Glucose Homeostasis In Obesity Research Articles

Omentin: A Key Player in Glucose Homeostasis, Atheroprotection, and Anti-Inflammatory Potential for Cardiovascular Health in Obesity and Diabetes.

Omentin is an adipokine mainly produced by visceral fat tissue. It has two isoforms, omentin-1 and omentin-2. Omentin-1 is predominantly secreted by visceral adipose tissue, derived specifically from the stromal vascular fraction cells of white adipose tissue (WAT). Levels of omentin-1 are also expressed in other WAT depots, such as epicardial adipose tissue. Omentin-1 exerts several beneficial effects in glucose homeostasis in obesity and diabetes. In addition, research has suggested that omentin-1 may have atheroprotective (protective against the development of atherosclerosis) and anti-inflammatory effects, potentially contributing to cardiovascular health. This review highlights the potential therapeutic targets of omentin-1 in metabolic disorders.

Slow digestion properties of long-sized isomaltooligosaccharides synthesized by a transglucosidase from Thermoanaerobacter thermocopriae.

Isomaltooligosaccharides (IMOs) are widely used as prebiotic ingredients that promote colon health; however, recent studies revealed that these are slowly hydrolyzed to glucose within the small intestine. Here, novel α-glucans with a higher number of α-1,6 linkages were synthesized from maltodextrins using the Thermoanaerobacter thermocopriae-derived transglucosidase (TtTG) to decrease susceptibility to hydrolysis and improve slow digestion properties. The synthesized long-sized IMOs (l-IMOs; 70.1% of α-1,6 linkages), comprising 10-12 glucosyl units, exhibited slow hydrolysis to glucose when compared to commercial IMOs under treatment with mammalian α-glucosidase level. In male mice, the ingestion of l-IMOs significantly decreased the post-prandial glycemic response compared to other samples (p<0.05). Therefore, enzymatically synthesized l-IMOs can be applied as functional ingredients for the modulation of blood glucose homeostasis in obesity, Type 2 diabetes, and other chronic diseases.

Leptin is a key regulator of glucose homeostasis in obesity

Approximately 9 out of 10 people with type-2 diabetes are overweight. Leptin is a hormone secreted from white fat cells that exerts control over both food intake and energy expenditure. We described the central mechanisms underlying the hypertensive effects of hyperleptinemia in obesity. Work presented here used continuous radiotelemetric glucose monitoring in mice in combination with multiple gold standard techniques in order to determine the effects of dorsomedial hypothalamic (DMH) leptin signalling on peripheral glucose control. A leptin receptor (LepR) antagonist administered directly into the brain impaired DIO mouse glucose tolerance demonstrating that leptin retains the ability to regulate blood glucose concentration in obesity. Knockdown of DMH LepR function using short hairpin adeno-associated virus (AAV) RNA significantly reduced brown adipose tissue (BAT) thermogenesis by -0.8 ± 0.1°C and increased basal blood glucose (14.3 ± 0.6mmol/l to 9.4 ± 0.5mmol/l) and impaired glucose tolerance. Conversely, chemogenic activation of LepR-expressing DMH neurons significantly elevated BAT thermogenesis (1.5 ± 0.2 °C increase). This increased BAT temperature was immediately followed by a decrease in plasma blood glucose concentration (7.6 ± 0.5 mmol/l to 5.8 ± 0.5 mmol/l). Work presented here demonstrates that increasing the activity of LepR expressing neurons in the DMH can improve glucose tolerance in obesity though an elevation of BAT metabolic activity. This work was supported by the National Heart Foundation of Australia (SES), The National Health and Medical Research Council of Australia (SES and MAC). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

1307-P: Leptin Action in the Nucleus of the Solitary Tract

Obesity and diabetes are characterized by a disruption in energy balance and glucose homeostasis in association with leptin resistance. Leptin action in the hypothalamus regulates glucose levels and body weight, but whether other brain regions facilitate leptin action remain unclear. Here, we investigate whether the nucleus of the solitary tract (NTS) of the brainstem is a crucial site for leptin action in regulating glucose homeostasis in 3d high-fat (HF) -fed male rats, as recent studies report leptin activates leptin receptor in the NTS to regulate feeding. In this study, we performed brain stereotaxic bilateral surgery targeting the NTS followed one week later by catheterization of the left carotid artery and right internal jugular vein for infusion/sampling purposes. Rats that attained &amp;gt;90% of presurgical weight received 3d of Lard oil enriched HF diet and were fasted 4-6 hr before undergoing a 2min pancreatic (basal insulin) -euglycemic clamp studies together with tracer glucose infusion to assess glucose metabolism independent of changes in plasma insulin and glucagon levels. Leptin (91.7 ng/uL at 0.33 ul/hr) or saline was infused into the NTS throughout the duration of the clamp studies. Correct placement of the NTS catheter was verified by infusion of bromophenol blue dye through the brain cannula. For the first time, we found that leptin vs. saline infusion into the NTS markedly increased the exogenous glucose infusion [lep: 4.6±0.2 vs. sal: 1.3±0.4 mg/kg/min; p&amp;lt;0.005; n=12, 5] required to maintain euglycemia [lep: 137.5±2.2 vs. sal: 145±3.1 mg/dl; p&amp;gt;0.05; n=12, 5], during the clamps. The drop in plasma glucose levels was due to an inhibition of glucose production [lep: 4.9±0.1 vs. sal: 8.4±0.7 mg/kg/min; p&amp;lt;0.01; n=12, 5], but not an increase in glucose uptake [lep: 10.4±0.5 vs. sal: 9.7±0.3 mg/kg/min; p&amp;gt;0.05; n=12, 5]. These findings demonstrate that the NTS mediates leptin action on glucose homeostasis. Future studies are needed to investigate the NTS leptin signaling cascade in glucose homeostasis in obesity and diabetes. Disclosure K.Bruce: None. R.Li: None. Y.Lim: None. J.T.Yue: None. T.K.Lam: None. Funding Canadian Institutes of Health Research Foundation Grant (FDN-143204)

1358-P: Small Intestinal Casein Sensing Regulates Food Intake and Glucose Tolerance in Rats

High protein diet reduces food intake and improves glucose homeostasis in rodents and humans with obesity and diabetes, but the mechanistic site (s) of action remain unclear. Small intestinal lipid and glucose sensing regulates energy and glucose homeostasis, but the metabolic role of gut protein sensing remains elusive. In this study, we infused 8% casein hydrolysate as protein source into the upper small intestine (USI) and performed fasting-refeeding studies. We found that USI casein infusion (1.28 kcal/min) suppressed food intake up to 6h in chow but not high fat (HF) - fed rats (chow USI: sal 47±2 vs. cas 36±2 kcal, n=18, p&amp;lt;0.01. HF USI: sal 39±3 vs. cas 40±3 kcal, n=11) . Interestingly, we discovered USI casein infusion instead improved intravenous glucose tolerance effectively in both chow and HF rats (AUC, chow USI: sal 1152±112 vs. cas 850.2±37, n=7, p&amp;lt;0.05. HF USI: sal 1172±54 vs. cas 758.3±42 kcal, n=9, p&amp;lt;0.05) . Next, we evaluated whether small intestinal calcium sensing receptor (CaSR) mediates protein sensing and first discovered that CaSR was expressed in the small intestine with higher expression in the ileum vs. USI (USI 1.0±0.1 vs. ileum 5.8±1, n=8, p&amp;lt;0.01) . Next, we inhibited CaSR with CaSR inhibitor NPS2143 (56 µM) and found that its USI co-infusion with casein prevented the effects on glucose tolerance in both chow and HF rats. Finally, we injected lentivirus expressing shRNA of CaSR or mismatch sequence into the USI and CaSR expression was reduced by ˜40% (n=6, p&amp;lt;0.001) . Importantly, USI casein effect in both chow and HF rats on glucose tolerance were lost (chow: MM cas 799.2±51 vs. LV-CaSR cas 1069±64, n=6, p&amp;lt;0.01; HF: MM cas 771.8±20 vs. LV-CaSR + cas 1240±89, n=4, p&amp;lt;0.05) . In summary, these data illustrate that USI protein sensing increases glucose tolerance in chow and HF rats via CaSR, and lowers feeding in chow but not HF rats. Future studies are needed to dissect the metabolic role of CaSR not only for USI but also ileal protein sensing in energy balance and glucose homeostasis in obesity and diabetes. Disclosure R.J.W.Li: None. D.Barros: None. Y.Lim: None. S.Zhang: None. A.Gao: None. T.K.Lam: None.

The effect of coffee consumption on glucose homeostasis and redox-inflammatory responses in high-fat diet-induced obese rats

Coffee effects on glucose homeostasis in obesity remain controversial. We investigated whether coffee mitigates the negative effects on glucose metabolism induced by a high-fat diet and the interrelationships with redox-inflammatory responses. Rats were treated with: control (CT-); coffee (CT+) 3.9 g of freeze-dried coffee/kg of diet; high-fat (HF-); or high-fat + coffee 3.9 g of freeze-dried coffee/kg of diet (HF+) diet. The high-fat diet increased weight gain, feed efficiency, HOMA β, muscle and hepatic glycogen, intestinal CAT and SOD activity, hepatic protein (CARB) and lipid oxidation (MDA), muscle Prkaa1 mRNA and IL6 levels, and decreased food intake, hepatic GR, GPX and SOD activities, intestinal CARB, intestinal Slc2a2 and Slc5a1 and hepatic Prkaa1 and Prkaa2 mRNA levels, hepatic glucose-6-phosphatase and muscle hexokinase (HK) activities, compared to the control diet. The high-fat diet with coffee increased hepatic GST activity and TNF and decreased IL6 and intestinal glucosidase activity compared with the high-fat diet. The coffee diet increased muscle glycogen, hepatic CARB and PEPCK activity, and decreased hepatic GR and SOD activities and intestinal CARB, compared with the control diet. Coffee increased insulin levels, HOMA IR/β, FRAP, muscle Prkaa1 mRNA levels and hepatic and muscle phosphofructokinase-1, and it decreased intestinal CAT, hepatic Slc2a2 mRNA levels and muscle HK activity, regardless of the diet type. In conclusion, chronic coffee consumption improves antioxidant and anti-inflammatory responses, but does not ameliorate glucose homeostasis in a high-fat diet-induced obesity model. In addition, coffee consumption increases insulin secretion and promotes muscle glycogen synthesis in rats maintained on a control diet.

Holdemanella biformis improves glucose tolerance and regulates GLP-1 signaling in obese mice.

Impaired glucose homeostasis in obesity is mitigated by enhancing the glucoregulatory actions of glucagon-like peptide 1 (GLP-1), and thus, strategies that improve GLP-1 sensitivity and secretion have therapeutic potential for the treatment of type 2 diabetes. This study shows that Holdemanella biformis, isolated from the feces of a metabolically healthy volunteer, ameliorates hyperglycemia, improves oral glucose tolerance and restores gluconeogenesis and insulin signaling in the liver of obese mice. These effects were associated with the ability of H. biformis to restore GLP-1 levels, enhancing GLP-1 neural signaling in the proximal and distal small intestine and GLP-1 sensitivity of vagal sensory neurons, and to modify the cecal abundance of unsaturated fatty acids and the bacterial species associated with metabolic health. Our findings overall suggest the potential use of H biformis in the management of type 2 diabetes in obesity to optimize the sensitivity and function of the GLP-1 system, through direct and indirect mechanisms.

Cold-Pressed Nigella Sativa Oil Standardized to 3% Thymoquinone Potentiates Omega-3 Protection against Obesity-Induced Oxidative Stress, Inflammation, and Markers of Insulin Resistance Accompanied with Conversion of White to Beige Fat in Mice.

Excessive lipid accumulation in white adipose tissue (WAT) results in adipocyte hypertrophy and chronic low-grade inflammation, which is the major cause of obesity-associated insulin resistance and consequent metabolic disease. The development of beige adipocytes in WAT (browning of WAT) increases energy expenditure and has been considered as a novel strategy to counteract obesity. Thymoquinone (TQ) is the main bioactive quinone derived from the plant Nigella Sativa and has antioxidative and anti-inflammatory capacities. Fish oil omega 3 (ω3) enhances both insulin sensitivity and glucose homeostasis in obesity, but the involved mechanisms remain unclear. The aim of this study is to explore the effects of TQ and ω3 PUFAs (polyunsaturated fatty acids) on obesity-associated inflammation, markers of insulin resistance, and the metabolic effects of adipose tissue browning. 3T3-L1 cells were cultured to investigate the effects of TQ and ω3 on the browning of WAT. C57BL/6J mice were fed a high-fat diet (HFD), supplemented with 0.75% TQ, and 2% ω3 in combination for eight weeks. In 3T3-L1 cells, TQ and ω3 reduced lipid droplet size and increased hallmarks of beige adipocytes such as uncoupling protein-1 (UCP1), PR domain containing 16 (PRDM16), fibroblast growth factor 21 (FGF21), Sirtuin 1 (Sirt1), Mitofusion 2 (Mfn2), and heme oxygenase 1 (HO-1) protein expression, as well as increased the phosphorylation of Protein Kinase B (AKT) and insulin receptors. In the adipose tissue of HFD mice, TQ and ω3 treatment attenuated levels of inflammatory adipokines, Nephroblastoma Overexpressed (NOV/CCN3) and Twist related protein 2 (TWIST2), and diminished adipocyte hypoxia by decreasing HIF1α expression and hallmarks of beige adipocytes such as UCP1, PRDM16, FGF21, and mitochondrial biogenesis markers Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), Sirt1, and Mfn2. Increased 5′ adenosine monophosphate-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) phosphorylation and HO-1 expression were observed in adipose with TQ and ω3 treatment, which led to increased pAKT and pIRS1 Ser307 expression. In addition to the adipose, TQ and ω3 also increased inflammation and markers of insulin sensitivity in the liver, as demonstrated by increased phosphorylated insulin receptor (pIR tyr972), insulin receptor beta (IRβ), UCP1, and pIRS1 Ser307 and reduced NOV/CCN3 expression. Our data demonstrate the enhanced browning of WAT from TQ treatment in combination with ω3, which may play an important role in decreasing obesity-associated insulin resistance and in reducing the chronic inflammatory state of obesity.

Characterizing Lymphangiogenesis and Concurrent Inflammation in Adipose Tissue in Response to VEGF-D.

The metabolic consequences of obesity arise from local inflammation within expanding adipose tissue. In pre-clinical studies targeting various inflammatory factors, systemic metabolism can be improved through reduced adipose inflammation. Lymphatic vessels are a critical regulator of inflammation through roles in fluid and macromolecule transport and immune cell trafficking and immunomodulation. Lymphangiogenesis, the expansion of the lymphatic network, is often a necessary step in restoring tissue homeostasis. Using Adipo-VD mice, a model of adipocyte-specific, inducible overexpression of the potent lymphangiogenic factor vascular endothelial growth factor-D (VEGF-D), we previously identified that dense de novo adipose lymphatics reduced immune accumulation and improved glucose homeostasis in obesity. On chow diet, however, Adipo-VD mice demonstrated increased adipose tissue immune cells, fibrosis, and inflammation. Here, we characterize the time course of resident macrophage accumulation and lymphangiogenesis in male and female Adipo-VD mice fed chow and high fat diets, examining multiple adipose depots over 4 months. We find that macrophage infiltration occurs early, but resolves with concurrent lymphatic expansion that begins robustly after 1 month of VEGF-D overexpression in white adipose tissue. In obesity, female Adipo-VD mice exhibit reduced lymphangiogenesis and maintain a more glycolytic metabolism compared to Adipo-VD males and their littermates. Adipose lymphatic structures appear to expand by a lymphvasculogenic mechanism involving lymphatic endothelial cell proliferation and organization with a cell source we that failed to identify; hematopoietic cells afford minimal structural contribution. While a net positive effect occurs in Adipo-VD mice, adipose tissue lymphangiogenesis demonstrates a dichotomous, and time-dependent, inflammatory tissue remodeling response.

A Role for Oncostatin M in the Impairment of Glucose Homeostasis in Obesity.

Oncostatin M (OSM) plays a key role in inflammation, but its regulation and function during obesity is not fully understood. The aim of this study was to evaluate the relationship of OSM with the inflammatory state that leads to impaired glucose homeostasis in obesity. We also assessed whether OSM immunoneutralization could revert metabolic disturbances caused by a high-fat diet (HFD) in mice. 28 patients with severe obesity were included and stratified into two groups: (1) glucose levels <100 mg/dL and (2) glucose levels >100 mg/dL. White adipose tissue was obtained to examine OSM gene expression. Human adipocytes were used to evaluate the effect of OSM in the inflammatory response, and HFD-fed C57BL/6J mice were injected with anti-OSM antibody to evaluate its effects. OSM expression was elevated in subcutaneous and visceral fat from patients with obesity and hyperglycemia, and correlated with Glut4 mRNA levels, serum insulin, homeostatic model assessment of insulin resistance, and inflammatory markers. OSM inhibited adipogenesis and induced inflammation in human adipocytes. Finally, OSM receptor knockout mice had increased Glut4 mRNA levels in adipose tissue, and OSM immunoneutralization resulted in a reduction of glucose levels and Ccl2 expression in adipose tissue from HFD-fed mice. OSM contributes to the inflammatory state during obesity and may be involved in the development of insulin resistance.

Leptin is a key regulator of glucose homeostasis in obesity

Leptin is a key regulator of glucose homeostasis in obesity

1133-P: Four Days of Hyperoxia Exposure Confers Sustained Improvement in Glucose Homeostasis

Obesity and type 2 diabetes are co-morbidities, and their prevalence is continually growing. In obesity, in the face of lipid accumulation, adipose tissue become hypoxic with reduced blood flow, accompanied by low grade inflammation and insulin resistance. We therefore hypothesized that exposure to high oxygen (hyperoxia) could improve glucose homeostasis in obesity. We treated normal and fast-food diet (40% fat)-induced obese mice (10 months old) with hyperoxia (95%) for 4 days and quantified the effects on glucose homeostasis and insulin sensitivity. We found that immediately after the hyperoxic treatment, glycemia was modestly higher compared to pretreatment levels. However, both fasting and post-challenge blood glucose levels were significantly decreased after 6 days of hyperoxia treatment in both normal (28±8%; p=0.01) and obese mice (36±4%; p=0.007)). Plasma insulin levels decreased by 41% in both normal (p=0.0026) and obese (p=0.0033) mice and Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) values were also significantly decreased (63±4%; p=0.0009 in normal and 55±13%; p=0.0049 in obese mice)after hyperoxia treatment, indicating that the improvements in glucose homeostasis were associated with improved insulin sensitivity. Surprisingly, these metabolic improvements were maintained more than one month after hyperoxia treatment, and occurred without significant effects on weight. These results demonstrate that exposure to hyperoxia improves fasting blood glucose levels, glucose tolerance and insulin sensitivity, suggesting that the hyperoxia treatment may provide a new approach for supportive treatment of diabetes and obesity. Disclosure S. Jain: None. A.V. Harrison: None. F. Lorenzo: None. D. McClain: None. Funding U.S. Department of Veterans Affairs; National Institute of Diabetes and Digestive and Kidney Diseases

Serum Apelin Level in Normal and Gestational Diabetic Rats: Effect of Treatment with Vitamin D

AbstractBackground: Apelin peptide was identified in a wide variety of tissues including adipose tissue and it was linked to glucose homeostasis in obesity and diabetes. Apelin and its receptors were also identified in the placenta, and play a role in fluid and glucose transport. Vitamin D affects glucose metabolism and its deficiency was linked to gestational diabetes.Aim of the Study: To estimate serum apelin level in normal and gestational diabetic rats and to study the effect of Vitamin D administration on serum apelin level in relation to some metabolic parameters in gestational diabetes.Material and Methods: Healthy adult female albino rats were divided into the following groups, Group I (n=8): Virgin control rats; Group II (n=16): Normal pregnant control group (NP) subdivided into Group IIa (n=8) sacrificed on day 11 and Group IIb (n=8) sacrificed on day 19 of gestation; Group III (n=22): Gestational Diabetic group (GDM), rats were subdivided into Group IIIa (n=11) sacrificed on day 11 and Group IIIb (n=11) sacrificed on day 19; Group IV (n=11): Gestational diabetic Vitamin D3 treated group (GDM + vit D3), gestational diabetic rats received vitamin D3 (50IU/kg/ day) intra-peritoneal from day 10 till sacrificed on day 19. The following parameters were measured in all groups: BMI, blood glucose, serum insulin, lipid profile, C Reactive Protein (CRP), Tumor Necrosis Factor a (TNFa) and HOMA-IR was calculated.Results: A significant increase in serum apelin level was found on day 11, while a significant decrease was found on day 19 of normal gestation relative to non-pregnant level. In GDM groups, apelin level significantly decreased in Group IIIa compared to Group IIa and in Group IIIb compared to Group II b. Vitamin D3 induced a significant increase in apelin level in Group IV compared to Group IIIb. Serum apelin level correlated negatively with blood glucose, HOMA-IR, TC, LDL and TNFa in Group III and IV.Conclusion: Gestational diabetes induced significant decrease in serum apelin level in pregnant rats compared to normal pregnant gestational age matched control. Vitamin D3 supplementation in gestational diabetic rats induced significant increase in apelin level in association with a decrease in insulin resistance.

Mild Impairment of Mitochondrial OXPHOS Promotes Fatty Acid Utilization in POMC Neurons and Improves Glucose Homeostasis in Obesity

Mitochondrial oxidative phosphorylation (OXPHOS) and substrate utilization critically regulate the function of hypothalamic proopiomelanocortin (POMC)-expressing neurons. Here, we demonstrate that inactivation of apoptosis-inducing factor (AIF) in POMC neurons mildly impairs mitochondrial respiration and decreases firing of POMC neurons in lean mice. In contrast, under diet-induced obese conditions, POMC-Cre-specific inactivation of AIF prevents obesity-induced silencing of POMC neurons, translating into improved glucose metabolism, improved leptin, and insulin sensitivity, as well as increased energy expenditure in AIFΔPOMC mice. On a cellular level, AIF deficiency improves mitochondrial morphology, facilitates the utilization offatty acids for mitochondrial respiration, and increases reactive oxygen species (ROS) formationin POMC neurons from obese mice, ultimately leading to restored POMC firing upon HFD feeding. Collectively, partial impairment of mitochondrial function shifts substrate utilization of POMC neurons from glucose to fatty acid metabolism and restores their firing properties, resulting in improvedsystemic glucose and energy metabolism in obesity.

Essential Fatty Acids Linoleic Acid and α-Linolenic Acid Sex-Dependently Regulate Glucose Homeostasis in Obesity.

To assess the associations of dietary linoleic acid (LA) and α-linolenic acid (ALA) with type 2 diabetes (T2D) risk in a population-based cohort and further explore the mechanism of action in a high-fat-diet (HFD) induced obese (DIO) mouse model. The occurrence of T2D among 15 100 Chinese adults from China Health and Nutrition Survey (CHNS, 1997-2011) were followed up for a median of 14 years. The relations of ALA and LA intakes with T2D risk were modified by BMI, with significant associations restricted to obese/overweight subjects. Among them, relative risks (95% confidence intervals) comparing extreme quartiles of intakes were 0.55 (0.32-0.93) in men and 0.53 (0.34-0.85) in women for ALA, while 0.71 (0.41-1.16) in men and 0.56 (0.36-0.89) in women for LA. DIO mice were fed with LA- or ALA-enriched HFD (0.2% wt wt-1 ) for 15 weeks and then significant sex-dependent changes of gut microbiota were detected. Endotoxemia, systematic and adipose inflammation were relieved in ALA-fed male and LA-fed female mice. Long-term intake of LA (for women) and ALA may have a protective effect on T2D development for obese/overweight subjects through sex-specific gut microbiota modulation and gut-adipose axis.

Fecal transplant from resveratrol-fed donors improves glycaemia and cardiovascular features of the metabolic syndrome in mice.

Oral administration of resveratrol attenuates several symptoms associated with the metabolic syndrome, such as impaired glucose homeostasis and hypertension. Recent work has shown that resveratrol can improve glucose homeostasis in obesity via changes in the gut microbiota. Studies involving fecal microbiome transplants (FMTs) suggest that either live gut microbiota or bacterial-derived metabolites from resveratrol ingestion are responsible for producing the observed benefits in recipients. Herein, we show that obese mice receiving FMTs from healthy resveratrol-fed mice have improved glucose homeostasis within 11 days of the first transplant, and that resveratrol-FMTs is more efficacious than oral supplementation of resveratrol for the same duration. The effects of FMTs from resveratrol-fed mice are also associated with decreased inflammation in the colon of obese recipient mice. Furthermore, we show that sterile fecal filtrates from resveratrol-fed mice are sufficient to improve glucose homeostasis in obese mice, demonstrating that nonliving bacterial, metabolites, or other components within the feces of resveratrol-fed mice are sufficient to reduce intestinal inflammation. These postbiotics may be an integral mechanism by which resveratrol improves hyperglycemia in obesity. Resveratrol-FMTs also reduced the systolic blood pressure of hypertensive mice within 2 wk of the first transplant, indicating that the beneficial effects of resveratrol-FMTs may also assist with improving cardiovascular conditions associated with the metabolic syndrome.

Imoxin attenuates high fructose-induced oxidative stress and apoptosis in renal epithelial cells via downregulation of protein kinase R pathway.

Double-stranded RNA (dsRNA)-activated protein kinase R (PKR), a ubiquitously expressed serine/threonine kinase, is a key inducer of inflammation, insulin resistance, and glucose homeostasis in obesity. Recent studies have demonstrated that PKR can respond to metabolic stress in mice as well as in humans. However, the underlying molecular mechanism is not fully understood. The aim of this study was to examine the effect of high fructose (HF) in cultured renal tubular epithelial cells (NRK-52E) derived from rat kidney and to investigate whether inhibition of PKR could prevent any deleterious effects of HF in these cells. PKR expression was determined by immunofluorescence staining and Western blotting. Oxidative damage and apoptosis were measured by flow cytometry. HF-treated renal cells developed a significant increase in PKR expression. A significant increase in reactive oxygen species generation and apoptosis was also observed in HF-treated cultured renal epithelial cells. All these effects of HF were attenuated by a selective PKR inhibitor, imoxin (C16). In conclusion, our study demonstrates PKR induces oxidative stress and apoptosis, is a significant contributor involved in vascular complications and is a possible mediator of HF-induced hypertension. Inhibition of PKR pathway can be used as a therapeutic strategy for the treatment of cardiovascular and metabolic disorders.

Deletion of Protein Kinase D1 in Pancreatic β-Cells Impairs Insulin Secretion in High-Fat Diet-Fed Mice.

Ββ-Cell adaptation to insulin resistance is necessary to maintain glucose homeostasis in obesity. Failure of this mechanism is a hallmark of type 2 diabetes (T2D). Hence, factors controlling functional β-cell compensation are potentially important targets for the treatment of T2D. Protein kinase D1 (PKD1) integrates diverse signals in the β-cell and plays a critical role in the control of insulin secretion. However, the role of β-cell PKD1 in glucose homeostasis in vivo is essentially unknown. Using β-cell-specific, inducible PKD1 knockout mice (βPKD1KO), we examined the role of β-cell PKD1 under basal conditions and during high-fat feeding. βPKD1KO mice under a chow diet presented no significant difference in glucose tolerance or insulin secretion compared with mice expressing the Cre transgene alone; however, when compared with wild-type mice, both groups developed glucose intolerance. Under a high-fat diet, deletion of PKD1 in β-cells worsened hyperglycemia, hyperinsulinemia, and glucose intolerance. This was accompanied by impaired glucose-induced insulin secretion both in vivo in hyperglycemic clamps and ex vivo in isolated islets from high-fat diet-fed βPKD1KO mice without changes in islet mass. This study demonstrates an essential role for PKD1 in the β-cell adaptive secretory response to high-fat feeding in mice.

IL-6 Improves Energy and Glucose Homeostasis in Obesity via Enhanced Central IL-6 trans-Signaling

Interleukin (IL)-6 engages similar signaling mechanisms to leptin. Here, we find that central application of IL-6 in mice suppresses feeding and improves glucose tolerance. In contrast to leptin, whose action is attenuated in obesity, the ability of IL-6 to suppress feeding is enhanced in obese mice. IL-6 suppresses feeding in the absence of neuronal IL-6-receptor (IL-6R) expression in hypothalamic or all forebrain neurons of mice. Conversely, obese mice exhibit increased soluble IL-6R levels in the cerebrospinal fluid. Blocking IL-6 trans-signaling in the CNS abrogates the ability of IL-6 to suppress feeding. Furthermore, gp130 expression is enhanced in the paraventricular nucleus of the hypothalamus (PVH) of obese mice, and deletion of gp130 in the PVH attenuates the beneficial central IL-6 effects on metabolism. Collectively, these experiments indicate that IL-6 trans-signaling is enhanced in the CNS of obese mice, allowing IL-6 to exert its beneficial metabolic effects even under conditions of leptin resistance.

High glucose impairs insulin signaling via activation of PKR pathway in L6 muscle cells

Double stranded RNA (dsRNA) activated protein kinase R (PKR), a ubiquitously expressed serine/threonine kinase is a key inducer of inflammation, insulin resistance and glucose homeostasis in obesity. Recent studies have demonstrated that PKR can respond to metabolic stress in mice as well as in humans. However the underlying molecular mechanism is not fully understood. The aim of the present study was to examine the effect of high glucose on cultured rat L6 muscle cells and to investigate whether inhibition of PKR could prevent any deleterious effects of high glucose in these cells. PKR expression was determined by immunofluorescence and immunoblotting. The expression of different insulin signaling gene markers were measured by RT-PCR. Oxidative stress and apoptosis were determined by flow cytometry. High glucose treated L6 muscle cells developed a significant increase in PKR expression. Impaired insulin signaling as well as reduced insulin stimulated glucose uptake was observed in high glucose treated L6 muscle cells. A significant increase in reactive oxygen species generation and apoptosis formation was also observed in high glucose treated cultured L6 muscle cells. All these effects of high glucose were attenuated by a selective PKR inhibitor imoxin. Our study demonstrates PKR may have an additive role against the deleterious effects of high glucose in diabetes. Prevention of PKR activation, by safer and specific inhibitors is a therapeutic option in metabolic disorders that needs to be explored further.