thapsigargin and Obesity

Topics: Aging; Animals; Behavior, Animal; Cells, Cultured; Diet, High-Fat; Disease Models, Animal; Doublecortin Domain Proteins; Endoplasmic Reticulum Stress; Hippocampus; Memory; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neurons; Obesity; Thapsigargin

Topics: Adipose Tissue; Alkynes; Anti-Retroviral Agents; Benzoxazines; Cyclopropanes; Diabetes Mellitus, Type 2; Drug Combinations; Endoplasmic Reticulum Stress; Fibroblast Growth Factors; Hep G2 Cells; HIV Infections; HIV Integrase Inhibitors; Humans; Klotho Proteins; Liver; Lopinavir; Maraviroc; Membrane Proteins; Muscle, Skeletal; Obesity; Oxidative Stress; Protease Inhibitors; Quinolones; Reverse Transcriptase Inhibitors; Ritonavir; Thapsigargin; Tunicamycin

Increased endoplasmic reticulum (ER) stress has emerged as a vital contributor to dysregulated glucose homeostasis, and impaired function of sarco-endoplasmic reticulum Ca

Topics: Animals; Blood Glucose; Body Weight; Calcium-Transporting ATPases; Cell Line; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Flavonoids; Insulin Resistance; Lipogenesis; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Muscle Fibers, Skeletal; Muscle, Skeletal; Obesity; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Thapsigargin; Up-Regulation

Obesity in reproductive-aged women is associated with a shorter luteal phase and lower progesterone levels. Lipid accumulation in follicles of obese women compromises endoplasmic reticulum (ER) function, activating ER stress in granulosa cells. We hypothesized that ER stress activation in granulosa-lutein cells (GLCs) would modulate progesterone production and contribute to obesity-associated progesterone deficiency. Pretreatment with an ER stress inducer, tunicamycin or thapsigargin, inhibited human chorionic gonadotropin (hCG)-stimulated progesterone production in cultured human GLCs. Pretreatment of human GLCs with tunicamycin inhibited hCG-stimulated expression of steroidogenic acute regulatory protein (StAR) and 3β-hydroxysteroid dehydrogenase (3β-HSD) messenger RNAs (mRNAs) without affecting expression of cytochrome P450 cholesterol side-chain cleavage enzyme (P450scc), as determined by real-time quantitative polymerase chain reaction. Pretreatment with tunicamycin also inhibited hCG-stimulated expression of StAR protein and 3β-HSD enzyme activity in cultured human GLCs, as determined by Western blot analysis and an enzyme immunoassay, respectively, but did not affect hCG-induced intracellular 3',5'-cyclic adenosine monophosphate accumulation. Furthermore, tunicamycin attenuated hCG-induced protein kinase A and extracellular signal-regulated kinase activation, as determined by Western blot analysis. In vivo administration of tunicamycin to pregnant mare serum gonadotropin-treated immature mice prior to hCG treatment inhibited the hCG-stimulated increase in serum progesterone levels and hCG-induced expression of StAR and 3β-HSD mRNA in the ovary without affecting serum estradiol levels or the number of corpora lutea. Our findings indicate that ER stress in the follicles of obese women contributes to progesterone deficiency by inhibiting hCG-induced progesterone production in granulosa cells.

Topics: 3-Hydroxysteroid Dehydrogenases; Animals; Aromatase; Cells, Cultured; Cholesterol Side-Chain Cleavage Enzyme; Chorionic Gonadotropin; Endoplasmic Reticulum Stress; Female; Gonadal Steroid Hormones; Granulosa Cells; Humans; Mice, Inbred C57BL; Obesity; Phosphoproteins; Progesterone; Receptors, LH; Thapsigargin; Tunicamycin

Maternal obesity and gestational diabetes mellitus (GDM) are two increasingly common and important obstetric complications that are associated with severe long-term health risks to mothers and babies. IL-1β, which is increased in obese and GDM pregnancies, plays an important role in the pathophysiology of these two pregnancy complications. In non-pregnant tissues, endoplasmic (ER) stress is increased in diabetes and can induce IL-1β via inflammasome activation. The aim of this study was to determine whether ER stress is increased in omental adipose tissue of women with GDM, and if ER stress can also upregulate inflammasome-dependent secretion of IL-1β. ER stress markers IRE1α, GRP78 and XBP-1s were significantly increased in adipose tissue of obese compared to lean pregnant women. ER stress was also increased in adipose tissue of women with GDM compared to BMI-matched normal glucose tolerant (NGT) women. Thapsigargin, an ER stress activator, induced upregulated secretion of mature IL-1α and IL-1β in human omental adipose tissue explants primed with bacterial endotoxin LPS, the viral dsRNA analogue poly(I:C) or the pro-inflammatory cytokine TNF-α. Inhibition of capase-1 with Ac-YVAD-CHO resulted in decreased IL-1α and IL-1β secretion, whereas inhibition of pannexin-1 with carbenoxolone suppressed IL-1β secretion only. Treatment with anti-diabetic drugs metformin and glibenclamide also reduced IL-1α and IL-1β secretion in infection and cytokine-primed adipose tissue. In conclusion, this study has demonstrated ER stress to activate the inflammasome in pregnant adipose tissue. Therefore, increased ER stress may contribute towards the pathophysiology of obesity in pregnancy and GDM.

Topics: Adipose Tissue; Adult; Biomarkers; Caspase 1; Connexins; Diabetes, Gestational; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Female; Glyburide; Humans; Inflammasomes; Interleukin-1alpha; Interleukin-1beta; Lipopolysaccharides; Male; Metformin; Mothers; Nerve Tissue Proteins; Obesity; Poly I-C; Pregnancy; Thapsigargin; Tumor Necrosis Factor-alpha

Glucagon-like peptide-1 (GLP-1) is secreted from intestinal L cells, enhances glucose-stimulated insulin secretion, and protects pancreas beta cells. However, few studies have examined hypernutrition stress in L cells and its effects on their function. Here, we demonstrated that a high-fat diet reduced glucose-stimulated secretion of GLP-1 and induced expression of an endoplasmic reticulum (ER) stress markers in the intestine of a diet-induced obesity mouse model.. To clarify whether ER stress in L cells caused the attenuation of GLP-1 secretion, we treated the mouse intestinal L cell line, GLUTag cells with palmitate or oleate.. Palmitate, but not oleate caused ER stress and decreased the protein levels of prohormone convertase 1/3 (PC1/3), an essential enzyme in GLP-1 production. The same phenomena were observed in GLUTag cells treated with in ER stress inducer, thapsigargin. Moreover, oleate improved palmitate-induced ER stress, reduced protein and activity levels of PC1/3, and attenuated GLP-1 secretion from GLUTag cells.. These results suggest that the intake of abundant saturated fatty acids induces ER stress in the intestine and decreases GLP-1 production.

Topics: Animals; Blotting, Western; Diet, High-Fat; Endoplasmic Reticulum Stress; Enzyme Inhibitors; Glucagon-Like Peptide 1; L Cells; Male; Mice; Mice, Inbred C57BL; Obesity; Oleic Acid; Palmitates; Proprotein Convertase 1; Real-Time Polymerase Chain Reaction; Thapsigargin

Since the increasing prevalence of obesity is one of the major health problems of the modern era, understanding the mechanisms of oro-gustatory detection of dietary fat is critical for the prevention and treatment of obesity. We have conducted the present study on Psammomys obesus, the rodent desert gerbil which is a unique polygenic natural animal model of obesity. Our results show that obese animals exhibit a strong preference for lipid solutions in a two-bottle test. Interestingly, the expression of CD36, a lipido-receptor, in taste buds cells (TBC), isolated from circumvallate papillae, was decreased at mRNA level, but remained unaltered at protein level, in obese animals. We further studied the effects of linoleic acid (LA), a long-chain fatty acid, on the increases in free intracellular calcium (Ca(2+)) concentrations, [Ca(2+)]i, in the TBC of P. obesus. LA induced increases in [Ca(2+)]i, largely via CD36, from intracellular pool, followed by the opening of store-operated Ca(2+) (SOC) channels in the TBC of these animals. The action of this fatty acid on the increases in [Ca(2+)]i was higher in obese animals than that in controls. However, the release of Ca(2+) from intracellular stores, studied also by employing thapsigargin, was lower in TBC of obese animals than control rodents. In this study, we show, for the first time, that increased lipid intake and altered Ca(2+) signaling in TBC are associated with obesity in Psammomys obesus.

Topics: Animals; Calcium Signaling; CD36 Antigens; Dietary Fats; Disease Susceptibility; Food Preferences; Gene Expression Regulation; Gerbillinae; Linoleic Acid; Male; Obesity; Taste Buds; Taste Perception; Thapsigargin

In obesity and diabetes, adipocytes show significant endoplasmic reticulum (ER) stress, which triggers a series of responses. This study aimed to investigate the lipolysis response to ER stress in rat adipocytes. Thapsigargin, tunicamycin, and brefeldin A, which induce ER stress through different pathways, efficiently activated a time-dependent lipolytic reaction. The lipolytic effect of ER stress occurred with elevated cAMP production and protein kinase A (PKA) activity. Inhibition of PKA reduced PKA phosphosubstrates and attenuated the lipolysis. Although both ERK1/2 and JNK are activated during ER stress, lipolysis is partially suppressed by inhibiting ERK1/2 but not JNK and p38 MAPK and PKC. Thus, ER stress induces lipolysis by activating cAMP/PKA and ERK1/2. In the downstream lipolytic cascade, phosphorylation of lipid droplet-associated protein perilipin was significantly promoted during ER stress but attenuated on PKA inhibition. Furthermore, ER stress stimuli did not alter the levels of hormone-sensitive lipase and adipose triglyceride lipase but caused Ser-563 and Ser-660 phosphorylation of hormone-sensitive lipase and moderately elevated its translocation from the cytosol to lipid droplets. Accompanying these changes, total activity of cellular lipases was promoted to confer the lipolysis. These findings suggest a novel pathway of the lipolysis response to ER stress in adipocytes. This lipolytic activation may be an adaptive response that regulates energy homeostasis but with sustained ER stress challenge could contribute to lipotoxicity, dyslipidemia, and insulin resistance because of persistently accelerated free fatty acid efflux from adipocytes to the bloodstream and other tissues.

Topics: Abdominal Fat; Adipocytes; Animals; Carrier Proteins; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Diabetes Mellitus; Endoplasmic Reticulum Stress; Enzyme Inhibitors; Fatty Acids; Homeostasis; Insulin Resistance; JNK Mitogen-Activated Protein Kinases; Lipase; Lipolysis; Male; MAP Kinase Signaling System; Obesity; p38 Mitogen-Activated Protein Kinases; Perilipin-1; Phosphoproteins; Primary Cell Culture; Rats; Rats, Sprague-Dawley; Thapsigargin; Tunicamycin

Diet-induced obesity (DIO) is linked to peripheral insulin resistance-a major predicament in type 2 diabetes. This study aims to identify the molecular mechanism by which DIO-triggered endoplasmic reticulum (ER) stress promotes hepatic insulin resistance in mouse models.. C57BL/6 mice and primary hepatocytes were used to evaluate the role of LIPIN2 in ER stress-induced hepatic insulin resistance. Tunicamycin, thapsigargin, and lipopolysaccharide were used to invoke acute ER stress conditions. To promote chronic ER stress, mice were fed with a high-fat diet for 8-12 weeks. To verify the role of LIPIN2 in hepatic insulin signaling, adenoviruses expressing wild-type or mutant LIPIN2, and shRNA for LIPIN2 were used in animal studies. Plasma glucose, insulin levels as well as hepatic free fatty acids, diacylglycerol (DAG), and triacylglycerol were assessed. Additionally, glucose tolerance, insulin tolerance, and pyruvate tolerance tests were performed to evaluate the metabolic phenotype of these mice.. LIPIN2 expression was enhanced in mouse livers by acute ER stress-inducers or by high-fat feeding. Transcriptional activation of LIPIN2 by ER stress is mediated by activating transcription factor 4, as demonstrated by LIPIN2 promoter assays, Western blot analyses, and chromatin immunoprecipitation assays. Knockdown of hepatic LIPIN2 in DIO mice reduced fasting hyperglycemia and improved hepatic insulin signaling. Conversely, overexpression of LIPIN2 impaired hepatic insulin signaling in a phosphatidic acid phosphatase activity-dependent manner.. These results demonstrate that ER stress-induced LIPIN2 would contribute to the perturbation of hepatic insulin signaling via a DAG-protein kinase C ε-dependent manner in DIO mice.

Topics: Activating Transcription Factor 4; Animals; Blood Glucose; Blotting, Western; Cells, Cultured; Chromatin Immunoprecipitation; Dietary Fats; Endoplasmic Reticulum; Insulin Resistance; Lipopolysaccharides; Liver; Male; Mice; Mice, Inbred C57BL; Obesity; Phosphatidate Phosphatase; Polymerase Chain Reaction; Thapsigargin; Tunicamycin

Obesity is associated with induction of the ER (endoplasmic reticulum)-stress response signalling and insulin resistance. PTP1B (protein tyrosine phosphatase 1B) is a major regulator of adiposity and insulin sensitivity. The aim of the present study was to investigate the role of L-PTP1B (liver-specific PTP1B) in chronically HFD (high-fat diet) and pharmacologically induced (tunicamycin and thapsigargin) ER-stress response signalling in vitro and in vivo. We assessed the effects of ER-stress response induction on hepatic PTP1B expression, and consequences of hepatic-PTP1B deficiency, in cells and mouse liver, on components of ER-stress response signalling. We found that PTP1B protein and mRNA expression levels were up-regulated in response to acute and/or chronic ER stress, in vitro and in vivo. Silencing PTP1B in hepatic cell lines or mouse liver (L-PTP1B(-/-)) protected against induction of pharmacologically induced and/or obesity-induced ER stress. The HFD-induced increase in CHOP (CCAAT/enhancer-binding protein homologous protein) and BIP (binding immunoglobulin protein) mRNA levels were partially inhibited, whereas ATF4 (activated transcription factor 4), GADD34 (growth-arrest and DNA-damage-inducible protein 34), GRP94 (glucose-regulated protein 94), ERDJ4 (ER-localized DnaJ homologue) mRNAs and ATF6 protein cleavage were completely suppressed in L-PTP1B(-/-) mice relative to control littermates. L-PTP1B(-/-) mice also had increased nuclear translocation of spliced XBP-1 (X box-binding protein-1) via increased p85α binding. We demonstrate that the ER-stress response and L-PTP1B expression are interlinked in obesity- and pharmacologically induced ER stress and this may be one of the mechanisms behind improved insulin sensitivity and lower lipid accumulation in L-PTP1B(-/-) mice.

Topics: Activating Transcription Factor 6; Animals; Cell Nucleus; Class Ia Phosphatidylinositol 3-Kinase; DNA-Binding Proteins; Endoplasmic Reticulum; Endoribonucleases; Eukaryotic Initiation Factor-2; Gene Deletion; Gene Knockdown Techniques; Glucose; Hep G2 Cells; Homeostasis; Humans; Lipid Metabolism; Liver; Mice; Obesity; Organ Specificity; Protein Serine-Threonine Kinases; Protein Transport; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Regulatory Factor X Transcription Factors; RNA, Messenger; Signal Transduction; Stress, Physiological; Thapsigargin; Transcription Factors; Tunicamycin; X-Box Binding Protein 1

Adiponectin acts as an insulin-sensitizing adipokine that protects against obesity-linked metabolic disease, which is generally associated with endoplasmic reticulum (ER) stress. The physiological effects of adiponectin on energy metabolism in the liver are mediated by its receptors. We found that the hepatic expression of adiponectin receptor 2 (AdipoR2) was lower, but the expression of markers of the ER stress pathway, 78 kDa glucose-regulated protein (GRP78) and activating transcription factor 3 (ATF3), was higher in the liver of ob/ob mice compared with control mice. To investigate the regulation of AdipoR2 by ER stress, we added thapsigargin, an ER stress inducer, to a human hepatocyte cell line, HepG2. Addition of the ER stress inducer increased the levels of GRP78 and ATF3, and decreased that of AdipoR2, whereas addition of a chemical chaperone, 4-phenyl butyric acid (PBA), could reverse them. Up- or down-regulation of ATF3 modulated the AdipoR2 protein levels and AdipoR2 promoter activities. Reporter gene assays using a series of 5'-deleted AdipoR2 promoter constructs revealed the location of the repressor element responding to ER stress and ATF3. In addition, using electrophoretic mobility shift and chromatin immunoprecipitation assays, we identified a region between nucleotides -94 and -86 of the AdipoR2 promoter that functions as a putative ATF3-binding site in vitro and in vivo. Thus, our findings suggest that the ER stress-induced decrease in both protein and RNA of AdipoR2 results from a concomitant increase in expression of ATF3, which may play a role in the development of obesity-induced insulin resistance and related ER stress in hepatocytes.

Topics: Activating Transcription Factor 3; Animals; Chromatin Immunoprecipitation; DNA; Electrophoretic Mobility Shift Assay; Endoplasmic Reticulum; Endoplasmic Reticulum Chaperone BiP; Gene Deletion; Gene Expression; Gene Expression Regulation, Neoplastic; Heat-Shock Proteins; Hep G2 Cells; Humans; Liver; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Phenylbutyrates; Promoter Regions, Genetic; Protein Binding; Receptors, Adiponectin; Regulatory Elements, Transcriptional; RNA, Small Interfering; Stress, Physiological; Thapsigargin; Transfection

Hepatic steatosis is present in insulin-resistant obese rodents and is concomitant with active lipogenesis. Hepatic lipogenesis depends on the insulin-induced activation of the transcription factor SREBP-1c. Despite prevailing insulin resistance, SREBP-1c is activated in the livers of genetically and diet-induced obese rodents. Recent studies have reported the presence of an ER stress response in the livers of obese ob/ob mice. To assess whether ER stress promotes SREBP-1c activation and thus contributes to lipogenesis, we overexpressed the chaperone glucose-regulated protein 78 (GRP78) in the livers of ob/ob mice using an adenoviral vector. GRP78 overexpression reduced ER stress markers and inhibited SREBP-1c cleavage and the expression of SREBP-1c and SREBP-2 target genes. Furthermore, hepatic triglyceride and cholesterol contents were reduced, and insulin sensitivity improved, in GRP78-injected mice. These metabolic improvements were likely mediated by restoration of IRS-2 expression and tyrosine phosphorylation. Interestingly, GRP78 overexpression also inhibited insulin-induced SREBP-1c cleavage in cultured primary hepatocytes. These findings demonstrate that GRP78 inhibits both insulin-dependent and ER stress-dependent SREBP-1c proteolytic cleavage and explain the role of ER stress in hepatic steatosis in obese rodents.

Topics: Animals; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Endoplasmic Reticulum; Endoplasmic Reticulum Chaperone BiP; Fatty Liver; Gene Expression; Glucose; Heat-Shock Proteins; Hepatocytes; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Lipid Metabolism; Liver; Male; Mice; Mice, Obese; Models, Biological; Molecular Chaperones; Nuclear Proteins; Obesity; Rats; Rats, Wistar; Rats, Zucker; Signal Transduction; Sterol Regulatory Element Binding Protein 1; Sterol Regulatory Element Binding Protein 2; Thapsigargin; Transcription Factors

Leptin and insulin are important anorexigenic hormones acting on the hypothalamus. However, most obese humans and animals have reduced hypothalamic responses to leptin and insulin. Increased endoplasmic reticulum (ER) stress has been shown to cause insulin resistance in the livers of obese animals. In the present study, we investigated a role of ER stress in the development of central leptin and insulin resistance. Intracerebroventricular (ICV) administration of the ER stress inducer thapsigargin (TG) increased food intake and body weight. Furthermore, ICV or intra-hypothalamic administration of TG inhibited the anorexigenic and weight-reducing effects of leptin and insulin. ICV administration of TG by itself activated signal-transduction-activated-transcript-3 (STAT3) and Akt in the hypothalamus, but prevented a further activation of hypothalamic STAT3 and Akt by leptin and insulin. We also found that the expression of the ER stress markers such as phosphorylation of the inositol-requiring kinase-1 (IRE1), spliced form of X-box-binding protein-1 (XBP-1s), glucose-regulated/binding immunoglobulin protein-78, and C/EBP homology protein (CHOP) increased in the hypothalami of diet-induced obese (DIO) mice. Furthermore, treatment of chemical chaperone 4-phenyl butylic acid significantly improved central leptin resistance in DIO mice. These findings suggest that increased hypothalamic ER stress in obese animals may induce central leptin and insulin resistance.

Topics: Animals; Blotting, Western; DNA-Binding Proteins; Endoplasmic Reticulum; Enzyme Inhibitors; Hypothalamus; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Obesity; Phosphatidylinositol 3-Kinases; Regulatory Factor X Transcription Factors; Reverse Transcriptase Polymerase Chain Reaction; RNA; STAT3 Transcription Factor; Thapsigargin; Transcription Factor CHOP; Transcription Factors; X-Box Binding Protein 1

Chromium has gained popularity as a nutritional supplement for diabetic patients. This study evaluated the effect of chronic administration of a chromium complex of D-phenylalanine (Cr(D-phe)(3)) on glucose and insulin tolerance in obese mice. The study tested the hypothesis that Cr(D-phe)(3) suppresses endoplasmic reticulum (ER) stress and insulin resistance in these animals.. C57BL lean and ob/ob obese mice were randomly divided to orally receive vehicle or Cr(D-phe)(3) (3.8 mug of elemental chromium/kg/day) for 6 months. Insulin sensitivity was evaluated by glucose and insulin tolerance tests. Protein levels of phosphorylated pancreatic ER kinase (PERK), alpha subunit of translation initiation factor 2 (eIF2alpha) and inositol-requiring enzyme-1 (IRE-1), p-c-Jun, and insulin receptor substrate-1 (IRS-1) phosphoserine-307 were assessed by western blotting. In vitro ER stress was induced by treating cultured muscle cells with thapsigargin in the presence or absence of Cr(D-phe)(3).. ob/ob mice showed poor glucose and insulin tolerance compared to the lean controls, which was attenuated by Cr(D-phe)(3). Markers of insulin resistance (phospho-c-Jun and IRS-1 phosphoserine) and ER stress (p-PERK, p-IRE-1, p-eIF2alpha), which were elevated in ob/ob mice, were attenuated following Cr(D-phe)(3) treatment. Chromium treatment was also associated with a reduction in liver triglyceride levels and lipid accumulation. In cultured myotubes, Cr(D-phe)(3) attenuated ER stress induced by thapsigargin.. Oral Cr(D-phe)(3) treatment reduces glucose intolerance, insulin resistance, and hepatic ER stress in obese, insulin-resistant mice.

Topics: Animals; Blood Glucose; Chromium; Diabetes Mellitus, Type 2; Disease Models, Animal; eIF-2 Kinase; Endoplasmic Reticulum; Glucose Intolerance; Insulin; Insulin Resistance; Leptin; Lipids; Liver; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Protein Serine-Threonine Kinases; Thapsigargin; Trace Elements

We investigated the effects of a diet containing EPAX-7010, rich in PUFAs such as eicosapentaenoic acid [20:5(n-3)] and docosahexaenoic acid [22:6(n-3)], i.e., a PUFA/EPAX regimen, on T-cell activation in diabetic pregnant rats and their obese pups.. Mild hyperglycemia in pregnant rats was induced by intraperitoneal injection of streptozotocin on Day 5 of gestation. T-cell blastogenesis was assayed by using (3)H-thymidine, whereas intracellular free calcium concentrations ([Ca(2+)]i) were measured by using Fura-2 in diabetic pregnant rats and their obese offspring.. Concavalin-A-stimulated T-cell proliferation was decreased in both pregnant diabetic rats and their obese pups as compared with control animals. Feeding the PUFA/EPAX diet restored T-cell proliferation in both groups of animals. We also employed ionomycin, which at 50 nM opens calcium channels, and thapsigargin (TG), which recruits [Ca(2+)]i from endoplasmic reticulum pool. We observed that ionomycin-induced increases in [Ca(2+)]i in T-cells of diabetic mothers and obese offspring were greater than in those of control rats. Furthermore, feeding PUFA/EPAX diet diminished significantly the ionomycin-evoked rise in [Ca(2+)]i in diabetic and obese animals. TG-induced increases in [Ca(2+)]i in T-cells of diabetic pregnant rats and their obese offspring were greater than in those of control rats. The feeding of the experimental diet significantly curtailed the TG-evoked increases in [Ca(2+)]i in both diabetic and obese rats.. Together, these observations provide evidence that T-cell activation and T-cell calcium signaling are altered during gestational diabetes and macrosomia. Hence, dietary fish oils, particularly eicosapentaenoic acid and docosahexaenoic acid, may restore these T-cell abnormalities.

Topics: Animals; Calcium; Concanavalin A; Diabetes Mellitus, Experimental; Dietary Fats, Unsaturated; Fatty Acids, Omega-3; Female; Fetal Macrosomia; Gestational Age; Ionomycin; Lymphocyte Activation; Obesity; Pregnancy; Pregnancy in Diabetics; Rats; Rats, Wistar; Signal Transduction; Spleen; T-Lymphocytes; Thapsigargin