NO synthesis from arginine is favored by α-linolenic acid in mice fed a high-fat diet.

Alterations in NO availability and signaling play a pivotal role at early stages of the metabolic syndrome (MetSynd). We hypothesized that dietary α-linolenic acid (ALA, 18:3 n-3) favors NO availability by modulating amino acid metabolism, with a specific impact on the arginine-NO pathway. Mice were fed a hyperlipidic diet (285 g lipid/kg, 51.1 % energy), rich in either saturated fatty acids (SFA, provided by palm oil, PALM group) or ALA (provided by linseed oil, LIN group). We measured whole-body NO synthesis and systemic arginine hydrolysis with a tracer-based method, plasma concentration of related metabolites, and hepatic mRNA level of related enzymes, and the study was completed by a transcriptomic analysis in the liver. As expected with this model, hyperlipidic diets resulted in increased adiposity and glycemia after 5 weeks. As compared to PALM mice, LIN mice had a higher plasma nitrite and nitrate concentration, a higher whole-body conversion of arginine into NO vs urea, and a similar plasma concentration of asymmetric dimethylarginine (ADMA), despite a higher expression of the liver dimethylargininase-1. In LIN mice, there was a higher expression of genes involved in PPARα signaling, but a little impact on gene expression related to amino acids and arginine metabolism. This effect cannot be directly ascribed to changes in arginase activity in the liver or ADMA metabolism, nor to direct regulation of the related target genes. In conclusion, dietary ALA favors NO synthesis, which could contribute to rescue NO availability when jeopardized by the nutritional conditions in relation with the initiation of the MetSynd.

Protein feeding pattern, casein feeding, or milk-soluble protein feeding did not change the evolution of body composition during a short-term weight loss program.

Studies have shown that timing of protein intake, leucine content, and speed of digestion significantly affect postprandial protein utilization. Our aim was to determine if one can spare lean body mass during energy restriction by varying the quality and the timing of protein intake. Obese volunteers followed a 6-wk restricted energy diet. Four groups were compared: casein pulse, casein spread, milk-soluble protein (MSP, = whey) pulse, and MSP spread (n = 10-11 per group). In casein groups, caseins were the only protein source; it was MSP in MSP groups. Proteins were distributed in four meals per day in the proportion 8:80:4:8% in the pulse groups; it was 25:25:25:25% in the spread groups. We measured weight, body composition, nitrogen balance, 3-methylhistidine excretion, perception of hunger, plasma parameters, adipose tissue metabolism, and whole body protein metabolism. Volunteers lost 7.5 ± 0.4 kg of weight, 5.1 ± 0.2 kg of fat, and 2.2 ± 0.2 kg of lean mass, with no difference between groups. In adipose tissue, cell size and mRNA expression of various genes were reduced with no difference between groups. Hunger perception was also never different between groups. In the last week, due to a higher inhibition of protein degradation and despite a lower stimulation of protein synthesis, postprandial balance between whole body protein synthesis and degradation was better with caseins than with MSP. It seems likely that the positive effect of caseins on protein balance occurred only at the end of the experiment.

Role of adipose tissue renin-angiotensin system in metabolic and inflammatory diseases associated with obesity.

Obesity is a leading cause of death worldwide because of its associated inflammatory disorders such as hypertension, cardiovascular and kidney diseases, dyslipidemia, glucose intolerance, and certain types of cancer. Adipose tissue expresses all components of the renin-angiotensin system necessary to generate angiotensin (Ang) peptides for local function. The angiotensin type 1 (AT1) and type 2 (AT2) receptors mediate the effect of Ang II and recent studies have shown that both receptors may modulate fat mass expansion through upregulation of adipose tissue lipogenesis (AT2) and downregulation of lipolysis (AT1). Thus, both receptors may have synergistic and additive effects to promote the storage of lipid in adipose tissue in response to the nutrient environment. The production of angiotensinogen (AGT) by adipose tissue in rodents also contributes to one third of the circulating AGT levels. Increased adipose tissue AGT production in the obese state may be responsible in part for the metabolic and inflammatory disorders associated with obesity. This supports the notion that besides the traditional role of Ang II produced by the liver in the control of blood pressure, Ang II produced by the adipose tissue may more accurately reflect the role of this hormone in the regulation of fat mass and associated disorders.

In vivo evidence for a role of adipose tissue SR-BI in the nutritional and hormonal regulation of adiposity and cholesterol homeostasis.

OBJECTIVES: This study examines the role of insulin and angiotensin II in high-density lipoprotein (HDL) metabolism by focusing on the regulation and function of scavenger receptor type-BI (SR-BI) in adipose tissue. METHODS AND RESULTS: Insulin or angiotensin II injection in wild-type mice induced a decrease in circulating HDL and it was associated with the translocation of SR-BI from intracellular sites to the plasma membrane of adipose tissue. Refeeding upregulated adipose HDL selective cholesteryl esters uptake and SR-BI proteins through transcriptional and posttranscriptional mechanisms. This occurred along with a decrease in serum HDL and an increase in adipose cholesterol content. Similar results were obtained with transgenic mice overexpressing locally angiotensinogen in adipose tissue. In adipose 3T3-L1 cell line, HDL induced lipogenesis by increasing liver X receptor binding activity. This mechanism was dependent of insulin and angiotensin II. CONCLUSIONS: Our results raise the possibility that adipose tissue SR-BI translocation might be a link between adipose tissue lipid storage and HDL clearance.

Treatment for 2 mo with n 3 polyunsaturated fatty acids reduces adiposity and some atherogenic factors but does not improve insulin sensitivity in women with type 2 diabetes: a randomized controlled study.

BACKGROUND: Information is lacking on the potential effect of n-3 polyunsaturated fatty acids (PUFAs) on the adipose tissue of patients with type 2 diabetes. OBJECTIVE: We evaluated whether n-3 PUFAs have additional effects on adiposity, insulin sensitivity, adipose tissue function (production of adipokines and inflammatory and atherogenic factors), and gene expression in type 2 diabetes. DESIGN: Twenty-seven women with type 2 diabetes without hypertriglyceridemia were randomly allocated in a double-blind parallel design to 2 mo of 3 g/d of either fish oil (1.8 g n-3 PUFAs) or placebo (paraffin oil). RESULTS: Although body weight and energy intake measured by use of a food diary were unchanged, total fat mass (P < 0.019) and subcutaneous adipocyte diameter (P < 0.0018) were lower in the fish oil group than in the placebo group. Insulin sensitivity was not significantly different between the 2 groups (measured by homeostasis model assessment in all patients and by euglycemic-hyperinsulinemic clamp in a subgroup of 5 patients per group). By contrast, atherogenic risk factors, including plasma triacylglycerol (P < 0.03), the ratio of triacylglycerol to HDL cholesterol (atherogenic index, P < 0.03), and plasma plasminogen activator inhibitor-1 (P < 0.01), were lower in the fish oil group than in the placebo group. In addition, a subset of inflammation-related genes was reduced in subcutaneous adipose tissue after the fish oil, but not the placebo, treatment. CONCLUSIONS: A moderate dose of n-3 PUFAs for 2 mo reduced adiposity and atherogenic markers without deterioration of insulin sensitivity in subjects with type 2 diabetes. Some adipose tissue inflammation-related genes were also reduced. These beneficial effects could be linked to morphologic and inflammatory changes in adipose tissue. This trial was registered at clinicaltrials.gov as NCT0037.

Postprandial low-grade inflammation does not specifically require TLR4 activation in the rat.

BACKGROUND: Toll-like receptor 4 (TLR4), an innate immune receptor, is suspected to play a key role in the postprandial inflammation that is induced by a high-fat meal rich in saturated fatty acids (SFA). Our objective was to test this hypothesis by using a specific competitive inhibitor of TLR4 (INH) vs vehicle (VEH) administered immediately before a high-SFA meal in rats. METHODS: First, in a cross-over kinetic study of 12 rats receiving INH and VEH i.v. 10 min before the test meal, we measured plasma inflammatory and vascular markers for 6 h. Then, in 20 rats, 3 h after INH or VEH followed by the test meal (parallel study), we measured the mRNA level of a set of cytokines (Il1-ß, Il-6, Tnfα, Mcp-1, Pai-1), and of Tlr4 and Tlr2 in the adipose tissue and the liver, and that of adhesion molecules (Icam-1 and Vcam-1) in the aorta. RESULTS: Plasma IL-6 and PAI-1 increased >4-fold at 3-4 h after test-meals, very similarly after INH as compared to VEH. The expression of TLR2 and of all measured cytokine genes in the adipose tissue was dramatically higher after INH (vs VEH). In the liver, gene expression of Il1-ß, Tnfα, Mcp-1 and Tlr2, was also higher after INH, though more moderately, whereas that of Il-6 and Pai-1 was similar between groups. INH did not affect mRNA level of Icam-1 and Vcam-1 in the aorta. CONCLUSION: TLR4 activation is not specifically required to mediate systemic postprandial inflammation and we propose that TLR2 and TLR4 exert a dual and interdependent mediation of the postprandial inflammatory response, at least in the adipose tissue.

Prevention of adipose tissue depletion during food deprivation in angiotensin type 2 receptor-deficient mice.

Angiotensin (Ang) II is produced locally in various tissues, but its role in the regulation of tissue metabolism is still unclear. Recent studies have revealed the role of type 2 Ang II receptor (AT2R) in the control of energy homeostasis and lipid metabolism. The contribution of the AT2R to adaptation to starvation was tested using AT2R-deficient (AT2R (y)(/-)) mice. Fasted AT2R (y)(/-) mice exhibited a lower loss of adipose tissue weight associated to a decreased free fatty acid (FFA) release from stored lipids than the controls. In vitro studies show that Ang II causes an AT1R-mediated antilipolytic effect in isolated adipocytes. AT1R expression is up-regulated by fasting in both genotypes, but the increase is more pronounced in AT2R (y/-) mice. In addition, the increased muscle beta-oxidation displayed in AT2R (y/-) mice on a fed state, persists after fasting compared with wild-type mice. In liver from fed mice, AT2R deficiency did not modify the expression of genes involved in fatty acid oxidation. However, in response to fasting, the large increase of the expression of this subset of genes exhibited by wild-type mice, was impaired in AT2R (y/-) mice. Taken together, decreased lipolytic capacity and increased muscle fatty acid oxidation participate in the decreased plasma FFA observed in fasted AT2R (y/-) mice and could account for the lower FFA metabolism in the liver. These data reveal an important physiological role of AT2R in metabolic adaptations to fasting.

Deletion of the angiotensin type 2 receptor (AT2R) reduces adipose cell size and protects from diet-induced obesity and insulin resistance.

The renin-angiotensin system with its active metabolite angiotensin (Ang) II has been related not only to hypertension but also to obesity and insulin resistance. Recent evidence obtained in vitro suggests that the type 2 Ang II receptor (AT2R) mediates the trophic action of Ang II on adipocyte differentiation and lipogenesis. We used AT2R(y/-) mice to delineate a potential role of AT2R in adipose tissue development and metabolism. AT2R(y/-) mice had a normal adiposity but displayed a striking adipose tissue phenotype characterized by small adipocytes and an increase in cell number. In muscle, the expression of several genes involved in lipid metabolism, including fatty acid translocase, uncoupling protein-3, peroxisome proliferator-activated receptors (alpha, delta), and carnitine palmitoyl transferase-1, was increased in AT2R-deficient mice. In response to high-fat feeding, these mice were protected against obesity and obesity-related glucose intolerance, as assessed by glucose tolerance tests. Moreover, lipid oxidation assessed by indirect calorimetry was higher in AT2R-deficient mice than in wild-type mice, irrespective of the diet. This suggests that AT2R-dependent signaling exerts a direct or indirect negative control on lipid utilization in muscles. These data support the idea that AT2R-dependent Ang II signaling increases adipose cell mass and glucose intolerance and thus could participate to the deleterious effects of a high-fat diet.

Dietary magnesium intake alters age-related changes in rat adipose tissue cellularity.

Obesity and related metabolic diseases are associated with increased risk of cardiovascular disease. We have previously shown the beneficial effects of dietary magnesium (Mg) supplementation on cardiovascular disease in rats. Therefore, we aimed to examine the effect of an Mg-deficient or supplemented diet on adipose tissue cellularity changes during aging, and on blood pressure (BP), in rats. Male rats received for one (young adult) or 22 months (old), an Mg-deficient (Def) (150 mg/kg), standard (Std) (800 mg/kg) or Mg-supplemented (Sup) (3200 mg/kg) diet. Adipose tissue development and cellularity, BP and leptinemia were evaluated. In rats fed a standard diet, the large increase in adipose tissue weight observed during aging was related to an increase in both size and number of adipocytes. In young adult rats, although adiposity was unchanged, Mg supplementation resulted in a shift of the frequency distribution of adipocytes toward greater sizes, adipose cell weight increasing by 62%. Mg deficiency did not modify adipocyte size, but increased their number (30% more than for the standard or Sup-diet). In old rats, the Def-diet led to relative adipocyte hypotrophy, which was counterbalanced by an increase in the number of adipocyte. Conversely, adipocyte size and number were similar in the Sup-diet and standard diet-fed rats. BP was modified in old rats according to dietary Mg, whereas it remained unchanged young adult rats regardless of the diet received. This study suggests that Mg intake may affect age-related changes in rat adipose tissue lipid storage capacity.

Quinoa extract enriched in 20-hydroxyecdysone affects energy homeostasis and intestinal fat absorption in mice fed a high-fat diet.

In a previous study, we have demonstrated that a supplementation of a high-fat diet with a quinoa extract enriched in 20-hydroxyecdysone (QE) or pure 20-hydroxyecdysone (20E) could prevent the development of obesity. In line with the anti-obesity effect of QE, we used indirect calorimetry to examine the effect of dietary QE and 20E in high-fat fed mice on different components of energy metabolism. Mice were fed a high-fat (HF) diet with or without supplementation by QE or pure 20E for 3 weeks. As compared to mice maintained on a low-fat diet, HF feeding resulted in a marked physiological shift in energy homeostasis, associating a decrease in global energy expenditure (EE) and an increase in lipid utilization as assessed by the lower respiratory quotient (RQ). Supplementation with 20E increased energy expenditure while food intake and activity were not affected. Furthermore QE and 20E promoted a higher rate of glucose oxidation leading to an increased RQ value. In QE and 20E-treated HFD fed mice, there was an increase in fecal lipid excretion without any change in stool amount. Our study indicates that anti-obesity effect of QE can be explained by a global increase in energy expenditure, a shift in glucose metabolism towards oxidation to the detriment of lipogenesis and a decrease in dietary lipid absorption leading to reduced dietary lipid storage in adipose tissue.

Overproduction of angiotensinogen from adipose tissue induces adipose inflammation, glucose intolerance, and insulin resistance.

Although obesity is associated with overactivation of the white adipose tissue (WAT) renin-angiotensin system (RAS), a causal link between the latter and systemic insulin resistance is not established. We tested the hypothesis that overexpression of angiotensinogen (Agt) from WAT causes systemic insulin resistance via modulation of adipose inflammation. Glucose tolerance, systemic insulin sensitivity, and WAT inflammatory markers were analyzed in mice overexpressing Agt in the WAT (aP2-Agt mice). Proteomic studies and in vitro studies using 3T3-L1 adipocytes were performed to build a mechanistic framework. Male aP2-Agt mice exhibited glucose intolerance, insulin resistance, and lower insulin-stimulated glucose uptake by the skeletal muscle. The difference in glucose tolerance between genotypes was normalized by high-fat (HF) feeding, and was significantly improved by treatment with angiotensin-converting enzyme (ACE) inhibitor captopril. aP2-Agt mice also had higher monocyte chemotactic protein-1 (MCP-1) and lower interleukin-10 (IL-10) in the WAT, indicating adipose inflammation. Proteomic studies in WAT showed that they also had higher monoglyceride lipase (MGL) and glycerol-3-phosphate dehydrogenase levels. Treatment with angiotensin II (Ang II) increased MCP-1 and resistin secretion from adipocytes, which was prevented by cotreating with inhibitors of the nuclear factor-κB (NF-κB) pathway or nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. In conclusion, we show for the first time that adipose RAS overactivation causes glucose intolerance and systemic insulin resistance. The mechanisms appear to be via reduced skeletal muscle glucose uptake, at least in part due to Ang II-induced, NADPH oxidase and NFκB-dependent increases in WAT inflammation.

n-3 and n-6 polyunsaturated fatty acids differentially regulate adipose angiotensinogen and other inflammatory adipokines in part via NF-κB-dependent mechanisms.

Excessive secretion of proinflammatory adipokines has been linked to metabolic disorders. We have previously documented anti-inflammatory effects of n-3 polyunsaturated fatty acids (n-3 PUFAs) in adipose tissue; however, the mechanisms by which these fatty acids regulate adipokine secretion remain unclear. Here, we determined differential effects of eicosapentaenoic acid (EPA, n-3 PUFA) vs. arachidonic acid (AA, n-6 PUFA) on expression and secretion of angiotensinogen (Agt), interleukin 6 (IL-6) and monocyte chemotactic protein (MCP-1) in 3T3-L1 adipocytes. While both PUFAs increased intracellular Agt protein and mRNA expression, Agt secretion into culture media was increased only by AA treatment, which in turn was prevented by co-treatment with EPA. At various AA/EPA ratios, increasing AA concentrations significantly increased secretion of the above three adipokines, whereas increasing EPA dose-dependently, while lowering AA, decreased their secretion. Moreover, IL-6 and MCP-1 were more significantly reduced by EPA treatment compared to Agt (IL-6>MCP>Agt). Next, we tested whether nuclear factor-κB (NF-κB), a major proinflammatory transcription factor, was involved in regulation of these adipokines by PUFAs. EPA significantly inhibited NF-κB activation compared to control or AA treatments. Moreover, EPA attenuated tumor necrosis factor-α-induced MCP-1 and further reduced its secretion in the presence of an NF-κB inhibitor. Taken together, we reported here novel beneficial effects of EPA in adipocytes. We demonstrated direct anti-inflammatory effects of EPA, which are at least in part due to the inhibitory effects of this n-3 PUFA on the NF-κB pathway in adipocytes. In conclusion, these studies further support beneficial effects of n-3 PUFAs in adipocyte inflammation and metabolic disorders.

Quinoa extract enriched in 20-hydroxyecdysone protects mice from diet-induced obesity and modulates adipokines expression.

Besides their well-known effect in the molting control in insects, ecdysteroids are steroid hormones that display potential pharmacologic and metabolic properties in mammals. The most common ecdysteroid, 20-hydroxyecdysone (20E) is found in many plants such as quinoa. The aim of the present study was to investigate the ability of quinoa extract (Q) enriched in 20E supplementation to prevent the onset of diet-induced obesity and to regulate the expression of adipocyte-specific genes in mice. Mice were fed a standard low-fat (LF) or a high-fat (HF) diet with or without supplementation by 20E-enriched Q or pure 20E for 3 weeks. Supplementation with Q reduced adipose tissue development in HF mice without modification of their body weight gain. This adipose tissue-specific effect was mainly associated with a reduced adipocyte size and a decrease in the expression of several genes involved in lipid storage, including lipoprotein lipase and phosphoenolpyruvate carboxykinase. Furthermore, Q-treated mice exhibited marked attenuation of mRNA levels of several inflammation markers (monocyte chemotactic protein-1, CD68) and insulin resistance (osteopontin, plasminogen activator inhibitor-1 (PAI-1)) as compared to HF mice. Q supplementation also reversed the effects of HF-induced downregulation of the uncoupling protein(s) (UCP(s)) mRNA levels in muscle. Similar results were obtained in mice fed a HF diet supplemented with similar amounts of pure 20E, suggesting that the latter accounted for most of the Q effects. Our study indicates that Q has an antiobesity activity in vivo and could be used as a nutritional supplement for the prevention and treatment of obesity and obesity-associated disorders.

Transgenic mice overexpressing Renin exhibit glucose intolerance and diet-genotype interactions.

Numerous animal and clinical investigations have pointed to a potential role of the renin-angiotensin system (RAS) in the development of insulin resistance and diabetes in conditions of expanded fat mass. However, the mechanisms underlying this association remain unclear. We used a transgenic mouse model overexpressing renin in the liver (RenTgMK) to examine the effects of chronic activation of RAS on adiposity and insulin sensitivity. Hepatic overexpression of renin resulted in constitutively elevated plasma angiotensin II (four- to six-fold increase vs. wild-type, WT). Surprisingly, RenTgMK mice developed glucose intolerance despite low levels of adiposity and insulinemia. The transgenics also had lower plasma triglyceride levels. Glucose intolerance in transgenic mice fed a low-fat diet was comparable to that observed in high-fat fed WT mice. These studies demonstrate that overexpression of renin and associated hyperangiotensinemia impair glucose tolerance in a diet-dependent manner and further support a consistent role of RAS in the pathogenesis of diabetes and insulin resistance, independent of changes in fat mass.

Consequences of PPAR(α) Invalidation on Glutathione Synthesis: Interactions with Dietary Fatty Acids.

Glutathione (GSH) derives from cysteine and plays a key role in redox status. GSH synthesis is determined mainly by cysteine availability and γ-glutamate cysteine ligase (γGCL) activity. Because PPARα activation is known to control the metabolism of certain amino acids, GSH synthesis from cysteine and related metabolisms were explored in wild-type (WT) and PPARα-null (KO) mice, fed diets containing either saturated (COCO diet) or 18 : 3 n-3, LIN diet. In mice fed the COCO diet, but not in those fed the LIN diet, PPARα deficiency enhanced hepatic GSH content and γGCL activity, superoxide dismutase 2 mRNA levels, and plasma uric acid concentration, suggesting an oxidative stress. In addition, in WT mice, the LIN diet increased the hepatic GSH pool, without effect on γGCL activity, or change in target gene expression, which rules out a direct effect of PPARα. This suggests that dietary 18 : 3 n-3 may regulate GSH metabolism and thus mitigate the deleterious effects of PPARα deficiency on redox status, without direct PPARα activation.

Olanzapine-induced accumulation of adipose tissue is associated with an inflammatory state.

Second-generation antipsychotics are widely used in the treatment of all forms of psychoses, but they often produce undesirable side effects, among which are weight gain and other elements of metabolic syndrome. The mechanisms of these adverse effects are not known. The liver and adipose tissue are the principal candidate organs implicated in the development of antipsychotic-induced metabolic adverse effects. The present study investigated in the rat the effects on liver and white adipose tissue of a chronic treatment (46 days) with olanzapine 2 mg/kg or haloperidol 1 mg/kg, as compared with a control solution. In the liver, the expression of key genes involved in glucose transport and lipid metabolism and of regulatory transcription factors, as well as the TNFalpha gene, was not altered in response to either antipsychotic. Similarly, key genes involved in glucose transport and lipid metabolism were not changed in adipose tissue. However, the white adipose tissue was inflammatory in olanzapine-treated rats, with extensive macrophage infiltration and a significant increase in TNFalpha expression. In the plasma, TNFalpha and IL-1beta concentrations were slightly elevated. Chronic olanzapine treatment therefore produces a low-grade inflammatory state, likely initiated in the adipose tissue. Such an inflammatory state is known to be associated with an increased risk of insulin-resistance and cardiovascular diseases. This antipsychotic-induced inflammatory syndrome may participate in the inflammatory syndrome often observed in patients with schizophrenia. The strong and rather selective effect of olanzapine on TNFalpha expression may open new therapeutic opportunities for the prevention of olanzapine-induced metabolic abnormalities.

Deficiency of angiotensin type 2 receptor rescues obesity but not hypertension induced by overexpression of angiotensinogen in adipose tissue.

Increased angiotensinogen (AGT) production by white adipose tissue has been related to not only obesity but also hypertension. Several studies have highlighted the importance of the angiotensin II type 2 receptor (AT2) in the regulation of blood pressure and fat mass, but the relevance of this transporter in a physiopathological model of increased AGT production, as it occurs in obesity, has not yet been investigated. We used transgenic mice that display either a deletion of AT2 (AT2 KO), an overexpression of AGT (OVEX), or both compound mutants (KOVEX). Results demonstrated that adipocyte hypertrophy and increased lipogenic gene expression induced by adipose AGT overproduction was rescued by deletion of AT2. In line with AGT overexpression, KOVEX and OVEX mice have similar increased plasma AGT levels. However, KOVEX mice display a higher blood pressure than OVEX mice. In kidney, renin expression was clearly reduced in OVEX mice, and its expression was normalized in KOVEX mice. Taken together, we demonstrated that the loss of AT2 expression was sufficient to rescue obesity induced by adipose tissue AGT overexpression and confirmed the necessary role of AT2 for the onset of obesity in this model. Furthermore, despite a reduction of adipose mass in KOVEX, AT2 deficiency caused increased renin production, further worsening the hypertension caused by AGT overexpression.

The natural concentration of the conjugated linoleic acid, cis-9,trans-11, in milk fat has antiatherogenic effects in hyperlipidemic hamsters.

Milk fat is usually considered to be proatherogenic, although its fatty acid composition can vary, due mainly to farming conditions. No study has evaluated whether such variation can modify the atherogenic properties of dairy fat. Aortic lipid deposition and related risk factors were examined in Syrian hamsters fed diets for 12 wk containing 200 g/kg of 2 commercial milk fats [high content of saturated fatty acids (HSF) and low content of saturated fatty acids (LSF)] contrasting, respectively, in total saturated fatty acids (72 vs. 67 g/100 g), 18:1, trans (4.24 vs. 7.26 g/100g), and conjugated linoleic acid (mainly cis-9,trans-11 or rumenic acid; 0.39 vs. 2.59 g/100 g). Hamsters fed the LSF-diet had 25% less aortic cholesteryl-ester deposition than those fed the HSF-diet; this was accompanied by an improved plasma cholesterol profile (lower LDL cholesterol and LDL:HDL cholesterol ratio), a lower local inflammatory status (aortic gene expression of cyclooxygenase-2), and lower aortic gene expression of vascular cell adhesion molecule-1 (all P < 0.05). Supplementation of the LSF-diet with rumenic acid (up to 9 g/kg) amplified the antiatherogenic effect of the original LSF-diet compared with the HSF-diet, i.e., less aortic cholesterol loading, increased reverse cholesterol transport potential (higher plasma HDL cholesterol concentration and ATP-binding cassette, subfamily A, transporter 1 gene expression in aorta), and decreased LDL-peroxidability index and gene expression of proinflammatory IL-1beta in the aorta (all P < 0.05). In conclusion, our results suggest that the atherogenic potential of milk fat can be greatly reduced in products with a naturally high abundance of rumenic acid, and argue for increasing this fatty acid in milk.

Gender-related response of lipid metabolism to dietary fatty acids in the hamster.

Gender and dietary fatty acids are involved in the regulation of lipid metabolism, disturbances of which can lead to pathologies such as metabolic syndrome or CVD. Possible interactions between these factors were investigated in male and female hamsters fed diets rich in either saturated fatty acids ( "butter" diet) or in alpha-linolenic acid ( "linseed oil" diet). Gender effect predominated over the diet effect on cholesterol (CH) metabolism; compared to males, females exhibited lower concentrations of plasma total CH (-20 %, P<0.001), LDL-CH (-40 %, P<0.001) and HDL-CH (-16 %, P<0.001), together with higher LDL receptor (+40 %) and lower HDL receptor (-60 %) hepatic content. Triacylglycerol (TG) metabolism was affected by diet above all: compared to animals fed the "butter" diet, those fed the "linseed oil" diet exhibited lower plasma (-23 %, P=0.046) and liver TG (-20 %, P=0.026) concentration which may result from both an increased beta-oxidation (P<0.001), without any change in PPARalpha mRNA, and a decreased hepatic lipogenesis (P=0.023), without increased sterol response element binding protein 1c (SREBP1c) mRNA. The response to diet was much more pronounced in males than in females, without gender effect on the transcription level of PPARalpha and SREBP1c. Finally, the "linseed oil" diet decreased the insulin resistance index (-80 %, P<0.001) with a more marked effect in males, in relation to their higher hepatic PPARgamma expression (+90 %, P=0.012). In conclusion, in our model, the response of either TG or CH to dietary fatty acids is modulated differently by gender. The possible relevance of these interactions to dietary practice should be taken into account in man.

The adipose renin-angiotensin system modulates systemic markers of insulin sensitivity and activates the intrarenal renin-angiotensin system.

BACKGROUND: The adipose tissue renin-angiotensin system (RAS) contributes to regulation of fat mass and may also impact systemic functions such as blood pressure and metabolism. METHODS AND RESULTS: A panel of mouse models including mice lacking angiotensinogen, Agt (Agt-KO), mice expressing Agt solely in adipose tissue (aP2-Agt/Agt-KO), and mice overexpressing Agt in adipose tissue (aP2-Agt) was studied. Total body weight, epididymal fat pad weight, and circulating levels of leptin, insulin, and resistin were significantly decreased in Agt-KO mice, while plasma adiponectin levels were increased. aP2-Agt mice exhibited increased adiposity and plasma leptin and insulin levels compared to wild type (WT) controls. Angiotensinogen and type I Ang II receptor protein levels were also elevated in kidney of aP2-Agt mice. CONCLUSION: These findings demonstrate that alterations in adipose RAS activity significantly impact both local and systemic physiology in a way that may contribute to the detrimental health effects of obesity.