Protective effects of dietary phytoestrogens in chronic renal disease.

Phytoestrogens are naturally occuring plant compounds that are present primarily in soybeans as isoflavones and in flaxseed as lignans. Because of their structural similarity to endogenous estrogens, phytoestrogens bind to both estrogen receptors (ER)-alpha and beta (but more strongly to ER-beta) and exert estrogen-like effects. There is increasing evidence that dietary phytoestrogens have a beneficial role in chronic renal disease. Nutritional intervention studies have shown that consumption of soy-based protein and flaxseed reduces proteinuria and attenuates renal functional or structural damage in animals and humans with various forms of chronic renal disease. It is not clear which component(s) of the soybean or flaxseed is (are) responsible for the protective effects observed in experimental animals and in limited studies in humans. Vegetable protein has been shown to have a beneficial effect on renal disease in animals and humans. Thus, the role of soy and flaxseed cannot be ruled out. Isoflavones and lignans are readily absorbed from the gut and converted to active metabolites, which may be partly responsible for the beneficial renal effects of soy protein and flaxseed. In addition, an interaction between type of protein and phytoestrogens is also possible. The biological actions of isoflavones and lignans have been well defined in different cell types in vitro and also in vivo, but how these compounds might reduce renal injury remains to be elucidated. Possible mechanisms include inhibition of cell growth and proliferation via ER-mediated mechanisms or non-ER-mediated pathways through inhibition of tyrosine protein kinases, modulation of growth factors involved in extracellular matrix synthesis and fibrogenesis, inhibition of cytokine-induced activation of transcription factors, inhibition of angiogenesis, antioxidative action, suppression of platelet activating factor and platelet aggregation, and immunomodulatory activity. To date, clinical trials in humans are few, of relatively short duration, and involve a small number of patients. Prospective randomized trials are needed to evaluate the long-term safety and effectiveness of dietary phytoestrogens on renal disease progression in patients with chronic renal failure.

Dietary phytoestrogens: a possible role in renal disease protection.

There is growing evidence that dietary phytoestrogens have a beneficial role in chronic renal disease. This review summarizes the recent findings from dietary intervention studies performed in animals and humans suggesting that consumption of soy-based protein rich in isoflavones and flaxseed rich in lignans retards the development and progression of chronic renal disease. In several animal models of renal disease, both soy protein and flaxseed have been shown to limit or reduce proteinuria and renal pathological lesions associated with progressive renal failure. In studies of human subjects with different types of chronic renal disease, soy protein and flaxseed also appear to moderate proteinuria and preserve renal function. However, most of these clinical trials were of relatively short duration and involved a small number of patients. Furthermore, it is not clear whether the renal protective effects of soy protein and flaxseed are caused by the isoflavones (daidzein and genistein) and lignans (matairesinol and secoisolariciresinol) or some other component. The biochemistry, metabolism, and mechanisms of actions of isoflavones and lignans are discussed. Isoflavones and lignans appear to act through various mechanisms that modulate cell growth and proliferation, extracellular matrix synthesis, inflammation, and oxidative stress. Some of these actions have been shown in vitro, but studies of the mechanisms operative in vivo are lacking. The diversity of cellular actions of isoflavones and lignans supports their protective effects in a variety of experimental and human types of chronic renal disease. Further investigations are needed to evaluate their long-term effects on renal disease progression in patients with chronic renal failure.

Leptin and its relation to obesity and insulin in the SHR/N-corpulent rat, a model of type II diabetes mellitus.

The spontaneously hypertensive/NIH-corpulent (SHR/N-cp) rat is a genetic animal model that exhibits obesity, metabolic features of hyperinsulinemia, hyperglycemia, and hyperlipidemia, which are characteristic of type II diabetes and mild hypertension. To determine the role of leptin, the protein product of the ob gene, in the development of obesity and diabetes in this model, we measured steady-state circulating levels of leptin in obese and lean SHR/N-cp rats and examined the relation between plasma leptin levels and metabolic variables at the stage of established obesity in these animals. Mean fasting plasma leptin concentration was 8-fold higher in obese than in lean rats (p < 0.01). This was associated with a 6-fold elevation in plasma insulin in the obese group. Fasting levels of plasma glucose, cholesterol, and triglyceride were all significantly higher in obese rats than in lean controls. Spearman correlation analysis showed a significant positive correlation between plasma leptin concentration and body weight among the animals (r = 0.73, p < 0.01). Similarly, plasma insulin concentration was significantly correlated with BW in all animals (r = 0.54, p < 0.05). There was also a significant positive correlation between plasma leptin and plasma insulin in the entire group (r = 0.70, p < 0.01). However, this relationship was significant only for lean rats but not for obese rats (r = 10.59, p < 0.05 for lean rats, and r = 0.23, p = NS, for obese rats). Plasma leptin also correlated positively with fasting plasma glucose (r = 0.75, p < 0.05), total cholesterol (r = 0.63, p < 0.05), and triglyceride (r = 0.67, p < 0.05). The marked elevation of plasma leptin in obese SHR/N-cp rats suggests that obesity in this animal model is related to up-regulation of the ob gene. Circulating leptin appears to be one of the best biological markers of obesity and that hyperleptinemia is closely associated with several metabolic risk factors related to insulin resistance in the diabesity syndrome.

Effects of dietary fats on red blood cell membrane insulin receptor in normo- and hypercholesterolemic miniature swine.

It has been demonstrated that the type of dietary fat affects insulin receptors in various tissues in normal humans and animals by altering membrane fluidity. This study compares the effects of n-3 fatty acids from fish oil and n-6 fatty acids from corn oil on red blood cell membrane insulin receptors in normal and hypercholesterolemic minipigs. A group of minipigs were made hypercholesterolemic by feeding cholesterol and lard for 2 months; the other group served as controls and was fed stock diet. Both groups were then fed experimental diets containing either corn oil or menhaden oil or a mixture of the two for 23 additional weeks. Blood was collected at 0, 2, 12 and 23 weeks after the start of the experimental diets and membranes were prepared from the red blood cells. Insulin binding to red blood cell membranes was measured by radioreceptor assay. Plasma insulin was measured by radioimmunoassay. Insulin binding to red blood cell membrane was compared with the fluidity of the membrane measured and reported earlier. There was no significant effect of cholesterol feeding on plasma insulin concentrations. After 23 weeks on experimental diet plasma insulin was significantly higher in minipigs fed menhaden oil compared to those fed corn oil. No such effect was observed in hypercholesterolemic minipigs. No significant effect of either hypercholesterolemia or fish oil was observed on red blood cell insulin binding. A significant negative relationship was observed between insulin binding and anisotropy at 4°C for all probes but at 37°C significant negative relationship was observed only with polar probes. The data suggest that n-3 fatty acids from fish oil significantly increases plasma insulin in minipigs compared to n-6 fatty acids from corn oil. However, the unsaturation has no significant effect on insulin receptors on erythrocytes. Similarly, prior hypercholesterolemic state also has no effect on plasma insulin levels or the insulin binding to red blood cell membranes.

Relationship between fatty acids and the endocrine system.

Significant interactions exist between fatty acids and the endocrine system. Hormones affect the metabolism of fatty acids and the fatty acid composition of tissue lipids. The principal hormones involved in lipid metabolism are insulin, glucagon, catecholamines, cortisol and growth hormone. The concentrations of these hormones are altered in chronic degenerative conditions such as diabetes and cardiovascular disease, which in turn lead to alterations in tissue lipids. Lipogenesis and lipolysis, which modulate fatty acid concentrations in plasma and tissues, are under hormonal control. Neuropeptides are involved in lipid metabolism in brain and other tissues. Polyunsaturated fatty acids (PUFA) are also precursors for eicosanoids including prostaglandins, leukotrienes, and thromboxanes, which have hormone-like activities. Fatty acids in turn alter both hormone and neuropeptide concentrations and their receptors. Saturated and trans fatty acids (TFA) decrease insulin concentration leading to insulin resistance. In contrast, PUFA increase plasma insulin concentration and decrease insulin resistance. In humans, omega-3 PUFA alter the levels of opioid peptides in plasma.

Is adrenomedullin a causal agent in some cases of type 2 diabetes?

The study of two populations with a recent onset of type 2 diabetes showed that a subset of the patients had higher levels of adrenomedullin (AM) than the rest of the diabetics. In this subset, physiological elevations of AM might have triggered the disease in predisposed individuals. Diabetics showed higher levels of AM than healthy controls. In addition, glycemia was measured in diabetic rats after injection of saline, AM, or antiAM antibody. AM elevated glycemia, whereas the antibody reduced circulating glucose to normal. These results suggest that manipulation of AM levels could represent a new approach in the management of diabetes for the appropriate individuals.

Role of angiotensin-converting enzyme inhibition in glucose metabolism and renal injury in diabetes.

The role of angiotensin-converting enzyme (ACE) inhibition in glucose metabolism and renal injury in diabetes has been extensively investigated in diabetic humans, as well as in animal models of diabetes. Accumulated data indicate that ACE inhibitors have either no adverse effect on glucose control or insulin sensitivity or may even improve them. ACE inhibitors also appear to have neutral or positive effects on lipid metabolism. The variability of results between studies may relate to differences in experimental design, the degree of glycemia or insulin resistance, potassium balance, and dose or duration of ACE inhibitor treatment, among others. In contrast, ACE inhibitors have proved effective in limiting proteinuria and retarding renal function loss in insulin-dependent diabetes mellitus (IDDM) or non-insulin-dependent diabetes mellitus (NIDDM) patients. In rats with experimental or spontaneous diabetes, ACE inhibitors also reduce proteinuria and limit glomerular as well as tubulointerstitial damage, independent of their effects on systemic arterial pressure. How ACE inhibitors limit renal injury in diabetes is not entirely clear, but hemodynamic and nonhemodynamic mechanisms may be involved. Increasing evidence suggests that the intrarenal renin-angiotensin system (RAS) may be altered or activated in the diabetic kidney. Such activation may be specifically inhibited by ACE inhibitors and may explain the superiority of this class of agents over other antihypertensive agents in reducing proteinuria and slowing the progression of diabetic nephropathy.

Long-term effects of perindopril on metabolic parameters and the heart in the spontaneously hypertensive/NIH-corpulent rat with non-insulin-dependent diabetes mellitus and hypertension.

The spontaneously hypertensive/NIH-corpulent (SHR/N-cp) rat is a genetic model that exhibits both non-insulin-dependent diabetes mellitus (NIDDM) and hypertension. To determine the impact of long-term treatment with the long-acting angiotensin-converting enzyme (ACE) inhibitor perindopril (PE) on the glucose metabolism, lipid levels, and heart in this model, studies were performed in three groups of SHR/N-cp rats maintained on a diet containing 54% carbohydrate with 18% sucrose and 36% starch. One group of obese rats received PE (0.5 to 1.0 mg/kg body weight/d) for 3 to 4 months, a second group of obese rats received no treatment, and a third group of lean rats were used as controls. The mean systolic blood pressure (SBP) increased gradually in both untreated obese and lean rats, with lean animals showing slightly higher levels compared with untreated obese rats. By contrast, SBP was reduced to normal levels in PE-treated obese rats throughout the treatment period. Compared with lean rats, obese rats showed significantly higher body weight and fasting serum levels of glucose, insulin, total cholesterol (TC), and triglyceride (TG). However, no significant differences were observed in these metabolic parameters between PE-treated and untreated obese rats. Plasma renin activity measured at the end of the treatment period was significantly higher in PE-treated rats compared with untreated obese and untreated lean rats. The mean heart weight and left ventricular weight, expressed in absolute terms or indexed to body weight, were significantly lower in PE-treated versus untreated obese and untreated lean rats. To further determine whether glucose metabolism is directly affected by PE treatment, in vitro glycogen synthesis was evaluated in isolated soleus muscles obtained from three additional groups of animals. The basal rate of muscle glycogen synthesis was significantly lower in obese compared with lean rats (P < .05), but did not differ between PE-treated and untreated obese rats. Maximal insulin-stimulated glycogen synthesis increased threefold in PE-treated obese rats, but this increase did not differ from the increases observed in untreated obese and lean rats. In conclusion, the present study shows that long-term PE treatment in obese SHR/N-cp rats with NIDDM and hypertension effectively controlled systemic arterial pressure and resulted in a significant reduction in left ventricular weight. However, these favorable effects of PE were not associated with significant improvement in glucose tolerance, hyperinsulinemia, and hyperlipidemia in this model. PE also had no direct stimulatory effects on either basal or insulin-mediated glycogen synthesis in the isolated soleus muscle of obese rats, perhaps because of the severe insulin-resistant state of the animals. Our results support the clinical observations that antihypertensive therapy with ACE inhibitors has neutral effects on glucose metabolism and insulin sensitivity in patients with combined hypertension and NIDDM.

Dietary menhaden and corn oils and the red blood cell membrane lipid composition and fluidity in hyper- and normocholesterolemic miniature swine.

Fatty acids in the diet are readily incorporated into lipids in various tissues. However, it is not clear whether all tissues have the same level of incorporation. Second, (n-6) unsaturated fatty acids increase the fluidity of membranes, but this has not been shown for (n-3) fatty acids. In this study, we measured the incorporation of (n-6) and (n-3) fatty acids into erythrocyte membrane lipids and studied their effects on the fluidity of erythrocyte membranes. One group of female miniature swine was made hypercholesterolemic by feeding the swine cholesterol and lard for 2 mo; the other group served as controls and was fed a stock diet. Both groups were then fed either corn oil or menhaden oil or a mixture of the two for 23 additional weeks. Blood was collected at 0, 2, 4, 12 and 23 wk after initialization of the experimental diets, and fatty acid composition of phospholipids was assessed. Membrane phospholipids of pigs fed menhaden oil had elevated (n-3) fatty acids (20:5 and 22:6), and lower 18:2 than those fed corn oil. There was no difference in 20:4 content. The fatty acid changes occurred as early as 2 wk after consumption of the corn oil or menhaden oil in pigs previously fed a stock diet, but it took longer in pigs previously fed lard + cholesterol, indicating residual effects of pretreatment. Menhaden oil increased anisotropy (indicating decreased fluidity) more than corn oil for the nonpolar probe diphenylhexatriene (DPH) at earlier time points, but not at 23 wk. Erythrocyte membrane fluidity was significantly related to membrane polyunsaturate content, with (n-6) fatty acids having a greater influence than (n-3) fatty acids. A comparison of the present red blood cell fatty acid compositions with brain synaptosome fatty acid compositions for the same animals showed poor correlations for some of the fatty acids. There was no significant direct relationship between docosahexaenoate (DHA) concentrations in erythrocyte membranes with DHA concentrations in brain synaptosomes from cerebellum, forebrain and caudate nucleus.

Opioid Peptides, Adrenocorticotrophic Hormone and Dietary Copper Intake in Humans.

Copper plays an important role in cardiac and brain function possibly through endocrine and neuroendocrine systems. The syndrome of copper deficiency is worsened by dietary fructose and other trace metals such as zinc. We investigated the effect of a low copper diet on plasma opioid peptides in 11 healthy young volunteers who were fed foods low in copper but adequate in all other nutrients. The study was divided into three dietary periods. Copper was added to the diet so that the diet contained 0.66 mg/day for 24 days (marginal Cu), 0.38 mg/day for 42 days (low Cu) and 2.49 mg/day for 24 days (adequate Cu). The indices of copper status, ceruloplasmin and plasma copper concentrations, declined and were significantly lower (p < 0.05) at the end of the low Cu period than at the beginning of the study and the end of the marginal Cu period. They increased significantly at the end of the adequate Cu diet to the levels of the marginal Cu diet. Plasma ß-endorphin (BEN), Leu-enkephalin (LE), Met-enkephalin (ME) and Adrenocorticotropic hormone (ACTH) were measured by radioimmunoassay at the beginning of the study and at the end of each dietary period. No significant differences were observed in BEN, LE or ME during any of the periods. There were only small increases in LE and ME at the end of marginal and low copper diet periods and no significant changes were observed on copper repletion. Plasma ACTH was significantly lower at the end of low copper compared to baseline value but was not lower after marginal copper. Copper repletion had no significant effect on ACTH. The data show that plasma opioid peptides did not respond significantly to differential copper intake.

Regulation of insulin secretion and blood glucose metabolism by adrenomedullin.

Adrenomedullin (AM), a recently discovered hypotensive peptide, is expressed in the endocrine pancreas of different species, as demonstrated by immunocytochemistry. Electron microscopic studies with double immunogold showed colocalization of AM and pancreatic polypeptide. A homogeneous expression of AM receptor was found throughout the islet using in situ hybridization. Six different insulin- producing cell lines have been analyzed by reverse transcription-PCR and showed expression of both AM and its receptor. Two experimental models have been used to study the effects of AM in pancreatic physiology. 1) Analysis of isolated rat islets shows that AM inhibits insulin secretion in a dose-dependent manner. The monoclonal antibody MoAb-G6, which neutralizes AM bioactivity, was able to increase insulin release 5-fold; this effect was reversed by the addition of synthetic AM. 2) Oral glucose tolerance tests showed that iv injection of AM reduces the levels of insulin in the bloodstream with a concomitant increase in circulating glucose. These studies implicate AM as a newly defined factor of the insulin regulatory system that could be involved in disorders such as diabetes and obesity.

Selective responses of hormones involved in carbohydrate and lipid metabolism and properties of erythrocyte membranes during the menstrual cycle in premenopausal women consuming moderate amounts of alcohol.

The effects of chronic consumption of moderate amounts of alcohol on hormones associated with lipid and carbohydrate metabolism, plasma concentrations of triacylglycerol and cholesterol, insulin receptors on erythrocyte membranes, and erythrocyte membrane fluidity were studied during three phases of the menstrual cycle in 37 premenopausal women. Subjects were given either 30 g ethanol or an equienergetic fruit juice for three menstrual cycles in a crossover design. Blood samples were analyzed during the luteal, midcycle, and follicular phases. Administration of alcohol induced a significant rise in plasma glucagon and cortisol uniformly across the entire menstrual cycle. A similar rise in plasma growth hormone was observed at midcycle during the period when subjects consumed alcohol. A marginal effect was observed on cholesterol and somatomedin C concentrations. Insulin binding to erythrocyte ghosts was not affected by either alcohol or menstrual-cycle phase. Erythrocyte membranes were more fluid during the follicular phase than during the luteal phase of the menstrual cycle when the women were consuming the alcohol. There were no perceptible interactions between alcohol and phases of the menstrual cycle for the indexes studied, except membrane fluidity.

Chromium improves insulin response to glucose in rats.

The effects of chromium (Cr) supplementation on insulin secretion and glucose clearance (KG) during intravenous glucose tolerance tests (IVGTTS) were assessed in rats with impaired glucose tolerance due to dietary Cr deficiency. Male Wistar rats were maintained after weaning on a basal low-Cr diet containing 55% sucrose, 15% lard, 25% casein. American Institute of Nutrition (AIN)-recommended levels of vitamins, no added Cr, and an altered mineral content as required to produce Cr deficiency and impaired glucose tolerance. The Cr-supplemented group ([+Cr] n = 6) were provided with 5 ppm Cr as CrCl3 in the drinking water, and the Cr-deficient group ([-Cr]n = 5) received purified drinking water. At 12 weeks on the diet, both groups of rats were hyperinsulinemic (+Cr, 103 +/- 13; -Cr, 59 +/- 12 microU/mL) and normoglycemic (+Cr, 127 +/- 7; -Cr, 130 +/- 4 mg/dL), indicating insulin resistance. After 24 weeks, insulin levels were normal (+Cr, 19 +/- 5; -Cr, 21 +/- 3 microU/mL) and all rats remained normoglycemic (+Cr, 124 +/- 8; -Cr, 131 +/- 6 mg/dL). KG values during IVGTTS were lower in -Cr rats (KG = 3.58%/min) than in +Cr rats (KG = 5.29%/min), correlating with significantly greater 40-minute glucose areas in the -Cr group (P < .01). Comparisons of 40-minute insulin areas indicated marked insulin hyperresponsiveness in the -Cr group, with insulin-secretory responses increased nearly twofold in -Cr animals (P < .05). Chromium deficiency also led to significant decreases in cyclic adenosine monophosphate (cAMP)-dependent phosphodiesterase (PDE) activity in spleen and testis (P < .01). In these studies, Cr deficiency was characterized by both beta-cell hypersecretion of insulin and tissue insulin resistance that were associated with decreased tissue levels of cAMP PDE activity.

Gender, dietary copper and carbohydrate source influence cardiac collagen and lysyl oxidase in weanling rats.

The present investigation was conducted to determine the effects of consumption of diets containing fructose or cornstarch on cardiac collagen metabolism in weanling male and female rats fed copper-deficient or copper-adequate diets for 5 wk. Although both male and female rats that consumed the copper-deficient diet containing fructose were similarly copper deficient, only the males showed severe cardiac pathologies and two died prematurely due to heart-related abnormalities. These pathologies were accompanied by a significant reduction of cardiac lysyl oxidase activity and elevated soluble and total cardiac collagen concentrations compared with rats fed copper-adequate diets. These abnormalities were less severe in copper-deficient rats fed cornstarch. The data show that the activity of the copper-containing enzyme lysyl oxidase is affected by both dietary carbohydrate and gender. The pathologies of heart tissue could be the result of abnormal crosslinking of collagen induced by the combination of copper deficiency, fructose feeding and the sex of the rats.

Opioid peptides, adrenocorticotrophic hormone, and idiopathic (orthostatic) edema.

The effect of dextroamphetamine sulfate (Dexedrine) on plasma opioid peptides, hormones, and other metabolites was studied in eight female subjects with idiopathic (orthostatic) edema and five healthy females. All subjects were given 20 mg of dextroamphetamine sulfate, a drug widely used in the treatment of this disorder, and blood samples were collected before and 30, 60, and 90 minutes after treatment. Patients with idiopathic (orthostatic) edema had significantly lower plasma sodium levels but higher blood urea nitrogen, aldosterone, and renin levels. D-amphetamine decreased aldosterone and renin levels in both groups. Plasma adrenocorticotropin levels were lower whereas met-enkephalin levels were higher in idiopathic (orthostatic) edema subjects compared to control subjects. D-amphetamine had no significant effect on plasma beta-endorphin, adrenocorticotrophic hormone, or enkephalins. Our data indicate that opioid peptides, especially enkephalins, and adrenocorticotrophic hormone may be involved in the pathogenesis of idiopathic (orthostatic) edema syndrome, but they seem uninvolved in the aldosterone- and renin-lowering action of amphetamine. It is possible that amphetamine is acting further down the chain, either directly on the adrenal and kidney or the microvasculature, rather than at hypothalamus-pituitary axis.

Comparison of effects of decapitation and anesthesia on metabolic and hormonal parameters in Sprague-Dawley rats.

The modes of euthanasia by either anesthesia or by decapitation were compared by assessing several metabolic and hormonal parameters from plasma and hormone receptors from liver plasma membranes. Two different anesthetics were used. Compared to decapitation, euthanasia by anesthesia significantly increased plasma glucose and triglyceride levels but not plasma cholesterol. Plasma insulin was also significantly increased by anesthetics. No significant differences were observed in plasma glucagon levels or insulin and glucagon receptors from liver plasma membranes between rats euthanized by decapitation and anesthesia. Glucagon receptors were however, affected by dietary carbohydrates. It is concluded that in studies involving measurements of metabolic and hormonal parameters, the use of anesthesia is to be avoided for euthanasia and that decapitation should be the method of choice.

Effects of omega 3 fatty acids and vitamin E on hormones involved in carbohydrate and lipid metabolism in men.

Forty healthy men were fed diets providing 40% of energy from fat and a minimum of 25 mg vitamin E for 28 wk. During the first 10 wk diets were supplemented with placebo, 15 g mixed fat/d. During the second 10 wk placebo was replaced by 15 g fish-oil concentrate/d. During the last 8 wk 200 mg vitamin E/d was added to fish oil. Compared with placebo, fish-oil feeding significantly increased plasma glucose and decreased triacylglycerol, insulin, glucagon, growth hormone, and somatomedin C. The changes in plasma cholesterol, cortisol, and dehydroepiandrosterone sulphate (DHEA-S) were not significant. Fish oil plus vitamin E further decreased insulin, growth hormone, and DHEA-S and reversed the effect of fish-oil on somatomedin C. The changes in glucose, glucagon, growth hormone, and cortisol were not significant. Thus, changes in plasma glucose and lipids caused by dietary fish oil alone and with fish oil plus vitamin E appear to be due to alterations in hormones involved in carbohydrate and lipid metabolism.

High-fat diet preference in developing and adult rats.

Diet preference tests in rats have yielded equivocal results, as some investigators have reported a strong preference for diets high in fat over those containing less fat, while others have failed to see this preference. To further explore this unresolved problem, two diet preference experiments were conducted. In Experiment 1, adult rats were maintained for at least three months on one of three powdered diets (control, high-carbohydrate or high-fat). Rats were then given a preference test with all three diets available. Animals from each group overwhelmingly preferred the high-fat diet. To determine whether this preference was also present in younger, developing rats, in Experiment 2, weanling animals were tested with the same three diets as in Experiment 1. As observed with adult animals, weanling rats also showed a strong preference for the high-fat diet. The idea that rats prefer a diet with a relatively high level of fat is supported. Possible explanations for these findings are discussed.

Dietary trans fatty acids modulate erythrocyte membrane fatty acyl composition and insulin binding in monkeys.

The substitution of trans- for half of the cis-monounsaturated fatty acids in the diet of Macaca fasicularis monkeys resulted in alterations in erythrocyte fatty acid composition and insulin receptor properties but not in membrane fluidity. Both cis and trans diets contained 10% fat and similar fatty acid compositions, except that approximately 50% of the cis-octadecenoate (c-18:1) in the cis diet was replaced with trans-octadecenoate isomers (t-18:1) in the trans diet. Compared with the cis diet, the trans diet resulted in the incorporation of approximately 11% t-18:1, an approximately 50% decrease in c-18:1, an approximately 16% decrease in total saturated fatty acids, and an approximately 20% increase in 18:2(n-6) in erythrocyte membrane lipids. The increase in 18:2(n-6) may reflect on homeostatic mechanisms designed to maintain overall membrane fluidity, as no diet-related changes in fluidity were observed with diphenylhexatriene steady state fluorescence polarization. Values observed for insulin binding and insulin receptor number were higher and binding affinity was lower in monkeys fed the cis diet. In the absence of an effect on overall membrane fluidity, altered receptor activity suggests that insulin receptor activity is dynamic, requiring specific fluid membrane subdomains or highly specific fatty acid-protein interactions.