Increased Plasma Insulin Research Articles

The Effects of Chronic Stress on Brown Adipose Tissue Remodeling and Metabolism

Adipose tissue has been found to exist in two predominant forms, white and brown. White adipose tissue (WAT) is the body's conventional storage organ, while brown adipose tissue (BAT) is responsible for non-shivering thermogenesis, which allows mammals to produce heat and regulate body temperature. Studies examining BAT and its role in whole-body metabolism have found that active BAT can lead to improved metabolic outcomes. While the beiging/ browning of WAT is a growing area of interest, the possibility of the BAT depot to “whiten” and store more triglycerides and adopt a lipid storage phenotype of WAT may have important health implications. Currently, there are limited studies that examine the direct effects of chronic stress in BAT and its ability to induce a white-like phenotype in this adipose tissue depot. This current research aimed to determine the impact of high levels of the murine stress hormone, corticosterone, on the whitening process of BAT. Six-week-old male C57BL/6J mice were exposed to high levels (100µg/ml) of corticosterone in their drinking water for four weeks. The effect of the corticosterone on BAT was investigated for its impact on insulin resistance, and the expression of uncoupling protein 1 (UCP1), which is integral to the non-shivering thermogenesis pathway. Corticosterone treatment significantly (p≤0.05) increased body weight, both WAT and BAT mass, and adipocyte size in each adipose depot. Corticosterone treatment significantly (p≤0.05) increased plasma insulin concentrations. The homeostatic model of assessment for insulin resistance (HOMA-IR) demonstrated that the corticosterone treated mice were also significantly (p≤0.05) more insulin resistant than controls. Surprisingly, the BAT of the corticosterone treated mice had significantly (p≤0.05) higher protein expression levels of UCP1 than controls. The alterations found in our in vivo model illustrated that chronic treatment with corticosterone for 4 weeks resulted in tissue remodeling, altered glucose metabolism, and adipose tissue whitening. By understanding these altered adipocyte morphologies and metabolic phenotypes in mice under chronic stress, we will be better equipped to uncover pathological effects of metabolic diseases weighing the world down today.

Telfairia occidentalis stimulates hepatic glycolysis and pyruvate production via insulin-dependent and insulin-independent mechanisms

BackgroundTelfairia occidentalis (TO), a plant consumed for its nutritional and medicinal values, exhibits hypoglycaemic effect. However, the metabolic fate of the glucose following TO-induced insulin secretion and consequent hypoglycaemia is not clear. ObjectiveThis study determined the effect of ethyl acetate and n-hexane fractions of TO leaf extracts on some biochemical parameters in the glucose metabolic pathway to explain the possible fate of blood glucose following TO-induced hypoglycaemia. MethodsEighteen male Wistar rats (180–200 g) divided into control, n-hexane TO fraction- and ethyl acetate TO fraction-treated groups (n = 6/group) were used. The control animals received normal saline while the treated groups received TO at 100 mg/kg for seven days. After 24 h following the last dose, the animals were anaesthetised using ketamine; blood samples were collected and livers harvested to determine some biochemical parameters. ResultsEthyl acetate TO fraction significantly increased plasma insulin, liver glucokinase activity and plasma pyruvate concentration, but significantly decreased plasma glucose and liver glycogen, without significant changes in plasma lactate, glucose-6-phosphate, liver glucose-6-phosphatase and lactate dehydrogenase activities when compared with control. N-hexane TO fraction significantly reduced liver glucose-6-phosphatase activity and glycogen but significantly increased plasma pyruvate, without significant changes in plasma glucose, insulin, glucose-6-phosphate and lactate concentrations; and liver glucokinase and lactate dehydrogenase activities. ConclusionThe present study showed that insulin-mediated TO-induced hypoglycaemia resulted in the stimulation of glycolysis and pyruvate production via insulin-dependent and insulin-independent mechanisms.

In Vitro and In Vivo Effects of Palmaria palmata Derived Peptides on Glucose Metabolism

Three synthetic peptides, ILAP, LLAP and MAGVDHI, derived from a Palmaria palmata protein hydrolysate were assessed for their antidiabetic potential in vitro and in vivo. In addition to inhibiting dipeptidyl peptidase-IV in a cell-based in situ assay all three peptides significantly increased the half-life of the incretin hormone glucagon-like peptide-1 (GLP-1). ILAP and LLAP mediated a significant increase (p < 0.001) in insulin secretion from BRIN-BD11 cells compared to the glucose control, while MAGVDHI had no insulinotropic activity at an eqimolar concentration (10–6 M). A significant increase in the concentration of cyclic adenosine monophosphate production in BRIN-BD11 cells mediated by ILAP (p < 0.001) and LLAP (p < 0.01) compared to the basal control, would indicate that insulin secretion may be mediated by membrane based activation. Furthermore, ILAP and LLAP acted as glucose-dependent insulinotropic polypeptide (GIP) secretagogues, stimulating a significant increase (p < 0.01) in the concentration of GIP released from enteroendocrine STC-1 cells compared to the glucose control. When tested in vivo in healthy male NIH Swiss mice, ILAP and LLAP, mediated a significant increase (p < 0.01) in plasma insulin and decrease (p < 0.05) in blood glucose, respectively, compared to the control. MAGVDHI mediated a significant (p < 0.001) sustained reduction in food intake in food deprived trained mice. These results demonstrate that the Palmaria palmata peptides studied herein have prospective antidiabetic activity and have the potential to act as agents that can be used alone or in combination with drugs, to aid in the prevention and management of Type 2 diabetes mellitus.

Comparative Effects of Intragastric and Intraduodenal Administration of Quinine on the Plasma Glucose Response to a Mixed-Nutrient Drink in Healthy Men: Relations with Glucoregulatory Hormones and Gastric Emptying.

In preclinical studies, bitter compounds, including quinine, stimulate secretion of glucoregulatory hormones [e.g., glucagon-like peptide-1 (GLP-1)] and slow gastric emptying, both key determinants of postprandial glycemia. A greater density of bitter-taste receptors has been reported in the duodenum than the stomach. Thus, intraduodenal (ID) delivery may be more effective in stimulating GI functions to lower postprandial glucose. We compared effects of intragastric (IG) and ID quinine [as quinine hydrochloride (QHCl)] administration on the plasma glucose response to a mixed-nutrient drink and relations with gastric emptying, plasma C-peptide (reflecting insulin secretion), and GLP-1. Fourteen healthy men [mean±SD age: 25±3y; BMI (in kg/m2): 22.5±0.5]received, on 4 separate occasions, in double-blind, randomly assigned order, 600 mgQHCl or control, IG or ID, 60min (IG conditions) or 30min (IG conditions) before a mixed-nutrient drink. Plasma glucose (primary outcome) and hormones were measured before, and for 2 h following, the drink. Gastric emptying of the drink was measured using a 13C-acetate breath test. Data were analyzed using repeated-measures 2-way ANOVAs (factors: treatment and route of administration) to evaluate effects of QHCl alone and 3-way ANOVAs (factors: treatment, route-of-administration, and time) for responses to the drink. After QHCl alone, there were effects of treatment, but not route of administration, on C-peptide, GLP-1, and glucose (P<0.05); QHCl stimulated C-peptide and GLP-1 and lowered glucose concentrations (IG control: 4.5±0.1; IG-QHCl: 3.9±0.1; ID-control: 4.6±0.1; ID-QHCl: 4.2±0.1 mmol/L)compared with control. Postdrink, there were treatment×time interactions for glucose, C-peptide, and gastric emptying, and a treatment effect for GLP-1 (all P<0.05), but no route-of-administration effects. QHCl stimulated C-peptide and GLP-1, slowed gastric emptying, and reduced glucose (IG control: 7.2±0.3; IG-QHCl: 6.2±0.3; ID-control: 7.2±0.3; ID-QHCl: 6.4±0.4 mmol/L) compared with control. In healthy men, IG and ID quinine administration similarly lowered plasma glucose, increased plasma insulin and GLP-1, and slowed gastric emptying. These findings have potential implications for lowering blood glucose in type 2 diabetes. This study was registered as a clinical trial with the Australian New Zealand Clinical Trials at www.anzctr.org.au as ACTRN12619001269123.

Optogenetic stimulation of cholinergic fibers for the modulation of insulin and glycemia

Previous studies have demonstrated stimulation of endocrine pancreas function by vagal nerve electrical stimulation. While this increases insulin secretion, expected concomitant reductions in circulating glucose do not occur. A complicating factor is the non-specific nature of electrical nerve stimulation. Optogenetic tools, however, provide the potential for cell-type specific neural stimulation using genetic targeting and/or spatially shaped excitation light. Here, we demonstrate light-activated stimulation of the endocrine pancreas by targeting parasympathetic (cholinergic) axons. In a mouse model expressing ChannelRhodopsin2 (ChR2) in cholinergic cells, serum insulin and glucose were measured in response to (1) ultrasound image-guided optical stimulation of axon terminals in the pancreas or (2) optical stimulation of axons of the cervical vagus nerve. Measurements were made in basal-glucose and glucose-stimulated conditions. Significant increases in plasma insulin occurred relative to controls under both pancreas and cervical vagal stimulation, while a rapid reduction in glycemic levels were observed under pancreatic stimulation. Additionally, ultrasound-based measurements of blood flow in the pancreas were increased under pancreatic stimulation. Together, these results demonstrate the utility of in-vivo optogenetics for studying the neural regulation of endocrine pancreas function and suggest its therapeutic potential for the control of insulin secretion and glucose homeostasis.

Arbutin alleviates diabetic symptoms by attenuating oxidative stress in a mouse model of type 1 diabetes

Arbutin is a well-known tyrosinase inhibitor that prevents the formation of melanin through the inhibition of tyrosinase. Therefore, it has been widely used as a cosmetic skin-lightening agent. Arbutin is able to scavenge free radicals within cells and previous studies have found that it also exhibited useful activities for the treatment of diuresis, bacterial infections, and cancer, as well as anti-inflammatory and anti-tussive activities. This study analyzed the effects of arbutin on streptozotocin (STZ)-induced diabetes mellitus in a murine model. Healthy male adult C57BL/6 mice (7 weeks old) were randomly allocated into one of the following three groups of six animals: Normal control with no STZ administration, STZ-induced diabetes, and STZ-induced diabetes treated with 0.3 g/kg/day of arbutin. After 12 days, the levels of insulin, C-peptide, and HbA1c were measured in serum, and the expression and enzymatic activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) were analyzed in pancreatic tissues by western blotting. Arbutin was found to significantly inhibit the increase in blood glucose and the loss of body weight in diabetic mice. Arbutin increased plasma insulin levels in mice with STZ-induced diabetes, whereas there was no detection of insulin in untreated diabetic mice. In addition, there was an increased expression and activity of SOD, CAT, and GPx in diabetic mice treated with arbutin. This investigation demonstrated that arbutin possesses antioxidant activities and can alleviate symptoms of type-1 diabetes mellitus (T1DM) in mice.

Mechanisms of action of the antidiabetic peptide [S4K]CPF-AM1 in db/db mice.

The antidiabetic effects and mechanisms of action of an analogue of a frog skin host-defence peptide belonging to the caerulein-precursor fragment family, [S4K]CPF-AM1 were investigated in db/db mice with a genetically inherited form of degenerative diabetes-obesity. Twice-daily treatment with the peptide (75 nmol/kg body weight) for 28 days significantly decreased blood glucose (P < 0.01) and HbA1c (P < 0.05) and increased plasma insulin (P < 0.05) concentrations with no effect on body weight, energy intake, body composition or plasma lipid profile. Peptide administration improved insulin sensitivity and intraperitoneal glucose tolerance. Elevated biomarkers of liver and kidney function associated with the db/db phenotype were significantly lowered by [S4K]CPF-AM1 administration. Peptide treatment significantly (P < 0.05) increased pancreatic insulin content and improved the responses of isolated islets to established secretagogues. Elevated expression of genes associated with insulin signalling (Slc2a4, Insr, Irs1, Akt1, Pik3ca, Ppm1b) in the skeletal muscle of db/db mice were significantly downregulated by peptide treatment. Genes associated with insulin secretion (Abcc8, Kcnj11, Slc2a2, Cacn1c, Glp1r, Gipr) were significantly upregulated by treatment with [S4K]CPF-AM1. Studies with BRIN-BD1I clonal β-cells demonstrated that the peptide evoked membrane depolarisation, increased intracellular Ca2+ and cAMP and activated the protein kinase C pathway. The data indicate that the antidiabetic properties of [S4K]CPF-AM1 mice are mediated by direct insulinotropic action and by regulation of transcription of genes involved in both the secretion and action of insulin.

The Effects of Maternal High Fat Diet on the Lingual CD36 Lipid Sensors of the Offspring Sprague Dawley Rats

Background: Recent studies have demonstrated that CD36 lingual fat sensor has a vital role in fat sensation and high fat diet (HFD) causes dysfunctions in oro-gustatory lipid sensors. Objective: This study aims to investigate the effects of HFD during maternal and /or maturation period on lingual CD36 expression in offspring rats. Methods: Initially, female Sprague Dawley rats were familiarized to experimental diets. After the mating period, pregnant rats were fed with control (C) and HFD during the maternal period. Then, offsprings in each group were fed with C and HFD during the maturation period (120 days). Daily caloric intake and weekly weight measurements of the offspring rats were followed. The plasma insulin and leptin levels were determined with ELISA. Blood glucose and triglyceride levels were measured. The protein and mRNA expressions of CD36 in the circumvallate papillae (CVP) were determined by western blotting, immunofluorescence, and RT-PCR. Also, alpha-gustducin was used as taste marker. Results: According to biochemical measurements, HFD/HFD group offsprings have significantly increased plasma insulin and leptin concentrations compared to C/C group (p<0.05 and p<0.01, respectively). CD36 protein expressions in CVP were significantly lower in HFD/HFD than C/HFD and HFD/C groups (p<0.05). Consistently, CD36 in taste buds had weak immunofluorescence signal in HFD/HFD group. However, mRNA transcripts level of CD36 in HFD/HFD group were significantly higher than C/HFD group (p<0.05). Conclusion: This study suggests that HFD exposure during both maternal and/or maturation period may affect the expression of lingual taste sensor level.

Chemerin impairs food intake and body weight in chicken: Focus on hypothalamic neuropeptides gene expression and AMPK signaling pathway

Unlike mammals, the role of adipokines and more particularly of chemerin in the regulation of food intake is totally unknown in avian species. Here we investigated the effect of chemerin on the food and water consumption and on the body weight in chicken. We studied the effects on the plasma glucose and insulin concentrations and the hypothalamic neuropeptides and AMPK signaling pathway. Female broiler chickens were intraperitoneally injected, daily for 13 days with either vehicle (saline; n = 25) or chemerin (8 μg/kg; n = 25 and 16 μg/kg; n = 25). Food and water intakes were recorded 24 h after each administration. Overnight fasted animals were sacrificed at day 13 (D13), 24 h after the last injection and hypothalamus and left cerebral hemispheres were collected. Chemerin and its receptors protein levels were determined by western-blot. Gene expression of neuropeptide Y (Npy), agouti-related peptide (Agrp), corticotrophin releasing hormone (Crh), pro-opiomelanocortin (Pomc), cocaine and amphetamine-regulated transcript (Cart) and Taste 1 Receptor Member 1 (Tas1r1) were evaluated by RT-qPCR. In chicken, we found that the protein amount of chemerin, CCRL2 and GPR1 was similar in left cerebral hemisphere and hypothalamus whereas CMKLR1 was higher in hypothalamus. Chemerin administration (8 and 16 μg/kg) decreased both food intake and body weight compared to vehicle without affecting water intake and the size or volume of different brain subdivisions as determined by magnetic resonance imaging. It also increased plasma insulin levels whereas glucose levels were decreased. These data were associated with an increase in Npy and Agrp expressions and a decrease in Crh, Tas1r1 mRNA expression within the hypothalamus. Furthermore, chemerin decreased hypothalamic CMKLR1 protein expression and AMPK activation. Taken together, these results support that chemerin could be a peripheral appetite-regulating signal through modulation of hypothalamic peptides expression in chicken.

Exogenous GLP-1 stimulates TCA cycle and suppresses gluconeogenesis and ketogenesis in late-fasted northern elephant seals pups

The post-weaning fast of northern elephant seal pups is characterized by a lipid-dependent metabolism and associated with a decrease in plasma glucagon-like peptide-1 (GLP-1), insulin, and glucose and increased gluconeogenesis (GNG) and ketogenesis. We have also demonstrated that exogenous GLP-1 infusion increased plasma insulin despite simultaneous increases in cortisol and glucagon, which collectively present contradictory regulatory stimuli of GNG, ketogenesis, and glycolysis. To assess the effects of GLP-1 on metabolism using primary carbon metabolite profiles in late-fasted seal pups, we dose-dependently infused late-fasted seals with low (LDG; 10 pM/kg; n=3) or high (HDG; 100 pM/kg; n=4) GLP-1 immediately following a glucose bolus (0.5g/kg), using glucose without GLP-1 as control (n=5). Infusions were performed in similarly aged animals 6-8 weeks into their post-weaning fast. The plasma metabolome was measured from samples collected at 5 time points just prior to and during the infusions, and network maps constructed to robustly evaluate the effects of GLP-1 on primary carbon metabolism. HDG increased key tricarboxylic acid (TCA) cycle metabolites, and decreased phosphoenolpyruvate and acetoacetate (P<0.05) suggesting that elevated levels of GLP-1 promote glycolysis and suppress GNG and ketogenesis, which collectively increase glucose clearance. These GLP-1-mediated effects on cellular metabolism help to explain why plasma GLP-1 concentrations decrease naturally in fasting pups as an evolved mechanism to help conserve glucose during the late-fasting period.

THE EFFECTS OF EUGLVCEMIC INSULIN CLAMP ON THE METABOLISM OF 3-HYDROXVBUTYRATE AND PLASMA FREE FAHY ACIDS BY THE HIND LIMB OF LACRATING SHEEP

The effects of exogenous insulin, with euglycemia, on the concentration differences, extraction ratio and uptake of 3- hydroxybutyrate and plasma free fatty acids by the lactating sheep hind limb were studied. Generally, the results showed that with increasing plasma insulin levels, while maintaining euglycemia, the concentrations, arterio-venous concentration differences, extraction ratio and uptake of 3-hydrubutyrate and free fatty acids Were significantly (P&lt;0.05) reduced, but Significant correlation was established between arterial concentration of 3-hydtoxvbutyrate and plasma free fatty acids and their uptake. A similar relationship was also obtained between the arterial concentrations of 3-hydroxybutyrate plasma free fatty acids.

Beneficial actions of the [A14K] analog of the frog skin peptide PGLa-AM1 in mice with obesity and degenerative diabetes: A mechanistic study

The antidiabetic actions of [A14K]PGLa-AM1, an analog of peptide glycine-leucine-amide-AM1 isolated from skin secretions of the octoploid frog Xenopus amieti, were investigated in genetically diabetic-obese db/db mice. Twice daily administration of [A14K]PGLa-AM1 (75 nmol/kg body weight) for 28 days significantly (P < 0.05) decreased circulating blood glucose and HbA1c and increased plasma insulin concentrations leading to improvements in glucose tolerance. The elevated levels of triglycerides, LDL and cholesterol associated with the db/db phenotype were significantly reduced by peptide administration. Elevated plasma alanine transaminase, aspartic acid transaminase, and alkaline phosphatase activities and creatinine concentrations were also significantly decreased. Peptide treatment increased pancreatic insulin content and improved the responses of isolated islets to established insulin secretagogues. No significant changes in islet β-cell and α-cell areas were observed in [A14K]PGLa-AM1 treated mice but the loss of large and medium-size islets was prevented. Peptide administration resulted in a significant (P < 0.01) increase in islet expression of the gene encoding Pdx-1, a major transcription factor in islet cells determining β-cell survival and function, resulting in increased expression of genes involved with insulin secretion (Abcc8, Kcnj11, Slc2a2, Cacn1c) together with the genes encoding the incretin receptors Glp1r and Gipr. In addition, the elevated expression of insulin signalling genes (Slc2a4, Insr, Irs1, Akt1, Pik3ca, Ppm1b) in skeletal muscle associated with the db/db phenotype was downregulated by peptide treatment These data suggest that the anti-diabetic properties of [A14K]PGLa-AM1 are mediated by molecular changes that enhance both the secretion and action of insulin.

Programming of Cardiovascular Dysfunction by Postnatal Overfeeding in Rodents.

Nutritional environment in the perinatal period has a great influence on health and diseases in adulthood. In rodents, litter size reduction reproduces the effects of postnatal overnutrition in infants and reveals that postnatal overfeeding (PNOF) not only permanently increases body weight but also affects the cardiovascular function in the short- and long-term. In addition to increased adiposity, the metabolic status of PNOF rodents is altered, with increased plasma insulin and leptin levels, associated with resistance to these hormones, changed profiles and levels of circulating lipids. PNOF animals present elevated arterial blood pressure with altered vascular responsiveness to vasoactive substances. The hearts of overfed rodents exhibit hypertrophy and elevated collagen content. PNOF also induces a disturbance of cardiac mitochondrial respiration and produces an imbalance between oxidants and antioxidants. A modification of the expression of crucial genes and epigenetic alterations is reported in hearts of PNOF animals. In vivo, a decreased ventricular contractile function is observed during adulthood in PNOF hearts. All these alterations ultimately lead to an increased sensitivity to cardiac pathologic challenges such as ischemia-reperfusion injury. Nevertheless, caloric restriction and physical exercise were shown to improve PNOF-induced cardiac dysfunction and metabolic abnormalities, drawing a path to the potential therapeutic correction of early nutritional programming.

Effect of heat stress and feeding management on growth performance and physiological responses of finishing pigs.

This study aimed to determine whether pig responses to heat stress (HS) were directly due to heat exposure (regardless of feeding level and pattern) or were indirectly due to the reduction of feed intake (FI) and to determine if increasing feeding frequency (splitting heat increments) can improve pig response to HS. A total of 48 pigs (66.1 ± 1.7 kg) were allocated to four groups in three replicates. After 7 d in thermoneutral (TN) conditions (22 °C; period 1 [P1; day -7 to -1]), pigs were placed in either TN or HS (32 °C) conditions for 20 d (period 2 [P2; day 0 to 19]). The diet was provided either ad libitum (AL; 2 distributions/d) or pair-fed (PF8; 8 distributions/d) using HS-AL pigs as the reference group. Thus, the four experimental groups were TN-AL, HS-AL, TN-PF8, and HS-PF8. The daily ration of PF8 pigs was distributed at every 90-min intervals from 0900 to 1930 hours. Data were analyzed using the PROC MIXED procedure with replicate (n = 3), experimental group (n = 4), and their interactions as fixed effects, and the REPEATED statement was used for repeated measures data. Pigs had a similar average daily feed intake (ADFI) during P1 (P > 0.05). In P2, HS-AL and PF8 pigs had lower ADFI (-19%), average daily gain (-25%), and final body weight (-6.1 kg) than TN-AL pigs (P < 0.01). TN-AL pigs had thicker backfat than TN-PF8 pigs (P < 0.05), while the HS pigs had intermediate results. HS pigs had a higher perirenal fat percentage based on the contrast analysis between PF8 pigs (P < 0.05). Thermoregulatory responses of pigs increased with HS exposure but did not differ between HS or between TN groups (P > 0.05). For TN pigs, variation in muscle temperature (Tmuscle) depended on feeding and physical activity, while for HS pigs, Tmuscle gradually increased throughout the day. The Tmuscle of PF8 pigs increased with each additional meal but plateaued earlier for HS-PF8 than TN-PF8 pigs; an increase in Tmuscle per meal was also lower in HS-PF8 than TN-PF8 (P < 0.05). Exposure to HS decreased plasma T3 and T4 (P < 0.05) and increased plasma creatinine (P < 0.05). Between the PF8 groups, HS pigs also had a transient increase in plasma insulin on day 8 (P < 0.05). The effect of HS on FI decreased the growth rate of pigs but there are heat-induced effects, such as altered physiological responses, which might explain the direct HS effects seen in other literature especially in terms of increased adiposity. The increased feed provision frequency in the present study did not improve the HS response of pigs.

Role of sex and diet in hypothalamic disturbances in wild‐type mice and the 3xTg‐AD mouse model of familial Alzheimer’s disease

AbstractBackgroundHypothalamic dysfunction occurs early in the clinical course of Alzheimer’s disease (AD), likely contributing to disturbances in feeding behavior and metabolic function that are often observable years prior to the onset of cognitive symptoms. Late‐life weight loss and low BMI are associated with increased risk of dementia and faster progression of disease. However, high fat diet and metabolic disease (e.g. obesity, type 2 diabetes), particularly in mid‐life, are associated with increased risk of AD, as well as exacerbated AD pathology and behavioral deficits in animal models. In the current study, we explored possible relationships between hypothalamic function, diet/metabolic status, and AD. Considering the sex bias in AD, with women representing two‐thirds of AD patients, we sought to determine whether these relationships may vary by sex.MethodsWT and 3xTg‐AD male and female mice were fed a control (10% fat) or high fat (HF; 60% diet) diet from ∼3‐7 months of age, then tested for metabolic and hypothalamic disturbances.ResultsOn control diet, male 3xTg‐AD mice displayed increased expression of genes indicative of inflammation in the hypothalamus, including Iba1 (+34%), GFAP (+53%), TNF‐α (+46%) and IL‐1β (∼6‐fold increase) compared to WT. Male 3xTg‐AD mice on control diet also model what is seen clinically in AD in terms of metabolic disturbances (decreased body weight, reduced fat mass, hypoleptinemia). In contrast, female 3xTg‐AD mice on control diet displayed metabolic disturbances opposite that of 3xTg‐AD males (increased body and fat mass, impaired glucose tolerance). HF diet resulted in expected metabolic alterations across groups (increased body and fat mass; glucose intolerance; increased plasma insulin and leptin, decreased ghrelin), though HF diet alone did not alter hypothalamic expression of inflammatory markers in WT mice, nor did it exacerbate hypothalamic inflammation in 3xTg‐AD males. HF diet resulted in the greatest metabolic disturbances in 3xTg‐AD females, in addition to markedly increased hypothalamic expression of GFAP and IL‐1β (+99% and ∼5‐fold increase, respectively, vs. WT control females).ConclusionsThese findings provide further evidence for the roles of hypothalamic and metabolic dysfunction in AD, which in the 3xTg‐AD mouse model appears to be dependent on both sex and diet.

Circulating cathepsin S improves glycaemic control in mice.

Cathepsin S (CTSS) is a cysteine protease that regulates many physiological processes and is increased in obesity and type 2 diabetes. While previous studies show that deletion of CTSS improves glycaemic control through suppression of hepatic glucose output, little is known about the role of circulating CTSS in regulating glucose and energy metabolism. We assessed the effects of recombinant CTSS on metabolism in cultured hepatocytes, myotubes and adipocytes, and in mice following acute CTSS administration. CTSS improved glucose tolerance in lean mice and this coincided with increased plasma insulin. CTSS reduced G6pc and Pck1 mRNA expression and glucose output from hepatocytes but did not affect glucose metabolism in myotubes or adipocytes. CTSS did not affect insulin secretion from pancreatic β-cells, rather CTSS stimulated glucagon-like peptide (GLP)-1 secretion from intestinal mucosal tissues. CTSS retained its positive effects on glycaemic control in mice injected with the GLP1 receptor antagonist Exendin (9-39) amide. The effects of CTSS on glycaemic control were not retained in high-fat-fed mice or db/db mice, despite the preservation of CTSS' inhibitory actions on hepatic glucose output in isolated primary hepatocytes. In conclusion, we unveil a role for CTSS in the regulation of glycaemic control via direct effects on hepatocytes, and that these effects on glycaemic control are abrogated in insulin resistant states.

Oral L-glutamine rescues fructose-induced poor fetal outcome by preventing placental triglyceride and uric acid accumulation in Wistar rats

BackgroundMetabolic adaptation of pregnant mothers is crucial for placental development and fetal growth/survival. However, evidence exists that indiscriminate consumption of fructose-enriched drink (FED) during pregnancy disrupts maternal-fetal metabolic tolerance with attendant adverse fetal outcomes. Glutamine supplementation (GLN) has been shown to exert a modulatory effect in metabolic disorders. Nevertheless, the effects of GLN on FED-induced poor fetal outcome, and in particular the impacts on placental uric acid/lipid accumulation are unknown. The present study was conducted to test the hypothesis that oral GLN improves fetal outcome by attenuating placental lipid accumulation and uric acid synthesis in pregnant rats exposed to FED. Materials and methodsPregnant Wistar rats (160–180 g) were randomly allotted to control, GLN, FED and FED + GLN groups (6 rats/group). The groups received vehicle by oral gavage, glutamine (1 g/kg) by oral gavage, fructose (10%; w/v) and fructose + glutamine, respectively, through gestation. ResultsData showed that FED during pregnancy caused placental inefficiency, reduced fetal growth, and caused insulin resistance with correspondent increase in fasting blood glucose and plasma insulin. FED also resulted in an increased placental triglyceride, total cholesterol and de novo uric acid synthesis by activating adenosine deaminase and xanthine oxidase activities. Moreover, FED during pregnancy led to increased lipid peroxidation, lactate production with correspondent decreased adenosine and glucose-6-phosphate dehydrogenase-dependent antioxidant defense. These alterations were abrogated by GLN supplementation. ConclusionThese findings implicate that high FED intake during pregnancy causes poor fetal outcome via defective placental uric acid/triglyceride-dependent mechanism. The findings also suggest that oral GLN improves fetal outcome by ameliorating placental defects through suppression of uric acid/triglyceride accumulation.

The Tailgate Study: Differing metabolic effects of a bout of excessive eating and drinking

Excess energy intake by spectators at a sporting event (i.e., a tailgate) might cause acute negative health effects. However, limited data exist regarding the effects of overeating and alcohol consumption on lipid metabolism and the potential to gain intrahepatic triacylglycerols (IHTG). We tested the hypothesis that overconsumption of food and alcohol would significantly increase both hepatic de novo lipogenesis (DNL) and IHTG. Eighteen males (mean ± SD, age: 31.4 ± 7.3 years, BMI: 32.1 ± 5.9 kg/m 2 ) were given alcoholic drinks to elevate blood alcohol for 5 h, while highly palatable food was presented. Blood samples were collected and DNL in TG-rich lipoproteins (TRL) was measured by GC/MS, IHTG was measured via MRS (n = 15), and substrate oxidation was measured via indirect calorimetry. Subjects consumed 5087 ± 149 kcal (191 ± 25% excess of total daily energy needs including 171 ± 24 g alcohol), which increased plasma insulin, glucose, TG, and decreased NEFA (ANOVA p ≤ 0.003 for all). Both DNL and TRL-TG increased ( p < 0.001), while IHTG did not change in the group as a whole ( p = 0.229). Individual subject data revealed remarkably differing responses for IHTG (nine increased, five decreased, one did not change). Despite maintaining equal breath alcohol levels, subjects with IHTG elevations exhibited higher DNL, consumed 90% less alcohol ( p = 0.048), tended to consume more carbohydrates, and exhibited lower whole-body fat oxidation (not significant) compared to those whose IHTG was reduced. This study demonstrates that acute excess energy intake may have differing effects on an individual's DNL and IHTG, and dietary carbohydrate may influence DNL more than alcohol. • No studies have quantitated effects of acutely consuming both food and alcohol on lipogenesis (DNL) and liver fat (IHTG). • Excess energy intake had differing effects on DNL and IHTG, increasing in some subjects and decreasing in others. • Storage of liver fat occurred in individuals who increased DNL in response to excess energy intake.

Impact of Long-Term HFD Intake on the Peripheral and Central IGF System in Male and Female Mice.

The insulin-like growth factor (IGF) system is responsible for growth, but also affects metabolism and brain function throughout life. New IGF family members (i.e., pappalysins and stanniocalcins) control the availability/activity of IGFs and are implicated in growth. However, how diet and obesity modify this system has been poorly studied. We explored how intake of a high-fat diet (HFD) or commercial control diet (CCD) affects the IGF system in the circulation, visceral adipose tissue (VAT) and hypothalamus. Male and female C57/BL6J mice received HFD (60% fat, 5.1 kcal/g), CCD (10% fat, 3.7 kcal/g) or chow (3.1 % fat, 3.4 kcal/g) for 8 weeks. After 7 weeks of HFD intake, males had decreased glucose tolerance (p < 0.01) and at sacrifice increased plasma insulin (p < 0.05) and leptin (p < 0.01). Circulating free IGF1 (p < 0.001), total IGF1 (p < 0.001), IGF2 (p < 0.05) and IGFBP3 (p < 0.01) were higher after HFD in both sexes, with CCD increasing IGFBP2 in males (p < 0.001). In VAT, HFD reduced mRNA levels of IGF2 (p < 0.05), PAPP-A (p < 0.001) and stanniocalcin (STC)-1 (p < 0.001) in males. HFD increased hypothalamic IGF1 (p < 0.01), IGF2 (p < 0.05) and IGFBP5 (p < 0.01) mRNA levels, with these changes more apparent in females. Our results show that diet-induced changes in the IGF system are tissue-, sex- and diet-dependent.

Beneficial effects of walnut (Juglans regia L.)\xa0oil-derived polyunsaturated fatty acid prevents a prooxidant status and hyperlipidemia in pregnant rats with diabetes

BackgroundGestational diabetes mellitus has a long-term effect on pregnant women. Walnut (Juglans regia L.) oil-derived polyunsaturated fatty acid (PUFA) possesses multifarious pharmacological activities. This study investigated the beneficial effects of walnut oil-derived PUFA on glucose metabolism, pregnancy outcomes, oxidative stress, and lipid metabolism in gestational diabetes mellitus.MethodsThe GDM rat model was generated by intraperitoneal injection of streptozotocin (40 mg/kg) on gestational day (GD) 6, GD7 and GD8. The differences between groups were estimated using one-way ANOVA followed by the Tukey’s multiple comparison test for post-hoc analysis.ResultsThe results indicated that PUFA could mitigate GDM in pregnant diabetic rats, as embodied by the decrease of fasting blood glucose and the increase of plasma insulin and hepatic glycogen levels. Also, PUFA could suppress oxidative stress in pregnant diabetic rats, as reflected by the decrease of malondialdehyde content, an increase of superoxide dismutase, catalase and gutathione peroxidase activities. PUFA could also mitigate the abnormal changes of lipid profiles in plasma and hepatic tissue. Moreover, the relative mRNA expression of sterol regulatory element-binding transcription factor-1, stearoyl-CoA desaturase-1, fatty acid synthase, and acetyl-coenzyme A carboxylase, was suppressed by PUFA in pregnant diabetic rats.ConclusionsThese results suggested that PUFA supplementation during pregnancy is beneficial in preventing diabetic complications in pregnant rats.