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Nonalcoholic fatty liver disease (NAFLD) is linked to obesity, type 2 diabetes, hyperlipidemia, and gut dysbiosis. Gut microbiota profoundly affects the host energy homeostasis, which, in turn, is affected by a high-fat diet (HFD) through the liver-gut axis, among others. Broccoli contains beneficial bioactive compounds and may protect against several diseases. This study aimed to determine the effects of broccoli supplementation to an HFD on metabolic parameters and gut microbiome in mice. Male (7–8 weeks old) C57BL/J6 mice were divided into four groups: normal diet (ND), high-fat diet (HFD), high-fat diet+10% broccoli florets (HFD + F), and high-fat diet + 10% broccoli stalks (HFD + S). Liver histology and serum biochemical factors were evaluated. Alterations in protein and gene expression of the key players in lipid and carbohydrate metabolism as well as in gut microbiota alterations were also investigated. Broccoli florets addition to the HFD significantly reduced serum insulin levels, HOMA-IR index, and upregulated adiponectin receptor expression. Conversely, no significant difference was found in the group supplemented with broccoli stalks. Both broccoli stalks and florets did not affect fat accumulation, carbohydrate, or lipid metabolism-related parameters. Modifications in diversity and in microbial structure of proteobacteria strains, Akermansia muciniphila and Mucispirillum schaedleri were observed in the broccoli-supplemented HFD-fed mice. The present study suggests that dietary broccoli alters parameters related to insulin sensitivity and modulates the intestinal environment. More studies are needed to confirm the results of this study and to investigate the mechanisms underlying these beneficial effects.

Cancer prevention is a high priority in the developed world and is important for decreasing morbidity and mortality. Following a Mediterranean diet has repeatedly been associated with health benefits, including reduction of cancer incidence. Regrettably, due to the nature of epidemiological studies and the complexity of the human diet, it is not possible to attribute this benefit to olive oil specifically, or to its constituent compounds. The majority of studies on olive oil and prevention of breast and colorectal cancer have been carried out in cell culture or animal models. Results from these models consistently show the inhibition of initiation, promotion, and/or progression of cancer cell growth following exposure to olive oil. However, these models have little resemblance to cancer etiology in humans and bioavailability of biologically active compounds is limited. Currently, there is insufficient rigorous scientific evidence for health claims promoting olive oil as a chemopreventive agent.

Introduction: Nonalcoholic fatty liver disease (NAFLD) is associated with metabolic syndrome, which often includes obesity, diabetes, and dyslipidemia. Several studies in mice and humans have implicated the involvement of the gut microbiome in NAFLD. While cannabis may potentially be beneficial for treating metabolic disorders such as NAFLD, the effects of cannabis on liver diseases and gut microbiota profile are yet to be addressed. In this study, we evaluated the therapeutic effects of cannabis strains with different cannabinoid profiles on NAFLD progression. Materials and Methods: NAFLD was induced by feeding mice a high-fat/cholesterol diet (HFCD) for 6 weeks. During this period, cannabis extracts were administrated orally at a concentration of 5 mg/kg every 3 days. Profile of lipids, liver enzymes, glucose tolerance, and gene expression related to carbohydrate lipid metabolism and liver inflammation were analyzed. The effect of cannabis strains on microbiota composition in the gut was evaluated. Results: A cannabidiol (CBD)-rich extract produced an increase in inflammatory related gene expression and a less diverse microbiota profile, associated with increased fasting glucose levels in HFCD-fed mice. In contrast, mice receiving a tetrahydrocannabinol (THC)-rich extract exhibited moderate weight gain, improved glucose response curves, and a decrease in liver enzymes. Conclusions: The results of this study indicate that the administration of cannabis containing elevated levels of THC may help ameliorate symptoms of NAFLD, whereas administration of CBD-rich cannabis extracts may cause a proinflammatory effect in the liver, linked with an unfavorable change in the microbiota profile. Our preliminary data suggest that these effects are mediated by mechanisms other than increased expression of the endocannabinoid receptors cannabinoid receptor 1 (CB1) and CB2.

Nonalcoholic steatohepatitis (NASH) is currently one of the most common liver diseases worldwide. The toxic effects of lipids and bile acids contribute to NASH. The regenerative pathway in response to damage to the liver includes activation of the inflammatory process and priming of hepatocytes to proliferate to restore tissue homeostasis. However, the effects of cholesterol on bile acid toxicity, inflammation, and fibrosis remain unknown. We have used two mouse models of bile acid toxicity to induce liver inflammation and fibrosis. A three-week study was conducted using wild-type mice receiving an atherogenic diet (1% (w/w) cholesterol and 0.5% (w/w) cholic acid) and its separate constituents. Mdr2-/- mice were fed a high-cholesterol-enriched diet or standard AIN-93 diet for 6 weeks. We measured serum transaminase levels to assess liver tissue necrosis and fibrosis; iNOS, SAA1, SAA2, and F4/80 levels to determine liver inflammation; PCNA and HGF levels to evaluate proliferative response; and Nrf-2, HIF-1¿, and downstream gene expression to establish protective responses. In both studies, high bile acid levels increased serum transaminases and liver fibrosis, whereas cholesterol supplementation attenuated these effects. Cholesterol supplementation activated survival and the robustness of HIF-1¿ and Nrf-2 gene expression in hepatocytes, induced liver inflammation and hepatocyte proliferation, and inhibited stellate cell hyperplasia and fibrosis. In conclusion, our data show for the first time that cholesterol intake protects against bile acid liver toxicity. The balance between hepatic cholesterol and bile acid levels may be of prognostic value in liver disease progression and trajectory, The manuscript was supported by the Israel Science Foundation grant 371/12 to ZM and OT.

Nonalcoholic fatty liver diseases (NAFLD) is one of the most common chronic liver disease in Western countries. Oxygen is a central component of the cellular microenvironment, which participate in the regulation of cell survival, differentiation, functions and energy metabolism. Accordingly, sufficient oxygen supply is an important factor for tissue durability, mainly in highly metabolic tissues, such as the liver. Accumulating evidence from the past few decades provides strong support for the existence of interruptions in oxygen availability in fatty livers. This outcome may be the consequence of both, impaired systemic microcirculation and cellular membrane modifications which occur under steatotic conditions. This review summarizes current knowledge regarding the main factors which can affect oxygen supply in fatty liver., Graphical abstract Current molecular knowledge indicate that liver oxygen deprivation is a culprit factor In fatty liver disease. Leading to hypoxia and hypoxic dependent lipid droplet formation.fx1

Background: Adipokines such as ghrelin, leptin, resistin and adiponectin have been proposed as being involved in energetic balance and bone turnover. There is scarce knowledge as to adipokine activity in hip fractured elderly patients in acute settings. We evaluated whether active nutritional support may reflect on adipokines levels and affect outcomes. Methods: A randomized controlled study measuring adipokine (ghrelin, leptin, resistin and adiponectin) levels in hip fractured geriatric patients receiving active nutritional support was conducted in the Ortho-Geriatric Unit Rabin Medical Center, Israel. The intervention group’s energy goal was calculated by repeated resting energy requirements whereas the control group received only standard nutritional support. Measurements were taken pre-operation, 48 h post-operative and on day 7 post-op. Results: Ghrelin and adiponectin levels showed significant changes in both study groups with no significant change between groups. Ghrelin levels were also significantly higher on day 7 in patients without complications (p=0.035). Leptin levels differed between groups (p=0.038). In the intervention group, leptin levels decreased initially, then sharply increased, whereas the control group’s levels consistently decreased in all 3 measurements. Resistin levels did not change significantly over time. Conclusion: Ghrelin and adiponectin may play a role in hip fractured patients irrespective of nutritional status whereas, ghrelin levels may also indicate post-operative complications. Leptin may be affected by energetic balance.

Nutrition is an integral part of type 2 diabetes (T2DM) treatment, but the optimal macronutrient composition is still debated and previous studies have not addressed the role of ethnicity in dietary response. The current study aims were to compare the effect of short-term glycemic response to low-carbohydrate high-fat (LC-HF) diet vs. high-carbohydrate low-fat (HC-LF) diet using continuous glucose monitoring (CGM) and to evaluate the response of individuals with T2DM of Yemenite (Y-DM) and non-Yemenite origin (NY-DM). Twenty T2DM males, ten Y-DM and ten NY-DM underwent meal tolerance test and indexes of insulin resistance and secretion were calculated. Subsequently, patients were connected to CGM to assess daily glycemic control and glucose variability in response to isocaloric HC-LF or LC-HF diet, receiving each diet for 2 days by providing prepared meals. Daily glucose levels, area under the glucose curve (G-AUC) and parameters of glucose variability [standard deviation (SD), mean amplitude of glycemic excursions (MAGE) and mean absolute glucose (MAG)] were evaluated. The LC-HF resulted in a significantly lower G-AUC (p

cope This study investigated the potential deleterious impact of dietary supplementation with green tea extract (GTE) on the progression of fatty liver disease, in a mouse model of cholesterol-induced steatohepatitis that represents chronic liver injury. Methods and results Male C57BL mice (n = 32, 8-wk-old) were fed for 6 wk with one of the following diets: normal control diet (ND, Con), Con + 1% w/w polyphenols from GTE (Con + GTE); high cholesterol diet, Con + 1% cholesterol + 0.5% cholate w/w (HCD); HCD + 1% green tea polyphenols w/w (HCD + GTE). Hepatic steatosis, oxidative, and inflammatory markers and bile acid synthesis pathways were measured. HCD supplementation resulted in hepatic steatosis and liver damage. In animals supplemented with the HCD + GTE an exacerbated hepatic steatosis, oxidative stress, and inflammatory response were observed compared to HCD supplemented animals. HCD + GTE supplementation elevated blood levels of liver enzymes and serum bile acids compared HCD-treated animals. HCD + GTE supplementation altered bile acid synthesis in the cholesterol clearance pathway, inducing a shift from the classically regulated CYP7A1 pathway to the alternative acidic pathway. Conclusion Prolonged GTE supplementation dramatically increased hepatic oxidative stress, inflammation and liver injury, and altered the bile acid synthesis pathway in mice fed a HCD.

The circadian clock influences nearly all aspects of metabolism. However, little is known regarding the effect of the energy status on circadian rhythms. Our aim was to test the effect of two opposing energy situations, metformin and lipid emulsion (LE), on clock and metabolic circadian expression in differentiated C2C12 myotubes. Metformin treatment led to depleted ATP levels accompanied by elevated NADH levels, whereas LE treatment led to increased ATP and NAD(+) levels. Nevertheless, both LE and metformin treatments activated the AMP-activated protein kinase (AMPK) pathway. In contrast, the effect on circadian rhythms was completely different. LE led to disrupted clock and metabolic gene expression, whereas metformin led to mainly high-amplitude shifted rhythms. Combination of metformin and LE led to an antagonistic effect on circadian gene expression. Although metformin and LE have an opposing effect on circadian gene expression and on the cellular energy status, they both lead to AMPK activation.

Cholesterol and chronic activation of hypoxia-inducible factor-1 (HIF-1) have been separately implicated in the pathogenesis and progression of liver diseases. In AML12 hepatocytes increased HIF-1α protein accumulation was evident after 2 h of incubation with cholesterol, whereas enhanced HIF-1 transcriptional activity was observed after 6 h. Investigations into the molecular mechanism have shown that cholesterol inhibited HIF-1α degradation. Mitochondrial dysfunction and enhanced mitochondrial reactive oxygen species (ROS) generation were observed in 2-h cholesterol-treated cells along with augmented nitric oxide (NO) levels. Further analysis indicated that HIF-1α stabilization at later time (6h), but not after 2h, of incubation with cholesterol was dependent on NO production. To elucidate the role of mitochondrial dysfunction in HIF-1α stabilization, mitochondrial DNA-depleted hepatocytes were prepared. In these cells the ability of cholesterol to activate the HIF-1 pathway was abolished. Similarly, catalase overexpression also attenuated cholesterol-induced HIF-1α accumulation. These results demonstrate that cholesterol promotes HIF-1 activation in a ROS- and NO-dependent manner. Chronic liver activation of HIF-1 by cholesterol may mediate its deleterious effects in the liver.

Objective Our goal was to evaluate the effect of breakfast size and composition on body weight, glycemic control, and metabolic markers in adults with type 2 diabetes mellitus (T2DM). Methods 59 overweight/obese adults with T2DM were randomized to one of two isocaloric diabetic diets for 3 months; big breakfast (BB), breakfast was rich in fat and protein and provided 33% of total daily energy or small breakfast (SB), breakfast was rich in carbohydrates and provided 12.5% of total daily energy. Results Although body weight was reduced similarly in both groups, the BB group showed greater HbA1c and systolic blood pressure reductions (HbA1c: −4.62% vs. −1.46%, p = 0.047; SBP −9.58 vs. −2.43 mmHg; p = 0.04). T2DM medication dose was reduced in a greater proportion of the BB participants (31% vs. 0%; p = 0.002) while in the SB, a greater proportion of participants had a dose increases (16.7% vs. 3.4%; p = 0.002). Hunger scores were lower in the BB group and greater improvements in fasting glucose were observed in the BB group. Conclusions A simple dietary manipulation enriching breakfast with energy as protein and fat appears to confer metabolic benefits and might be a useful alternative for the management of T2DM.

Steatosis increases the sensitivity of hepatocytes to hypoxic injury. Thus, this study was designed to elucidate the role of hypoxia-inducible factor-1α (HIF1α) in steatotic hepatocytes during hypoxia. AML12 hepatocytes and isolated rat hepatocytes were treated with a free fatty acid mixture of oleate and palmitate (2:1, 1 mM) for 18 h, which generated intrahepatocyte fat accumulation. The cells were then exposed to hypoxia (1% oxygen, 6–24 h). After hypoxia, a further increase in cellular fat accumulation was seen. In steatotic hepatocytes, a decreased HIF1α activation by hypoxia was observed. The capacity of these cells to express HIF1α-dependent genes responsible for the utilization of nutrients for energy was also impaired. This resulted in significantly lower intracellular ATP levels and greater cell death in steatotic hepatocytes compared with control hepatocytes. In contrast, overexpression of constitutively active HIF1α significantly increased cell viability as well as ATP and GLUT1 mRNA levels in steatotic hepatocytes under hypoxia. Hypoxia significantly enhanced HIF1α mRNA levels in control but not in steatotic hepatocytes. Concomitantly, an increase in oxidative stress was found in steatotic hepatocytes under hypoxic conditions compared with control cells. This included higher reactive oxygen species generation, lower cellular and nuclear GSH levels, and higher accumulation of 4-hydroxynonenal protein adducts. Hypoxia-mediated oxidative stress was accompanied by inactivation of basal nuclear factor-κB (NF-κB) DNA binding. Treatment with N -acetyl- l -cysteine, a reducing agent, improved NF-κB DNA-binding capacity and restored HIF1α induction. Conversely, overexpression of an NF-κB super-suppressor in control hepatocytes (IκBαΔN-transfected cells) resulted in complete inhibition of HIF1α expression, confirming that indeed NF-κB regulates HIF1α expression in hypoxic hepatocytes. In conclusion, hypoxia in combination with hepatic steatosis was shown to promote augmented oxidative stress, leading to NF-κB inactivation and impaired HIF1α induction and thereby increased susceptibility to hypoxic injury.

The aim of the current study was to characterize β-cell function, insulin sensitivity and line of inheritance in patients with recent-onset type 2 diabetes of Yemenite and non-Yemenite Jewish origin. A cohort study including 121 GAD negative diabetic patients, 59 of Yemenite and 62 of non-Yemenite origin, treated by diet ± oral antihyperglycemic monotherapy who underwent 180-min meal tolerance test (MMT). Based on MMT, indexes of insulin resistance and secretion were calculated. There were no significant differences in age, sex, diabetes duration, BMI, HbA1c and lipid profile. A significant difference was found in family history of diabetes: 63 % of patients of Yemenite origin had maternal inheritance versus 35 % in the non-Yemenite origin (p

This study was designed to investigate the effect of a low-calorie diet with carbohydrates eaten mostly at dinner on anthropometric, hunger/satiety, biochemical, and inflammatory parameters. Hormonal secretions were also evaluated. Seventy-eight police officers (BMI >30) were randomly assigned to experimental (carbohydrates eaten mostly at dinner) or control weight loss diets for 6 months. On day 0, 7, 90, and 180 blood samples and hunger scores were collected every 4 h from 0800 to 2000 hours. Anthropometric measurements were collected throughout the study. Greater weight loss, abdominal circumference, and body fat mass reductions were observed in the experimental diet in comparison to controls. Hunger scores were lower and greater improvements in fasting glucose, average daily insulin concentrations, and homeostasis model assessment for insulin resistance (HOMA(IR)), T-cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) levels were observed in comparison to controls. The experimental diet modified daily leptin and adiponectin concentrations compared to those observed at baseline and to a control diet. A simple dietary manipulation of carbohydrate distribution appears to have additional benefits when compared to a conventional weight loss diet in individuals suffering from obesity. It might also be beneficial for individuals suffering from insulin resistance and the metabolic syndrome. Further research is required to confirm and clarify the mechanisms by which this relatively simple diet approach enhances satiety, leads to better anthropometric outcomes, and achieves improved metabolic response, compared to a more conventional dietary approach.

Accumulating evidence indicates that mitochondria have a key role in non-alcoholic fatty liver disease (NAFLD). C57BL/6J mice were fed a choline-deficient, ethionine-supplemented (CDE) diet. Histological studies demonstrated accumulation of fat vacuoles in up to 90% of hepatocytes in mice fed the CDE diet for 14 days. In addition, a decrease in mitochondrial levels, together with an increase in superoxide radicals' levels were observed, indicating elevation of oxidative stress in hepatocytes. ATP levels were decreased in livers from CDE-fed mice after overnight fasting. This was accompanied by a compensative and significant increase in peroxisome-proliferator-activated receptor-γ coactivator 1α (PGC1α) mRNA levels in comparison to control livers. However, there was a reduction in PGC1α protein levels in CDE-treated mice. Moreover, the expression of mitochondrial biogenesis genes nuclear respiratory factor 1 (NRF-1), mitochondrial transcription factor A (TFAM), mitochondrial transcription factor B1 (TFB1M) and mitochondrial transcription factor B2 (TFB2M), which are all regulated by PGC1α activity, remained unchanged in fasted CDE-treated mice. These results indicate impaired activity of PGC1α. The impaired activity was further confirmed by chromatin immunoprecipitation analysis, which demonstrated decreased interaction of PGC1α with promoters containing NRF-1 and NRF-2 response elements in mice fed the CDE diet. A decrease in PGC1α ability to activate the expression of the gluconeogenic gene phosphoenol-pyruvate carboxykinase was also observed. This study demonstrates, for the first time, that attenuated mitochondrial biogenesis in steatotic livers is associated with impaired biological activity of PGC1α.

The risk of death from cardiovascular diseases (CVDs), which are exacerbated by oxidative stress, is higher in diabetic women. This phenomenon has been attributed to the loss of estradiol-vascular protection. Such knowledge led us to examine the potential of glabridin, a phytoestrogen, to substitute estradiol up-regulation of antioxidant enzymes under high glucose conditions. Chronic glucose stress was found to down-regulate catalase (CAT) and paraoxonase 2 (PON2) mRNA expression by 20% and 17%, respectively, and to decrease PON2 activity by 83% in macrophages. Inflammatory conditions had an additive effect on PON2 expression in a time-dependent manner. Treatment with glabridin, under high glucose stress, increased PON2 activity by 60% and up-regulated its mRNA expression by 3.5 fold. Furthermore, glabridin up-regulated the expression of manganese superoxide dismutase (Mn-SOD) and CAT in monocytes. In conclusion, glabridin has the potential of strengthening the antioxidant defense mechanism and may serve as an antiatherogenic agent in diabetes.

Scope Galactomannan and citrus pectin are considered 'super fibers' known for altering gut microbiota composition and improving glucose and lipid metabolism. The study aims to investigate the fiber's effect on a nonalcoholic steatohepatitis (NASH) model. Methods and results Two feeding experiments are carried out using groups of 7-8 week-old male C57BL/6J mice. The diets used are based on a high cholesterol/cholate diet (HCD), such as a nutritional NASH model. Mice are fed a diet with or without 15% fiber-citrus pectin (HCD-CP) or galactomannan (HCD-G) together with the HCD (first experiment), which commenced 3 weeks prior to the HCD (second experiment). Liver damage is evaluated by histological and biochemical parameters. Galactomannan leads to lesser weight gain and improved glucose tolerance, but increased liver damage. This is shown by elevated levels of liver enzymes compared to that with HCD alone. Fibers induce higher steatosis, as evaluated by liver histology. This intriguing result is linked to various changes in the gut microbiota, such as elevated Proteobacteria levels in the galactomannan group, which are correlated with disturbed metabolism and dysbiosis. Conclusions In a NASH mouse model, galactomannan increases liver damage but improves glucose metabolism. Changes in the microbiota composition may answer this enigmatic observation.

The circadian clock controls energy homeostasis by regulating circadian expression of proteins involved in metabolism. Disruption of circadian rhythms leads to obesity and metabolic disorders. Little is known regarding the control of the biological clock over adiponectin signaling pathway in adipose tissue, the adiponectin producer, and muscle, an adiponectin target tissue under fasting, low-fat (LF), or high-fat (HF) diet. Mice were fed LF or HF diet for 7 weeks and fasted on the last day. The circadian mRNA expression of clock genes and components of adiponectin metabolic pathway (mAdipoR1, mAdipoR2, mPparalpha, mPpargamma, mAmpk, and mAcc) in the muscle and adipose tissue were tested. Using average daily levels of multiple time points around the circadian cycle, we assessed mRNA levels of the different adiponectin signaling components. In addition, serum glucose, adiponectin, and insulin were measured. Under LF diet, adiponectin signaling pathway components exhibited circadian rhythmicity at the mRNA levels. Fasting and HF diet followed by fasting disrupted this circadian expression causing a phase advance or delay, respectively. Changes were also found in the expression levels of adiponectin receptor, mAmpk, mAcc, mPparalpha, and mPpargamma reflecting a defect in adiponectin signaling. As both peroxisome proliferator-activated receptor alpha (PPARalpha) and mAMPK are linked to the core clock mechanism, they could mediate the disruptions seen in clock gene expression under HF diet. In turn, the circadian clock affects the daily rhythm of these adiponectin signaling components.

Summary Background & aims Fatty liver, inflammation, fibrosis and cirrhosis are associated with portal hypertension. Nitric oxide (NO) is a universal messenger molecule that plays diverse and essential physiological roles in multiple organ systems. A decrease in NO production can lead to disruption in blood flow and portal hypertension. We therefore sought to evaluate the in vivo effect of lipid accumulation in the liver on NO production, endothelial nitric oxide synthase (eNOS) expression and liver function. Methods Rats were intravenously infused with lipid emulsion (20% w/w triglycerides) for 1, 2, 4 and 6 days. Liver histology, blood parameters, and liver eNOS protein expression were studied. Results Histological evaluation and blood liver enzymes showed liver damage after 6 days of infusion, while a decrease in eNOS levels began at day 4. The latter was accompanied by an increase in 4-hydroxynonenal-protein adducts, a marker of oxidative stress. Conclusions These findings support the hypothesis that downregulation of eNOS in steatotic livers is an early event in non-alcoholic fatty liver disease progression.

Caveolin-1, a component of caveolae, regulates signaling pathway compartmentalization by interacting with tyrosine (Tyr) kinase receptors and their substrates. Perturbations in caveolae lipid composition have been shown in vitro to displace proteins from lipid microdomains, thereby altering their functionality and subsequent downstream signaling. The role of caveolin-1 in insulin receptor (IR) signaling has been widely investigated in vitro mainly in 3T3-L1 adipocyte cells. However, in vivo experiments investigating this connection in liver tissue have not been carried out. The objective of the present study was to investigate the effects of a high-cholesterol diet on caveolin-1 expression and IR localization and activity in the rat liver. Compared with a standard diet, rats fed with diet rich in cholesterol significantly altered liver caveolae by increasing both caveolin-1 (66%, P < 0.05) and caveolin-2 (55%, P < 0.05) expression while caveolin-1 mRNA levels were reduced. Concomitantly, a 25% increase in localization of the caveolae-resident signaling protein IR was observed. The distribution of caveolar and noncaveolar phosphorylated IR was unaffected but insulin-induced IR activation was significantly enhanced following consumption of the high-cholesterol diet (120%, P < 0.001). However, the downstream molecules IRS-1 and Akt have shown impaired activity in cholesterol-fed rats suggesting insulin resistance condition. Insulin stimulation failed to induce Tyr phosphorylation of caveolin-1 in cholesterol-fed rats. These findings suggest a mechanism by which a high-cholesterol diet altered caveolin-1 expression in vivo accompanied by altered IR localization and activity.

Many infections are associated with diabetes, as the ability of the body to fight pathogens is impaired. Recently, low levels of defensins have been found in diabetic rodents. However, whether hyperglycemia and/or insulin deficiency/insensitivity is the reason for the reduced defensin levels is still unknown. To study the functionality of the innate immune system during hyperglycemia, the expression levels of human beta-defensin-1 (hBD-1) was measured in human embryonic kidney (HEK-293) and colon adenocarcinoma (HCT-116) cells treated with different concentrations of glucose and insulin. Increasing concentrations of glucose enhanced hBD-1 expression and these levels were further elevated after insulin treatment. Insulin treatment also led to the up-regulation of human sodium/glucose transporter 1 (hSGLT1), which further increases intracellular glucose levels. Thus, our findings suggest for the first time that insulin signaling is important for hBD-1 optimal expression by elevating intracellular glucose levels and by mediating gene expression.

Objective Triacylglycerols (TGs) are being considered as an independent risk factor in atherosclerosis and metabolic syndrome, acting by dysregulation of the TG/high-density lipoprotein axis. Accumulation of lipids in subendothelial space attracts macrophages, leading to atherosclerotic plaque formation and increased plaque instability due to formation of foam cells and macrophage death. The aim of this study was to evaluate lipotoxic effects in macrophages caused by TG uptake. Methods J774.2 macrophages were exposed to soybean or olive oil–based lipid emulsions as a source of TGs (1 mg/mL) in a presence or absence of lipase inhibitor paraoxon (20 μM) or to bovine serum albumin–complexed palmitic (150 μM), linoleic (600 μM), and oleic (600 μM) fatty acids. Results The results demonstrated accumulation of TGs, G 1 /S arrest, and cell death with necrotic morphologic features after exposure to TG emulsions. These effects were prevented by treatment with an antioxidant N -acetyl-cysteine (0.5 mM). Paraoxon inhibited intracellular TG degradation but did not prevent lipotoxicity and cell death. Olive oil TG triggered macrophage death in a manner similar to soybean oil. Treatment of the macrophages with free fatty acid, mainly with palmitic acid, showed a reactive oxygen species–independent cell death pathway, which was different from that of TG and was not prevented by N -acetyl-cysteine. Conclusion This study shows a direct lipotoxic pathway for TG molecules in macrophages, which is not associated with degradation of TG molecule to free fatty acids. This study for the first time can explain at a cellular level how TGs as an independent risk factor aggravate atherosclerotic outcomes.

Many infections are associated with diabetes, as the ability of the body to fight pathogens is impaired. Recently, altered levels of defensins and polymorphism in Toll-like receptors (TLRs), two crucial components of the innate immune system, have been associated with diabetes. To study the functionality of the innate immune system during diabetes, we measured the expression levels of rat beta-defensin 1 (rBD-1), rBD-2, rTLR2, and rTLR4 in the kidney, lung, liver, and brain of streptozotocin-induced diabetic rats with and without insulin treatment. In the kidneys of diabetic rats, lower levels of rBD-1, rTLR2, and rTLR4 were found. These low levels could be restored with insulin treatment. In contrast, rBD-2 was highly induced in the lungs of diabetic rats, most likely, as a result of a pro-inflammatory response. In the liver and brain of diabetic rats, lower levels of TLRs and/or defensins could not be restored with insulin treatment. Our findings suggest for the first time that high blood glucose and/or insulin deficiency abrogates the expression level of the innate immune system components, defensins and TLRs, explaining the recurrent infections during diabetes. These findings may lay the grounds for future design of novel treatments that will induce defensins and TLRs and, as a result, bolster the immune system in diabetic patients.

Scope Hyperglycemia is associated with oxidative stress, which accelerates cardiovascular complications. This study investigates the potential of glabridin to regulate paraoxonase 2 (PON2) levels, in vivo, and explores the glabridin protective effect on PON2 through tryptophan-fluorescence quenching and mass spectrometry. Methods and results Adult mouse offspring of saturated fatty acids fed mothers, which developed hyperglycemia after exposure to a high fat diet in their adult life, had lower levels of heart PON2 mRNA and protein expression than did the control mice (64 and 26%, respectively). Glabridin supplementation significantly upregulated PON2 mRNA and protein expression in the liver (2.1-fold and 2.6-fold, respectively) and heart (2.5-fold and 1.6-fold, respectively) in these mice. In vitro studies demonstrated that the fluorescence quenching of PON2 by glabridin was a result of the formation of a glabridin–PON2 interaction. The binding constant (7.61 × 105 M−1) and the ΔG (–33.55kJ/mol) indicated that this interaction was driven by a hydrophobic force, which confers protection against CuSO4-induced PON2 oxidation. Conclusion Such results indicate that glabridin preserves the anti-atherogenic abilities of PON2 by maintaining its levels, in vivo. The glabridin–PON2 interaction may be the mechanism by which glabridin protects PON2 from oxidation, thus contributing to the protection of PON2 activity in hyperglycemia.

Effective nutritional guidelines for reducing abdominal obesity and metabolic syndrome are urgently needed. Over the years, many different dietary regimens have been studied as possible treatment alternatives. The efficacy of low-calorie diets, diets with different proportions of fat, protein, and carbohydrates, traditional healthy eating patterns, and evidence-based dietary approaches were evaluated. Reviewing literature published in the last 5 y reveals that these diets may improve risk factors associated with obesity and metabolic syndrome. However, each diet has limitations ranging from high dropout rates to maintenance difficulties. In addition, most of these dietary regimens have the ability to attenuate some, but not all, of the components involved in this complicated multifactorial condition. Recently, interest has arisen in the time of day foods are consumed (food timing). Studies have examined the implications of eating at the right or wrong time, restricting eating hours, time allocation for meals, and timing of macronutrient consumption during the day. In this paper we review new insights into well-known dietary therapies as well as innovative time-associated dietary approaches for treating obesity and metabolic syndrome. We discuss results from systematic meta-analyses, clinical interventions, and animal models.

cope In females, hyperglycemia abolishes estrogen-vascular protection, leading to inflammation and oxidative stress that are related to diabetes-associated cardiovascular complications. Such knowledge led us to examine the potential of glabridin, as a replacement of estrogen anti-inflammatory activity under high-glucose conditions. Methods and results In macrophage-like cells, chronic glucose stress (28 and 44 mM) upregulated inducible nitric oxide synthase (iNOS) mRNA expression by 42 and 189%, respectively. Pretreatment with glabridin, under chronic glucose stress, downregulated the LPS-induced nitric oxide secretion and nitrotyrosine formation, by 39 and 21%, respectively. Pretreatment with estradiol did not prevent the LPS-induced nitrotyrosine formation. Furthermore, glabridin, brought about a decrease in the LPS-induced iNOS mRNA expression by 48%, as compared to cells pretreated with estradiol. Glabridin decreased protein levels of liver iNOS by 69% in adult mouse offspring which developed hyperglycemia after early fetal exposure to a saturated fatty acid-enriched maternal diet. Glabridin also decreased liver nitrotyrosine levels in offspring of regular diet-fed mothers after further receiving high-fat diet. Conclusion Such results indicate that glabridin retains anti-inflammatory abilities to regulate the synthesis and activity of iNOS under high-glucose levels, implying that a glabridin supplement may serve as an anti-inflammatory agent in diabetes-related vascular dysfunction.

Background Interventional studies have shown that increased intake of fruit and vegetables reduces blood pressure (BP). However, the contribution of specific dietary components has not been evaluated. The aim of the present study was to determine, in patients with stage I hypertension, the antihypertensive effect of juice of the so-called sweetie fruit (a hybrid between grapefruit and pummelo) with and without high flavonoid content. Methods A double-blind, cross-over study was conducted in 12 patients. Each patient received alternately high-flavonoid (HF) sweetie juice and low-flavonoid (LF) sweetie juice, each for a 5-week period. The LF sweetie juice had 25% of naringin and 30% of narirutin content compared with the original HF sweetie juice. Results The HF sweetie juice was more effective than LF sweetie juice in reducing diastolic blood pressure (P = .04). Systolic blood pressure declined in both groups; however there was no significant difference between subjects given HF sweetie versus those given LF sweetie juice. Conclusions In this study HF sweetie juice was shown to have a significant beneficial effect in reducing diastolic blood pressure, compared with the effect observed with LF sweetie juice, in patients with stage I hypertension. These data suggest that the active ingredients associated with the antihypertensive effect of sweetie juice are the flavonoids naringin and narirutin.

This study was designed to evaluate the effects of triacylglycerol (TG) on nitric oxide (NO) production, expression of endothelial (e) and inducible (i) nitric oxide synthase (NOS) and variables related to oxidative stress in rat isolated hepatocytes. Hepatocytes were isolated and exposed to TG in the form of a lipid emulsion (0.01-0.1% LE). Exposure to LE dose dependently decreased nitrite levels. Nitrite levels were inhibited 67% and intracellular reactive oxygen species (ROS) levels were increased 250% at 0.1% LE. The decline in nitrite levels was accompanied by 37 and 67% reductions in iNOS and eNOS expressions, respectively. To evaluate whether the increased oxidative stress inhibited NOS synthesis, cells were treated for 48 h with rotenone (a mitochondrial complex 1 inhibitor) or buthionine sulfoximine (a glutathione synthesis inhibitor). Both compounds elevated ROS production, which was followed by inhibition of nitrite production. To determine whether there is an association between LE-mediated ROS production and the inhibition of NO synthesis by the LE, hepatocytes were treated with antioxidants. N-Acetyl-l-cysteine (NAC), ascorbate, and resveratrol attenuated the reduction of nitrite levels due to LE alone. NAC inhibited the reductions in eNOS and iNOS transcription and protein levels. Nuclear factor-kappaB (NF-kappaB), one of the transcription factors involved in eNOS and iNOS transcriptional regulation, was decreased 15% in the nucleus by LE treatment. These results suggest that TG reduces nitrite production by elevating intracellular ROS levels (prolonged oxidative stress), and the downregulation of NOS enzymes may occur at least in part via the NFkappaB pathway.

Alpha-lipoic acid is a known hypoglycemic agent that may be useful in the treatment of diabetes. The objective of this study was to investigate the fate of glucose in isolated muscles incubated with lipoic acid by determining its direct effects on specific metabolic, signaling pathways. Soleus muscles from healthy rats were incubated with lipoic acid in the absence or presence of insulin. Glucose transport, glycogen synthesis, glucose oxidation, lipid synthesis were determined, affects on major pathways associated with insulin signaling were evaluated. Glucose transport was not significantly altered by the addition of lipoic acid to the incubation medium. However, lipoic acid decreased glycogen synthesis in comparison to controls. Glucose oxidation was moderately increased while de-novo lipid synthesis from glucose was inhibited. Wortmannin repressed insulin stimulation of glucose incorporation into glycogen, an effect that was augmented by the combined treatment of wortmannin, lipoic acid. Basal, insulin-stimulated serine phosphorylation of Akt was not changed by the addition of lipoic acid to the incubation medium. These data show that in this in vitro model, lipoic acid did not significantly affect glucose uptake but dramatically modified pathways of glucose metabolism within muscle tissue.

Green tea polyphenol extracts (GTE) are sold commercially as cholesterol-reducing agents and for weight reduction however, they have also been reported to be hepatotoxic. Our results from both in vitro and in vivo studies indicate that green tea polyphenols can potentiate liver injury after and during treatment with high cholesterol diet to induce experimental NASH. Eight week old male C57BL mice (n=32) were fed for 6 weeks with one of the following diets: Control diet (Con); Con +1% w/w polyphenols from green tea extract (Con+GTE); High cholesterol diet, Con+ 1% cholesterol+ 0.5% cholate w/w (HCD); HCD + 1 % polyphenols w/w (HCD+GTE). Hepatic steatosis, oxidative and inflammatory markers and bile acid synthesis pathways were measured. GTE enhanced hepatic steatosis but only in animals exposed to the high cholesterol diet. In HCD treated animals GTE elevated blood levels of liver enzymes SGOT, SGPT, and bile acids. Inflammatory and oxidative markers in the liver were also significantly increased including liver mRNA expression of TNF-alpha, IL-6, SAA1, SAA2, iNOS and levels of 4-hydroxynonenal protein adducts. The mechanism of action for GTE/cholesterol hepatotoxicity was found to be related to alteration in bile acids synthesis pathways. This study shows that liver injury in the presence of lipids could be the reason for weigh loss by high dose of polyphenols.

Sustained weight reduction is needed in order to end the “vicious cycle” of abdominal obesity—a known risk factor for diabetes and coronary heart disease. However, most obese subjects fail to maintain long-term diets; they regain lost body weight and develop metabolic syndrome. Adipose tissue itself contributes to weight cycling and metabolic pathology, since it functions as an endocrine organ. Fat cells synthesize and secrete adipocytokines that regulate hunger and satiety, as well as adipocytokines that impact insulin resistance, the metabolic syndrome, and inflammation. The idea of studying the effect of a low-calorie diet with carbohydrates eaten primarily at dinner came about after analyzing results from research in Muslim populations during Ramadan. For the month of Ramadan, Muslims fast during the day and consume a carbohydrate-rich meal after sundown. This dramatically modifies the diurnal pattern of leptin secretion. Our experimental diet improved the diurnal secretion patterns of the “satiety hormone,” leptin, the “hunger hormone,” ghrelin, and adiponectin—“the link between abdominal obesity, insulin resistance and the metabolic syndrome.” Lower hunger scores and greater improvements in anthropometric, biochemical, and inflammatory parameters were observed compared to controls. We believe that this novel nutritional approach should be considered as a first line of treatment, prior to pharmaceutical or surgical interventions.

Glycogen synthase (GS), a key regulatory enzyme in glycogen synthesis, is controlled by multisite phosphorylation and allosteric regulation and is activated by insulin. This study investigated changes in GS activity and expression in hepatocytes isolated from rats under altered nutritional and diabetic conditions. Experiments were carried out in healthy rats fed a chow diet, rats on high simple sugar (60% of energy from fructose and sucrose) or high fat (46% of energy from fat) diet, and in rats with streptozotocin induced diabetes. In the presence of insulin, activated GS activity (GS(I) form) was increased by 89% in hepatocytes isolated from healthy rats. The stimulatory effect of insulin on GS activity and expression was blunted by cycloheximide and actinomycin treatment. In rats fed a high simple sugar or high fat diet, insulin stimulation of GS(I) in isolated hepatocytes was impaired and GS expression was significantly lower in rats fed the high fat diet in comparison to controls. GLUT-2 protein expression was significantly lowered by both the high fat and high simple sugar diets. In hepatocytes isolated from diabetic rats, total GS activity (GS(T)) was lower than in hepatocytes from healthy animals. Insulin added to the incubation medium did not stimulate GS activity, demonstrating impaired sensitivity to insulin in diabetic rats. However, insulin administration significantly increased GS expression indicating that a defect in synthase phosphorylation may be responsible for impaired GS activity in the diabetic state. The results presented in this study further confirm that GS activity is affected by both dietary and hormonal factors which can be measured in a rat hepatocyte model.

The present study was aimed at evaluating the effect of high intracolonic butyrate concentrations, either through fermentation of a soluble fiber-enriched diet or via intracolonic butyrate instillation, on colon cancer in a chemically induced (dimethylhydrazine) rat model. The effects were tested in four groups of dimethylhydrazine-treated rats: (i) rats fed a standard diet, (ii) rats fed a diet enriched with 15% citrus pectin, a soluble fiber that ferments and produces a high concentration of intracolonic butyrate, (iii) rats fed a standard diet and intrarectally instilled with a sodium butyrate solution (50 mM), (iv) rats fed a standard diet and intrarectally instilled with sodium butyrate vehicle solution (100 mM NaCl). The apoptotic index in the distal colon of rats fed pectin was higher than in colonic tissue from rats fed a standard diet. The expression of caspase-1, a cysteine protease implicated in the regulation of programmed cell death, as detected by both Northern and Western analysis, showed the highest mRNA and protein levels in colonic tissue from rats intrarectally instilled with butyrate. Immunohistology confirmed the Western blot findings. Expression of the cleaved poly(ADP-ribose) polymerase product, a downstream nuclear substrate for caspase-3 in the apoptotic pathway, was elevated in both the pectin-fed and butyrate-instilled groups. Expression of the antiapoptotic protein Bcl-2 was significantly reduced following pectin feeding as well as butyrate instillation. The highest expression of Bcl-2 was observed in tumor tissue. A marked reduction in aberrant crypt number was observed in colonic tissue obtained from both the pectin-fed and butyrate-instilled groups relative to rats from the standard diet group. The average tumor volume per rat in both the pectin-fed and butyrate-instilled groups was significantly lower than in rats from the standard diet and the sodium butyrate vehicle-instilled groups. We conclude that high butyrate levels, either instilled or obtained following fermentation of soluble dietary fibers, inhibit early and late events in colon tumorigenesis by controlling the transcription expression and activity of key proteins involved in the apoptotic cascade.

Background Diabetes commonly leads to long-term complications such as cataract. This study investigated the effects of α-lipoic acid (LPA) and its γ-linolenic acid (GLA) conjugate on cataract development in diabetic sand rats. Methods Two separate experiments were conducted. In Experiment 1, sand rats were fed a ‘high-energy’ diet (70% starch), an acute model of Type 2 diabetes, and injected with LPA. In Experiment 2, the animals received a ‘medium-energy’ diet (59% starch), a chronic diabetic model, and were intubated with LPA or its GLA conjugate. Throughout the experiments, blood glucose levels and cataract development were measured. At the termination of the experiments, lens aldose reductase (AR) activity and lenticular reduced glutathione (GSH) levels were analyzed. Results LPA injection significantly inhibited cataract development and reduced blood glucose levels in rats fed the ‘high-energy’ diet. Lens AR activity tended to be lower, while lenticular GSH levels increased. In sand rats fed a ‘medium-energy’ diet (59% starch), LPA intubation had no effect on blood glucose levels and cataract development but GSH levels were increased. In contrast, sand rats intubated with GLA conjugate showed the highest blood glucose levels and accelerated cataract development. The conjugate treatment also decreased lenticular GSH content. Conclusions The hypoglycemic effects of LPA are beneficial in the prevention of acute symptoms of Type 2 diabetes. It remains to be shown that the antioxidant activity of LPA is responsible for prevention or inhibition of cataract progression in sand rats. Copyright © 2000 John Wiley & Sons, Ltd.

This study investigated the effect of a natural tomato extract (TE) on cataract formation in two animal models. A TE containing 5% lycopene was included in the diet of diabetic sand rats at 0.2%, and Sprague Dawley rats were fed a high-galactose diet (30 g/100 g of diet), supplemented with either the lycopene-rich extract at concentrations of 0.2, 0.4, and 0.8% or BHT (0.2%). TE had no significant effect on plasma glucose levels or cataract development in sand rats; however, in rats maintained on a diet rich in galactose, both BHT and TE decreased cataract incidence, and grades were lower than in control animals. In addition, lens protein and reduced glutathione levels were higher and aldose reductase activity was lower than in the control group. The results suggest that antioxidants act as protective agents when oxidative stress is a primary cause of cataract formation but may be less effective in preventing cataracts in hyperglycemic animals.

Glucose metabolism was studied in 31 pregnant ewes fed mixtures (50:50) of chopped alfalfa hay and corn grain given in whole (HWC) or extruded form (HEC). Number of fetuses was 1 (n = 10), 2 (n = 11) or 3 (n = 10). Diets were supplied at three dietary levels: maintenance (1.0 M), 1.25 x maintenance (1.25 M) or twice maintenance (2.0 M). Glucose metabolism was estimated by a double isotope dilution procedure at days 97-121 of pregnancy. Glucose entry rate (GER) was higher (P < 0.04), and glucose irreversible loss rate (GILR) tended to be higher (P < 0.07) in ewes given HEC than HWC. Dietary level (P < 0.001) and the number of fetuses (P < 0.005) affected GER and GILR positively. These results provide a probable explanation for higher birth weights previously found in lambs born to HEC-, compared with HWC-fed dams.

Glucocorticoids induce circadian gene expression in cultured cells and change the phase of circadian gene expression in vivo. In addition, glucocorticoids induce differentiation of preadipocyte to adipocytes. We set out to test the effect of dexamethasone, a glucocorticoid receptor agonist, on circadian rhythms in 3T3-L1 differentiated adipocytes. Our results show that differentiated adipocytes exhibit robust circadian rhythms without dexamethasone. Dexamethasone induces phase changes and increases the amplitude of circadian gene expression in nondifferentiated 3T3-L1 preadipocytes. However, dexamethasone had an opposite effect on differentiated adipocytes, leading to low-amplitude circadian expression. In conclusion, although glucocorticoids reset circadian rhythms, once rhythms are reset, glucocorticoid administration hinders circadian expression.

Structural modifications of the intestine following fiber intake may play an important role in the physiological effects induced by dietary fiber. The aim of this study was to examine possible mechanisms for the hypocholesterolemic effects of dietary fibers by evaluating both biochemical and morphometric parameters. Thirty male Sprague-Dawley rats were divided into 3 groups and fed either a fiber-free, 15% fiber high methoxy pectin, or 15% cellulose diet for a 4-wk period. Plasma cholesterol levels, hepatic enzyme activity, and fecal bile acid excretion were determined, and changes in the intestinal structure were evaluated. Daily fecal bile acid excretion was significantly higher in rats fed the pectin diet accompanied by elevated HMG-CoA reductase activity. Pectin feeding led to significant elongation of both the small and large intestine whereas cellulose only affected colon length. Computerized image analysis of intestinal cross-sections showed enlarged muscle area in the ileum and midcolon of pectin-fed rats and greater mucosal area in the colon. Circular muscle cell hypertrophy was also observed in the colon length. Computerized image analysis of intestinal cross-sections showed enlarged muscle area in the ileum and midcolon of pectin-fed rats and greater mucosal area in the colon. Circular muscle cell hypertrophy was also observed in the colon. In contrast, the effects of cellulose feeding were limited to elongation of the colon accompanied by muscle cell hypertrophy, and little effect on ileal morphology was documented. These data indicate that the hypocholestrolemic effects of pectin may be due to increased bile acid secretion accompanied by significant morphological changes in the ileum and colon.

summary Background & aims: Optimizing nutritional intake has been recommended for geriatric patients undergoing hip-fracture surgery. Whether nutritional support guided by repeated measurements of resting energy requirements (REE) improves outcomes in these patients is not known. Methods: A randomized, controlled, unblinded, prospective, cohort study comparing provision of energy with a goal determined by repeated REE measurements using indirect calorimetry, with no intervention. Oral nutritional supplements were started 24 h after surgery and the amount adjusted to make up the difference between energy received from hospital food and measured energy expenditure. Results: 50 Geriatric patients were included in the study. Patients in the intervention group (n ¼ 22) received significantly higher daily energy intake than the control group (n ¼ 28) (1121.3 � 299.0 vs. 777.1 � 301.2 kcal, p ¼ 0.001). This was associated with a significantly less negative cumulative energy balance (� 1229.9 � 1763 vs. � 4975.5 � 4368 kcal, p ¼ 0.001). A significant negative correlation was found between the cumulative energy balance and total complication rate (r ¼� 0.417, p ¼ 0.003) as well as for length of hospital stay (r ¼� 0.282, p ¼ 0.049). Conclusion: We have demonstrated that nutritional support actively supervised by a dietician and guided by repeated measurements of REE was achievable and improved outcomes in geriatric patients following surgery for hip fractures. Clinicaltrials.gov Identifier: NCT017354435.

The effects of various sources of dietary fibre on the high glycaemic index of an Israeli ethnic food, melawach, were investigated in subjects with non-insulin-dependent diabetes mellitus (NIDDM). Locust-bean (Ceratonia siliqua) gum significantly decreased the glucose response to, and glycaemic index of, melawach in these diabetic subjects (P < 0·05). It also tended to decrease their insulinaemic response and insulinaemic index, but differences were not significant. Dietary fibre from lupin (Lupinus albus) and insoluble maize-cob fibre did not affect glucose and insulin levels in NIDDM volunteers. Subjects with a BMI < 30 kg/m2 exhibited similar glucose, but not insulin, responses to fibre. Locust-bean gum had no significant effect on glycaemic response in NIDDM subjects with a BMI > 30 kg/m2, whereas insulinaemic response decreased. The results indicate that foods containing the same nutrients in almost the same amounts, but differing in added dietary fibre, lead to different physiological responses in diabetic subjects. Furthermore, insulin response should be considered when fibre is incorporated into the diabetic's diet.

The morphological changes in the intestinal tunica muscularis induced by prolonged dietary fiber intake were determined in rat small intestine and colon with the aid of computerized image analysis. Thirty male Sprague-Dawley rats were fed either a fiber free, 15% cellulose or 15% pectin diet for 8 weeks. Intestine length was measured and stained cross sections of the jejunum, ileum, and colon were quantitated using image analysis. In the distal colon, muscle cell size was also determined. Despite lower weight gain in the pectin fed rats, both the small intestine and colon length were significantly increased. Cellulose feeding had a lesser effect on intestine length. Pectin fed rats had significantly increased relative tunica muscularis area (37.2 +/- 2.2 mm2) in ileum cross sections when compared to control (24.3 +/- 1.8 mm2) and cellulose fed rats (26.1 +/- 1.1 mm2). In the mid-colon, the tunica muscularis area was found to be pectincellulosecontrol (33.5 +/- 2.2; 29.7 +/- 1.7; 25.8 +/- 1.5 respectively) with significant differences reached between pectin and control rats. In jejunal samples, no differences were observed among the groups. Circular smooth muscle cell size in the distal colon was significantly increased following cellulose feeding but was less pronounced in the case of pectin. We conclude that fiber supplementation leads to morphological changes in the rat intestine including changes in length and tunica muscularis volume.

The effect of ruminally degradable starch on the reproductive performance of sheep was studied in 50 Booroola x Assaf crossbred ewes, of which 32 were carriers of the FeCB (Booroola) allele and 18 were not carriers. The sheep were group-fed, according to body weight (BW), diets composed of pea straw, soybean concentrate and corn grain offered in two meals per day. Dietary differences in ruminally undegradable starch (RUS) were obtained during the 29 day treatment period by feeding grain as whole corn (WC, 1.4 g RUS day−1 kg−1 BW) or extruded (EC, 0.4 g RUS day−1 kg−1 BW ). Oestrus was synchronized by inserting progestagen pessaries at Day 8, and withdrawing pessaries and injecting 400 IU of pregnant mare serum gondaotrophin at Day 20 after initiation of dietary treatments (Day 0). Ovulation rate (OR) was estimated by laparoscopy. The FecB allele was associated with a significant increase in OR (2.88 vs. 1.40, P⪕ 0.0001) and prolificacy (1.85 vs. 1.32 lamb born per ewe lambing, P⪕0.09). Within FecB allele carriers, all WC-fed ewes had multiple ovulations, compared with 61% of EC-fed ewes (P⪕0.005). OR values were 3.29±0.27 and 2.46±0.31 corpora lutea (CL) per ewe ovulating and prolificacy was 2.13±0.22 and 1.57±0.23 lamb per ewe lambing in WC- and EC-fed ewes, respectively (P⪕ 0.09). In non-carrier ewes, dietary treatments did not affect OR (1.44 and 1.36 CL per ewe ovulating in WC- and EC-fed ewes) or prolificacy (1.20 and 1.44 lamb per ewe lambing, in the same order). In a second experiment, aimed to assess the effect of dietary RUS on circulating insulin levels, blood was sampled before and at hourly intervals for 10 h after a meal from ten ewes fed rations with WC or EC. Insulin levels were higher in EC than in WC-fed ewes before and 3 h after a meal (P⪕ 0.05). EC feeding may be associated with higher peripheral insulin concentration but does not enhance OR. Data are used to show that: (1) provision of about 100 g RUS day−1 exerts a positive effect on the OR and prolificacy of FecB carriers; (2) dietary treatments may affect OR in sheep of different ovulation potential differently; (3) no positive relationship was found between circulating plasma insulin concentration and OR.

Disruption of circadian rhythms leads to obesity and metabolic disorders. Timed restricted feeding (RF) provides a time cue and resets the circadian clock, leading to better health. In contrast, a high-fat (HF) diet leads to disrupted circadian expression of metabolic factors and obesity. We tested whether long-term (18 wk) clock resetting by RF can attenuate the disruptive effects of diet-induced obesity. Analyses included liver clock gene expression, locomotor activity, blood glucose, metabolic markers, lipids, and hormones around the circadian cycle for a more accurate assessment. Compared with mice fed the HF diet ad libitum, the timed HF diet restored the expression phase of the clock genes Clock and Cry1 and phase-advanced Per1, Per2, Cry2, Bmal1, Rorα, and Rev-erbα. Although timed HF-diet-fed mice consumed the same amount of calories as ad libitum low-fat diet-fed mice, they showed 12% reduced body weight, 21% reduced cholesterol levels, and 1.4-fold increased insulin sensitivity. Compared with the HF diet ad libitum, the timed HF diet led to 18% lower body weight, 30% decreased cholesterol levels, 10% reduced TNF-α levels, and 3.7-fold improved insulin sensitivity. Timed HF-diet-fed mice exhibited a better satiated and less stressed phenotype of 25% lower ghrelin and 53% lower corticosterone levels compared with mice fed the timed low-fat diet. Taken together, our findings suggest that timing can prevent obesity and rectify the harmful effects of a HF diet.

Patients with chronic obstructive pulmonary disease (COPD) and a control group were given meals with either high or low glycemic index (GI). Meals were isocaloric and each type contained 50 g of carbohydrates. COPD patients being treated with theophylline or theophylline+prednisone exhibited impaired glucose curves following a glucose (50 g) load. Their insulin levels were also higher than in the control group. High-GI meals caused a deterioration in the glucose response of COPD subjects, particularly those treated with theophylline+prednisone. In contrast, low-GI lead to a moderate increase in glucose response. A similar effect was observed on insulin levels. Inclusion of low-GI food into the diets of COPD patients may be useful in diet planning, mainly when steroids are used as a means of treatment.

Ethnopharmacological relevance Chiliadenus iphionoides (Boiss. & Blanche) Brullo (Asteraceae), a small aromatic shrub found throughout Israel, is used traditionally in the treatment of diabetes mellitus. In this study, Chiliadenus iphionoides anti-diabetic activity was characterized using cellular and animal models. Materials and methods Pancreatic β cells, adipocytes, and skeletal myotubes were treated with an ethanolic extract of Chiliadenus iphionoides to study the extract's effects on insulin secretion and glucose uptake. The sand rat (Psammomys obesus) was used to study Chiliadenus iphionoides acute and long term effects in vivo. An oral starch tolerance test was performed as well as a 30 day feeding study. Results Chiliadenus iphionoides extract increased insulin secretion in β cells as well as glucose uptake in adipocytes and skeletal myotubes. The extract also displayed hypoglycemic activity in the diabetic sand rat. Conclusions Chiliadenus iphionoides exhibits considerable anti-diabetic activity, although the mechanism of action remains to be determined.

A high dietary fiber breakfast cereal (Disivit TM ), prepared from oats, corn, wheat and soybean, was tested for its therapeutic efficacy in patients suffering from constipation and hyperlipidemia. In a double-blind, cross-over trial, a daily dose of 50 grams Disivit TM cereal, containing 12.5 grams dietary fiber, was administered to 20 constipated patients for 2 weeks, and to 20 hyperlipidemic patients for 4 weeks. The high fiber cereal was alternated with a low fiber placebo given for a similar time period; fiber and placebo were given in random order. In the constipated patients taking fiber cereal, bowel movement frequency and stool consistency improved significantly and laxative intake was reduced. In the hyperlipidemic patients taking fiber, the serum cholesterol dropped significantly (but also during placebo treatment), the serum triglycerides dropped (but without attaining statistical significance) and the HDL and LDL levels were not altered. In summary, the fiber cereal appears to be a suitable short-term treatment for constipation, although its long-term efficacy requires further study. Regarding hyperlipidemia, the trend of the cereal to lower the serum cholesterol and triglycerides warrants further study, by adding more soluble fiber to the cereal formula or using a longer treatment period.

The primary objective of this study was to investigate the impact of lipid oversupply on the AMPK pathway in skeletal muscle, liver, and adipose tissue. Male Wistar rats were infused with lipid emulsion (LE) or phosphate-buffered saline for 5 h/day for 6 days. Muscles exposed to LE for 6 days exhibited increased AMPK and acetyl-CoA carboxylase (ACC) phosphorylation, along with a greater association between AMPK and Ca(2+)/calmodulin-dependent protein kinase kinase (CaMKK). No differences in muscle protein phosphatase 2C (PP2C) activity, LKB1 phosphorylation or AMPK and LKB1 association were observed. Muscle ACCbeta, and adiponectin receptor 1 (AdipoR1) mRNA levels and PPARgamma-co-activator 1alpha (PGC1alpha) protein levels were also increased in LE-treated rats. In contrast, AMPK and ACC phosphorylation decreased and PP2C activity increased in rat livers exposed to LE. Hepatic mRNA levels of ACCalpha, PPARalpha, AdipoR1, AdipoR2, and sterol regulatory element-binding protein-1c (SREBP1c) were also reduced after LE infusion. In adipose tissue, there was no significant alteration in AMPK or ACC phosphorylation. These results demonstrate that following lipid oversupply the AMPK pathway was enhanced in rat skeletal muscle while diminished in the liver and was unchanged in adipose tissue. CaMKK in skeletal muscle and PP2C in the liver, at least in part, appear to mediate these alterations. Alterations in AMPK pathway in the liver induced metabolic defects associated with lipid oversupply.

Publisher Summary Different studies have shown that the consumption of olive oil may have a potential role in lowering the risk of malignant neoplasms, especially breast and stomach cancer and also ovary, colon and endometrium cancer. Different mechanisms for the modulatory actions of olive oil and other dietary lipids on cancer have been proposed. Among them, there is experimental evidence about an influence on the hormonal status, cell membrane structure and function, signal transduction pathways, gene expression, and the immune system. Nevertheless, the definite mechanisms by which the effects of olive oil are mediated are not well understood and require further elucidation. Colomer and Menendez suggested that the molecular explanation concerning the anticancer actions of olive oil might relate to the ability of oleic acid (OA) to specifically regulate cancer-related oncogenes. Exogenous supplementation of cultured breast cancer cells with physiological concentrations of oleic acid was found to suppress the overexpression of Her-2, a well-characterized oncogene playing a key role in the etiology, progression and response to chemotherapy and endocrine therapy in approximately 20% of breast carcinomas. Exogenous supplementation with oleic acid dramatically down-regulates Her-2/neu-coded p185Her-2/neu oncoprotein in human breast cancer cell lines, bearing amplification of the Her-2/neu oncogene. Importantly, oleic-acid–induced suppression of Her-2/neu overexpression was not significantly prevented by the effective scavenger of reactive oxygen species vitamin E, thus ruling out that lipid peroxidation may be involved in this effect.

Insulin resistance is a predominant feature in women with polycystic ovarian syndrome (PCO). The cellular mechanisms for this insulin resistance have not been defined. In this study, major steps in the insulin action cascade, receptor binding, kinase activity, and glucose transport activity were evaluated in isolated adipocytes prepared from PCO subjects (n = 8) without acanthosis nigricans and in a group of age and weight-matched controls [normal cycling (NC) n = 8]. The PCO group was hyperinsulinemic and displayed elevated insulin responses to an iv glucose load. The binding of 125I-insulin to adipocytes was similar in cells from PCO and NC subjects. In PCO, autophosphorylation of the insulin receptor-subunit in the absence of insulin was normal but a significant decrease (30% below control) in maximal insulin stimulated autophosphorylation was observed. However, receptor kinase activity measured against the exogenous substrate poly glu:tyr (4:1) was normal. Cells from PCO subjects transported glucose at the same rate, in both the absence and presence of a maximal insulin concentration, as those from NC subjects. Strikingly, there was a large rightward shift in the insulin dose-response curve for transport stimulation in PCO cells (EC50 = 87 +/- 14 pmol in NC vs. 757 +/- 138 in PCO, P less than 0.0005); 8-fold greater insulin concentrations were required to attain comparable glucose transport rates in cells from PCO against NC. In conclusion, our results suggest that insulin resistance in PCO, as assessed in the adipocyte, is accompanied by normal function of insulin receptors, but involves a novel postreceptor defect in the insulin signal transduction chain between the receptor kinase and glucose transport.