Differences in response to corticotropin-releasing factor after short- and long-term consumption of a high-fat diet

We previously reported an exaggerated endocrine and weight loss response to stress in rats fed a high-fat (HF) diet for 5 days. Others report blunted stress-induced anxiety in rats made obese on a HF diet. Experiments described here tested whether sensitivity to stress-related peptides was changed in obese and nonobese HF-fed rats. Third ventricle infusion of corticotropin-releasing factor (CRF) in rats made obese on HF diet (40% kcal fat) produced an exaggerated hypophagia, which is thought to be mediated by CRF(2) receptors. Obese rats responded to a lower dose of CRF for a longer time than rats fed a low-fat (LF) diet (12% kcal fat). CRF-induced release of corticosterone, which is thought to be mediated by CRF(1) receptors, was not exaggerated in obese HF-fed rats. In contrast, rats fed HF diet for 5 days showed the same food intake and corticosterone response to CRF as LF-fed rats. CRF mRNA expression in the paraventricular nucleus of the hypothalamus was stimulated by mild stress (ip saline injection and placement in a novel cage) in LF-fed rats but not in rats fed HF diet for 5 days because of a nonsignificant increase in expression in nonstressed HF-fed rats. In addition, nonstressed levels of urocortin (UCN) I mRNA expression in the Edinger-Westphal nucleus were significantly inhibited in HF-fed rats. These data suggest that rats that have become obese on a HF diet show a change in responsiveness to stress peptides, whereas the increased stress response in nonobese HF-fed rats may be associated with changes in basal CRF and UCN I mRNA expression.     

Adult Consequences of Post-weaning High Fat Feeding on the Limbic–HPA Axis of Female Rats

The peripubertal period is critical for the final maturation of circuits controlling energy homeostasis and stress response. However, the consequence of juvenile fat consumption on adult physiology is not clear. This study analyzed the adult consequences of post-weaning fat feeding on limbic–hypothalamic–pituitary–adrenal (HPA) axis components and on metabolic regulators of female rats. Wistar rats were fed either a high fat (HF) diet or the normal chow from weaning to puberty or to 3 months of age. Additional groups crossed their diets at puberty onset. Plasma leptin, insulin, and corticosterone levels were determined by radioimmunoassay and their brain receptors by western blot analysis. Adult HF-fed animals though not overweight, had higher corticosterone and reduced glucocorticoid receptor levels in the hypothalamus and hippocampus, compared to the controls. The alterations in HPA axis emerged already at puberty onset. Leptin receptor levels in the hypothalamus were reduced only by continuous fat feeding from weaning to adulthood. The pre-pubertal period appeared more vulnerable to diet-induced alterations in adulthood than the post-pubertal one. Switching from fat diet to normal chow at puberty onset restored most of the diet-induced alterations in the HPA axis. The corticosteroid circuit rather than the leptin or insulin system appears as the principal target for the peripubertal fat diet-induced effects in adult female rats.     

Effects of high-fat diet on insulin receptor function in rat hippocampus and the level of neuronal corticosterone

AimChronic consumption of a high-fat (HF) diet contributes to peripheral insulin resistance and elevated plasma corticosterone. However, the effect of HF consumption on the neurofunctional insulin receptors and neuronal corticosterone level is unclear. We tested the hypothesis that HF consumption can lead to peripheral insulin resistance, elevated neuronal corticosterone, and impaired neuronal responses to insulin.Main methodsMale Wistar rats were fed with normal diet or HF diet for 4, 8 or 12 weeks. At the end of each dietary period, plasma was collected for investigating peripheral insulin resistance parameters and corticosterone. Brains were then rapidly removed for studying the function of neuronal insulin receptors (IRs) by extracellular recording in CA1 hippocampus, neuronal IR signaling by immunoblot technique and neuronal corticosterone.Key findingsElevated plasma corticosterone level was initially seen in 4-week HF-fed rats. Peripheral insulin resistance developed at 8-week HF-fed rats. However, the elevated neuronal corticosterone level was found at 12-week HF consumption. The neuronal IR response demonstrated by insulin-mediated long-term depression in CA1 hippocampus was diminished in 12-week HF-fed rats. The phosphorylation levels of neuronal IR, IR substrate 1 and Akt/PKB were decreased in 12-week HF-fed rats with no change in these proteins. There was a correlation among peripheral insulin resistance, neuronal stress (elevated neuronal corticosterone), and neuronal insulin resistance in HF group.SignificanceOur findings suggest that HF consumption can lead to the elevation of corticosterone and peripheral insulin resistance, which could contribute to neuronal insulin resistance and neuronal stress.     

Leptin action is modified by an interaction between dietary fat content and ambient temperature

Mice adapted to a high-fat diet are reported to be leptin resistant; however, we previously reported that mice fed a high-fat (HF) diet and housed at 23 degrees C remained sensitive to peripheral leptin and specifically lost body fat. This study tested whether leptin action was impaired by a combination of elevated environmental temperature and a HF diet. Male C57BL/6 mice were adapted to low-fat (LF) or HF diet from 10 days of age and were housed at 27 degrees C from 28 days of age. From 35 days of age, baseline food intake and body weight were recorded for 1 wk and then mice on each diet were infused with 10 microg leptin/day or PBS from an intraperitoneal miniosmotic pump for 13 days. HF-fed mice had a higher energy intake than LF-fed mice and were heavier but not fatter. Serum leptin was lower in PBS-infused HF- than LF-fed mice. Leptin significantly inhibited energy intake of both LF-fed and HF-fed mice, and this was associated with a significant increase in hypothalamic long-form leptin receptors with no change in short-form leptin receptor or brown fat uncoupling protein-1 mRNA expression. Leptin significantly inhibited weight gain in both LF- and HF-fed mice but reduced the percentage of body fat mass only in LF-fed mice. The percentage of lean and fat tissue in HF-fed mice did not change, implying that overall growth had been inhibited. These results suggest that dietary fat modifies the mechanisms responsible for leptin-induced changes in body fat content and that those in HF-fed mice are sensitive to environmental temperature.     

Treatment with low-dose resveratrol reverses cardiac impairment in obese prone but not in obese resistant rats

We hypothesized that a low-dose resveratrol will reverse cardiovascular abnormalities in rats fed a high-fat (HF) diet. Obese prone (OP) and obese resistant (OR) rats were fed an HF diet for 17 weeks; Sprague-Dawley rats fed laboratory chow served as control animals. During the last 5 weeks of study, treatment group received resveratrol daily by oral gavage at a dosage of 2.5 mg/kg body weight. Assessments included echocardiography, blood pressure, adiposity, glycemia, insulinemia, lipidemia, and inflammatory and oxidative stress markers. Body weight and adiposity were significantly higher in OP rats when compared to OR rats. Echocardiographic measurements showed prolonged isovolumic relaxation time in HF-fed OP and OR rats. Treatment with resveratrol significantly improved diastolic function in OP but not in OR rats without affecting adiposity. OP and OR rats had increased blood pressure which remained unchanged with treatment. OP rats had elevated fasting serum glucose and insulin, whereas OR rats had increased serum glucose and normal insulin concentrations. Resveratrol treatment significantly reduced serum glucose while increasing serum insulin in both OP and OR rats. Inflammatory and oxidative stress markers, serum triglycerides and low-density lipoprotein were higher in OP rats, which were significantly reduced with treatment. In conclusion, HF induced cardiac dysfunction in both OP and OR rats. Treatment reversed abnormalities in diastolic heart function associated with HF feeding in OP rats, but not in OR rats. The beneficial effects of resveratrol may be mediated through regression of hyperglycemia, oxidative stress and inflammation.     

Insulin-like growth factor I mediates high-fat diet-induced adipogenesis in Osborne-Mendel rats

To determine if high-fat (HF) diet-induced changes in adipose tissue cellularity are associated with the presence of paracrine growth factor(s) that alter preadipocyte proliferation, Osborne-Mendel rats were fed either a HF (76% energy) or a low-fat (LF, 12% energy) diet for 85 days. HF-fed rats had greater (P < 0.05) fat pad size, total fat cell number, number of small (30-70 microm) and large (80-140 microm) adipocytes, and percentage of 100- to 140-microm adipocytes compared with LF-fed rats. Preadipocytes in primary cell culture treated with inguinal adipose tissue conditioned medium (ATCM) prepared from HF-fed rats had greater (P < 0.05) proliferation compared with cultures treated with ATCM from LF-fed rats. Proliferative capacity of ATCM prepared from HF-fed rats was attenuated after the stripping of the medium of insulin-like growth factor I using an immunomagnetic bead separation system. These data are consistent with the concept that insulin-like growth factor I is involved in the paracrine regulation of adipogenesis.     

Association between 12α-hydroxylated bile acids and hepatic steatosis in rats fed a high-fat diet

High-fat (HF) diet induces hepatic steatosis that is a risk factor for noncommunicable diseases such as obesity, type 2 diabetes and cardiovascular disease. Previously, we found that HF feeding in rats increases the excretion of fecal bile acids (BAs), specifically 12α-hydroxylated (12αOH) BAs. Although the liver is the metabolic center in our body, the association between hepatic steatosis and 12αOH BAs in HF-fed rats is unclear. Thus, we investigated extensively BA composition in HF-fed rats and evaluated the association between hepatic steatosis and 12αOH BAs. Acclimated male inbred WKAH/HkmSlc rats were divided into two groups and fed either control or HF diet for 8 weeks. Feeding HF diet increased hepatic triglyceride and total cholesterol concentrations, which correlated positively with 12αOH BAs concentrations but not with non-12αOH BAs in the feces, portal plasma and liver. Accompanied by the increase in 12αOH BAs, the rats fed HF diet showed increased fat absorption and higher mRNA expression of liver Cidea. The enhancement of 12αOH BA secretion may contribute to hepatic steatosis by the promotion of dietary fat absorption and hepatic Cidea mRNA expression. The increase in 12αOH BAs was associated with enhanced liver cholesterol 7α-hydroxylase (Cyp7a1) and sterol 12α-hydroxylase (Cyp8b1) mRNA expression. There was a significant increase in 7α-hydroxycholesterol, a precursor of BAs, in the liver of HF-fed rats. Altogether, these data suggest that the HF diet increases preferentially 12αOH BAs synthesis by utilizing the accumulated hepatic cholesterol and enhancing mRNA expression of Cyp7a1 and Cyp8b1 in the liver.     

Grape skin extract protects against programmed changes in the adult rat offspring caused by maternal high-fat diet during lactation

Maternal overnutrition during suckling period is associated with increased risk of metabolic disorders in the offspring. We aimed to assess the effect of Vitis vinifera L. grape skin extract (ACH09) on cardiovascular and metabolic disorders in adult male offspring of rats fed a high-fat (HF) diet during lactation. Four groups of female rats were fed: control diet (7% fat), ACH09 (7% fat plus 200 mg kg^?1 d^?1 ACH09 orally), HF (24% fat), and HF+ACH09 (24% fat plus 200 mg kg^?1 d^?1 ACH09 orally) during lactation. After weaning, all male offspring were fed a control diet and sacrificed at 90 or 180 days old. Systolic blood pressure was increased in adult offspring of HF-fed dams and ACH09 prevented the hypertension. Increased adiposity, plasma triglyceride, glucose levels and insulin resistance were observed in offspring from both ages, and those changes were reversed by ACH09. Expression of insulin cascade proteins IRS-1, AKT and GLUT4 in the soleus muscle was reduced in the HF group of both ages and increased by ACH09. The plasma oxidative damage assessed by malondialdehyde levels was increased, and nitrite levels decreased in the HF group of both ages, which were reversed by ACH09. In addition, ACH09 restored the decreased plasma and mesenteric arteries antioxidant activities of superoxide dismutase, catalase and glutathione peroxidase in the HF group. In conclusion, the treatment of HF-fed dams during lactation with ACH09 provides protection from later-life hypertension, body weight gain, insulin resistance and oxidative stress. The protective effect ACH09 may involve NO synthesis, antioxidant action and activation of insulin-signaling pathways.     

Cardioprotective and antihypertensive effects of Enicostemma littorale Blume extract in fructose-fed rats

We investigated the protective effects of Enicostemma littorale Blume (EL) extract on hypertension and insulin resistance along with its associated cardiovascular complications in high fructose (HF) fed rats. For this, rats were divided among 4 groups: (i) control, fed laboratory chow; (ii) fed with a high level of fructose; (iii) fed with a high level of fructose plus E. littorale extract; and (iv) fed with a high level of fructose plus rosiglitazone (Rg). EL and Rg treatments were given simultaneously with HF diet. The results show that untreated HF-fed rats showed altered oral glucose tolerance, increased fasting insulin, and increased fasting glucose. These rats also exhibited hypertriglyceridemia, moderate hypertension, platelet hyperaggregability, decreased prothrombin time, activated partial thromboplastin time, altered vascular reactivity, and increased serum levels of enzymes (creatine kinase, type muscle-brain (CK-MB), aspartate aminotransferase (SGOT), lactate dehydrogenase (LDH), and alanine aminotransferase (SGPT). This is the first demonstration of platelet hyperaggregation and prothrombotic alteration in HF-fed rats. HF-fed rats treated with EL showed improved insulin resistance, along with reduced hypertriglyceridemia, hypertension, platelet aggregability, blood coagulation, serum enzymes (CK-MB, SGOT, LDH and SGPT), and vascular reactivity. These effects of EL in HF-induced hypertensive rats might be associated with the suppression of hyperinsulinemia and hypertriglyceridemia, along with its antiatherogenic and antithrombogenic potential. These data indicate that the aqueous extract of EL has great therapeutic potential for the prevention and (or) management of insulin resistance and the associated hypertension.     

Central leptin gene therapy fails to overcome leptin resistance associated with diet-induced obesity

The objective of this study was to determine if central overexpression of leptin could overcome the leptin resistance caused by 100 days of high-fat feeding. Three-month old-F344XBN male rats were fed either control low fat chow (Chow), which provides 15% of energy as fat, or a high-fat/high-sucrose diet (HF), which provides 59% of energy as fat. Over several weeks, the HF-fed animals spontaneously split into two groups of animals: those that became obese on the HF diet (DIO) and those that did not gain extra weight on the HF diet [diet resistant (DR)]. After 100 days of HF feeding, animals were given a single intracerebroventricular injection containing 5.75E10 particles of rAAV encoding leptin (rAAV-leptin) or control virus (rAAV-con). Chow animals responded robustly to rAAV-leptin, including significant anorexia, weight loss, and lipopenia. In contrast, DIO were completely unresponsive to rAAV-leptin. DR rats responded to rAAV-leptin, but in a more variable fashion than Chow. Unlike what was observed in Chow, the anorectic response to rAAV-leptin rapidly attenuated and was no longer significant by day 14 postvector delivery. Both DIO and DR animals were found to have reduced long-form leptin receptor expression and enhanced basal P-STAT-3 in the hypothalamus with respect to Chow. rAAV-leptin caused an increase in STAT3 phosphorylation and proopiomelanocortin expression in the hypothalamus and an increase in uncoupling protein-1 in brown adipose tissue in both Chow and DR animals, but failed to do so in DIO. This suggests that central overexpression of leptin is not a viable strategy to reverse diet-induced obesity.     

Effect of dietary polyunsaturated fat and 7,12-dimethylbenz(a)-anthracene on rat splenic natural killer cells and prostaglandin E synthesis

Summary Dietary polyunsaturated fat has been shown to stimulate mammary tumorigenesis induced in rats by 7,12-dimethylbenz(a)anthracene (DMBA). Studies were undertaken to investigate the effect of polyunsaturated fat and DMBA on splenic natural killer (NK) activity and prostaglandin E (PGE) synthesis. In a first experiment, splenic NK activity at 33, 55, 75, and 110 days of age was measured in Sprague-Dawley rats fed 0.5% low fat (LF), 5% normal fat (NF), or 20% high fat (HF) corn oil diets from 23 days of age. At 55 days of age, half of the rats from the 75 and 110 day age groups were given 5 mg DMBA. Ten days after the initiation of the diets splenic NK activity against YAC-1 lymphoma was decreased from 50% cytotoxicity in rats fed NF diet to 21% cytotoxicity in rats fed HF diet, but was not affected by LF feeding. No difference in NK activity was observed among the groups at the later time periods. DMBA had no effect on NK activity at 20 or 55 days after its administration. In a second experiment, where DMBA (15 mg/rat) was given to half of the rats at 50 days of age and NF or HF diets were started 3 days later, NK activity was 35% in rats fed NF diet and 21% in rats fed HF diet, 5 days after the diets were started. No difference in NK activity in rats fed either diet was observed at later time periods. DMBA decreased both NK activity and spleen cellularity transiently. In both experiments, PGE synthesis by spleen cells cultured for 18 h was not affected by dietary fat intake, but was slightly increased 3 days after DMBA administration. Results from these experiments suggest that the stimulation of DMBA-induced mammary tumorigenesis by polyunsaturated fat and by DMBA itself may possibly be mediated by a transient decrease in splenic NK cell activity.This work was supported by grants CA-35641, CA-33240, CA-13038 and Core Grant CA-24538 from the National Cancer Institute     

Prolonged hyperphagia with high-fat feeding contributes to exacerbated weight gain in rats with adult-onset obesity

Leptin-resistant rats, when given a high-fat (HF) diet, have a delayed normalization of caloric intake and greater weight gain than those on a chow diet. Because aged, obese rats are leptin resistant, these data predict that they will also have a delayed normalization of caloric intake and exacerbated weight gain when provided a HF diet. To investigate this hypothesis, along with the consequences of a HF diet on voluntary wheel running, we compared various ages of rats on a HF or chow diet. HF-fed young rats spontaneously divided into diet-induced obese and diet-resistant rats. However, all aged rats were susceptible to the weight-gaining effects of HF feeding. Rate of initial weight gain was proportional to age, and peak caloric intake on the HF diet and the days required to normalize caloric intake to basal levels increased with age. Responsiveness to peripheral leptin before HF feeding revealed a dose-response decrease in food intake and body weight in the young but no responses in the aged to even the highest dose, 0.5 mg/day. In addition, both age and HF feeding decreased the tendency for wheel running, suggesting the propensity for inactivity with age and HF feeding may contribute to age-related obesity and accelerate the rate of diet-induced obesity. These results demonstrate that aged rats are more susceptible to the detrimental effects of a HF diet.     

High fat feeding and dietary <Emphasis Type="SmallCaps">l</Emphasis>-arginine supplementation differentially regulate gene expression in rat white adipose tissue

Dietary l-arginine (Arg) supplementation reduces white-fat gain in diet-induced obese rats but the underlying mechanisms are unknown. This study tested the hypothesis that Arg treatment affects expression of genes related to lipid metabolism in adipose tissue. Four-week-old male Sprague–Dawley rats were fed a low-fat (LF) or high-fat (HF) diet for 15 weeks. Thereafter, lean or obese rats continued to be fed their same respective diets and received drinking water containing 1.51% Arg–HCl or 2.55% l-alanine (isonitrogenous control). After 12 weeks of Arg supplementation, rats were euthanized to obtain retroperitoneal adipose tissue for analyzing global changes in gene expression by microarray. The results were confirmed by RT-PCR analysis. HF feeding decreased mRNA levels for lipogenic enzymes, AMP-activated protein kinase, glucose transporters, heme oxygenase 3, glutathione synthetase, superoxide dismutase 3, peroxiredoxin 5, glutathione peroxidase 3, and stress-induced protein, while increasing expression of carboxypeptidase-A, peroxisome proliferator activated receptor (PPAR)-α, caspase 2, caveolin 3, and diacylglycerol kinase. In contrast, Arg supplementation reduced mRNA levels for fatty acid binding protein 1, glycogenin, protein phosphates 1B, caspases 1 and 2, and hepatic lipase, but increased expression of PPARγ, heme oxygenase 3, glutathione synthetase, insulin-like growth factor II, sphingosine-1-phosphate receptor, and stress-induced protein. Biochemical analysis revealed oxidative stress in white adipose tissue of HF-fed rats, which was prevented by Arg supplementation. Collectively, these results indicate that HF diet and Arg supplementation differentially regulate gene expression to affect energy-substrate oxidation, redox state, fat accretion, and adipocyte differentiation in adipose tissue. Our findings provide a molecular mechanism to explain a beneficial effect of Arg on ameliorating diet-induced obesity in mammals.     

Ghrelin secretion is not reduced by increased fat mass during diet-induced obesity

Ghrelin is a stomach hormone that stimulates growth hormone (GH) secretion, adiposity, and food intake. Gastric ghrelin production and secretion are regulated by caloric intake; ghrelin secretion increases during fasting, decreases with refeeding, and is reduced by diet-induced obesity. The aim of the present study was to test the hypotheses that 1) an increase in body adiposity will play an inhibitory role in the reduction of gastric ghrelin synthesis and secretion during chronic ingestion of a high-fat (HF) diet and 2) chronic ingestion of an HF diet will suppress the rise in circulating ghrelin levels in response to acute fasting. Adult male Sprague-Dawley rats were fed a standard AIN-76A (approximately 5-12% of calories from fat) or an HF (approximately 45% of calories from fat) diet. The effect of increased adiposity on gastric ghrelin homeostasis was assessed by comparison of stomach ghrelin production and plasma ghrelin levels in obese and nonobese rats fed the HF diet. HF diet-fed, nonobese rats were generated by administration of triiodothyronine to lower body fat accumulation. Our findings indicate that an increased fat mass per se does not exert an inhibitory effect on ghrelin homeostasis during ingestion of the HF diet. Additionally, the magnitude of change in plasma ghrelin in response to fasting was not blunted, indicating that a presumed, endogenous signal for activation of ingestive behavior remains intact, despite excess stored calories in HF-fed rats.     

Sensitivity to stress-induced reproductive dysfunction is associated with a selective but not a generalized increase in activity of the adrenal axis

Stress-induced reproductive dysfunction is a relatively common cause of infertility in women. In response to everyday life stress, some individuals readily develop reproductive dysfunction (i.e., they are stress sensitive), whereas others are more stress resilient. Female cynomolgus monkeys, when exposed to mild combined psychosocial and metabolic stress (change in social environment + 20% reduced calorie diet), can be categorized as stress sensitive (SS; they rapidly become anovulatory in response to stress), medium stress resilient (MSR; they slowly become anovulatory in response to prolonged stress), or highly stress resilient (HSR; they maintain normal menstrual cycles in response to stress). In this study, we examined whether increased sensitivity to stress-induced reproductive dysfunction is associated with elevated adrenal axis activity by measuring 1) the diurnal release of ACTH and cortisol, 2) ACTH and cortisol in response to an acute psychological stress, 3) the percent suppression of cortisol in response to dexamethasone negative feedback, 4) the diurnal release of ACTH and cortisol following exposure to mild psychosocial and metabolic stress, 5) the concentration of cortisol in hair, and 6) adrenal weight. SS monkeys (n = 5) did not differ from MSR (n = 5) or HSR (n = 7) monkeys in any measurement of baseline HPA axis activity or the integrated measurements of chronic HPA axis activity. However, MSR + SS monkeys (n = 10) did secrete more cortisol than HSR monkeys during the daytime hours (1000-1800) following exposure to a novel social environment and reduced diet. We conclude that increased activity of the HPA axis is unlikely to be the primary mechanism causing increased sensitivity to stress-induced reproductive dysfunction.     

Influence of high-calorie (cafeteria) diets on the population of Paneth cells in the small intestine of the rat

A high-calorie (cafeteria) diet is known to cause changes in the intestinal morphology and functioning that seem to be related to calorie overfeeding. Among the cell lineages found in the small intestine epithelium, the Paneth cell (PC) population is known to be influenced by factors related mainly to the intestinal microbiota. The role of PCs in the intestinal cell concert remains unclear, because experimental evidence suggests PC involvement in local processes other than protection against pathogens. Participation of PC in digestive mechanisms has been proposed on this basis. We have analyzed the effect of high-carbohydrate (HC) and high-fat (HF) cafeteria diets on the PC population in the small intestine of the adult rat. For 8 weeks, both HC and HF diets caused a gain in body weight, but whereas the HC-fed rats showed reduced counts of intestinal crypts per 5-mum section, the HF-fed group showed the opposite. In control rats, the number of crypts per section showed a slight tendency to decrease along the duodenum - ileum axis, whereas the number of PCs per crypt was increased towards the ileum. As a result, the number of PCs per section (calculated from these data) remained constant along the three segments of the intestine. The hypercaloric diets did not modify the general tendencies seen in the crypt and PC counts, but reduced the number of PCs per section in the duodenum by 50%. HC-fed, but not HF-fed, rats showed a similar reduction in jejunum also. These changes do not correlate particularly with any of the predictable effects of diet composition, so that a multifactorial control of PC density is proposed.     

Effects of angiotensin II AT1 receptor inhibition and exercise training on insulin action in rats on high-fat diet

AimThis study was to determine whether combination of the angiotensin II AT1 receptor blocker (ARB), candesartan cilexetil, and exercise training can prevent the development of high-fat diet-induced insulin resistance.Main methodsF344/NSlc rats were fed normal chow diet or high-fat (HF) diet for 7 weeks. The HF-fed rats were either administered candesartan cilexetil (5 mg·kg^? 1·day^? 1), exercise-trained, or received a combination of these 2 treatments.Key findingsOral glucose tolerance tests (OGTT) showed that combined treatment with candesartan cilexetil and exercise increased glucose tolerance as compared with each treatment alone in HF-fed rats. Moreover, euglycemic–hyperinsulinemic clamp analysis showed improvement in glucose infusion rate with exercise training or candesartan cilexetil treatment alone, and further improvement was observed with the combination treatment. Systolic blood pressure improved with candesartan cilexetil but not with exercise alone. Finally, Glut-4 protein expression in soleus muscle was decreased with HF diet, and the expression was increased by exercise and not candesartan cilexetil treatment.SignificanceThese results suggest that the combination of candesartan cilexetil and exercise training improves insulin resistance as compared with each treatment alone.     

Maternal green tea extract supplementation to rats fed a high-fat diet ameliorates insulin resistance in adult male offspring

Maternal overnutrition is associated with increased risk of metabolic disorders in the offspring. This study tested the hypothesis that maternal green tea (GT) supplementation can alleviate metabolic derangements in high-fat-diet-fed rats born of obese dams. Female Sprague–Dawley rats were fed low-fat (LF, 7%), high-fat (HF, 30%) or HF diet containing 0.75% or 1.0% GT extract (GT1, GT2) prior to conception and throughout gestation and lactation. Both doses of GT significantly improved metabolic parameters of HF-fed lactating dams (P<.05). Birth weight and litter size of offspring from HF dams were similar, but GT supplementation led to lighter pups on day 21 (P<.05). The weaned male pups received HF, GT1 or GT2 diet (dam/pup diet groups: LF/HF, HF/HF, HF/GT1, HF/GT2, GT1/HF and GT2/HF). At week 13, they had similar weight but insulin resistance index (IRI), serum nonesterified fatty acid (NEFA) and liver triglyceride of rats born to GT dams were 57%, 23% and 26% lower, accompanied by improved gene/protein expressions related to lipid and glucose metabolism, compared with the HF/HF rats (P<.05). Although HF/GT1 and HF/GT2 rats had lower serum NEFA, their insulin and IRI were comparable to HF/HF rats. This study shows that metabolic derangements induced by an overnourished mother could be offset by supplementing GT to the maternal diet and that this approach is more effective than giving GT to offspring since weaning. Hence, adverse effects of developmental programming are reversible, at least in part, by supplementing bioactive food component(s) to the mother's diet.     

Effects of diabetes on the dietary lipid alteration of R3230AC mammary carcinoma growth in rats

To examine the effects of diabetes on the alteration of R3230AC mammary tumor growth by dietary lipids, streptozotocin-induced diabetic rats were fed diets containing either 20% corn oil (HF), 20% hydrogenated cottonseed oil (HCTO), or 0% fat (FF). Diabetes resulted in lower tumor weights and body weights compared to those of intact animals. Unlike intact animals, relative tumor weight (g tumor/100 g body wt) of diabetic animals fed HF diets were not greater than those from animals fed FF diets. However, in these diabetic animals, growth of tumors in HF-fed rats was faster than in HCTO-fed rats, a relationship similar to that seen in intact rats. A surprising result was the almost twofold greater tumor weight/100 g body wt observed in diabetic FF-fed rats compared to those fed HCTO diets. Insulin binding to tumor plasma membranes from diabetic animals was higher in rats fed HF diets than in rats fed FF or HCTO diets. The tumor plasma membrane fatty acid composition of diabetic rats fed FF and HCTO diets displayed higher proportions of the monounsaturates (C18:1 and C21:1) and decreased amounts of the polyunsaturates (C18:2 and C20:4) compared to the levels observed in membranes from HF-fed rats. These results, as well as the insulin binding data, were similar to those obtained using intact animals. The data presented here indicate that the more rapid growth of the R3230AC mammary tumor seen in intact animals fed high polyunsaturated fat vs fat-free diets did not occur in diabetic animals.