and gonadal mRNA expression of acyl CoA:diacylglycerol acyltransferase‐2 (DGAT‐2), fatty acid binding protein‐4 (FABP‐4) and leptin were measured. The high n‐3 PUFA group showed higher levels of total n‐3 PUFA in gonadal TAG compared to the medium and low n‐3 PUFA groups (P < 0.001). The high n‐3 PUFA male group had a lower adipocyte area compared to the medium and low n‐3 PUFA group (P < 0.001); however, no difference was observed in females. The high n‐3 PUFA male group showed lower mRNA expression of FABP‐4, DGAT‐2 and leptin compared to the low n‐3 PUFA group, with no difference in females. Plasma lipid levels were lower in the high n‐3 PUFA group compared to the other groups. Our findings show for the first time that n‐3 PUFA prevents adipocyte hypertrophy by downregulating FABP‐4, DGAT‐2 and leptin; the effects are however sex‐specific.