Abstract 018: Neuronal (Pro)renin Receptor Deletion Prevents High-fat Diet Induced High Blood Pressure and Type II Diabetes

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Caleb J Worker ◽  
Wencheng Li ◽  
Yumei Feng
Keyword(s):  
Blood Pressure ◽  
Metabolic Syndrome ◽  
Body Weight ◽  
Insulin Sensitivity ◽  
Angiotensin Ii ◽  
Glucose Tolerance ◽  
High Fat Diet ◽  
Fasting Blood Glucose ◽  
Renin Angiotensin System ◽  
High Fat

We recently reported that the (pro)renin receptor (PRR) is a key component of the brain renin-angiotensin system, mediating the majority of Ang II formation, and plays a pivotal role in the development of hypertension. Its importance in obesity-related metabolic syndrome is, however, unknown. We hypothesize that brain PRR plays a regulatory role in high-fat diet (HFD) induced metabolic syndrome. To test our hypothesis, neuron-specific PRR knockout (PRRKO) mice and wildtype (WT) littermates were fed with either HFD (60% calories from fat) or normal fat chow (NFD, 10% calories from fat) with matching calories for 16 weeks. Weekly body weight (BW) and monthly fasting blood glucose (FBG) measurements were recorded and end point glucose tolerance (GTT) and insulin sensitivity tests (IST) were performed. Blood pressure (BP) was recorded using radiotelemetry in conscious free moving mice. We observed no difference in BW or food intake between genotypes in either HFD or NFD. The baseline BP and heart rate (HR) were similar between PRRKO and WT mice; however, following 16 weeks HFD the BP (101±6 vs. 111±3 mmHg, P=0.035) and HR (536±12 vs. 578±4 BPM, P=0.046) were significantly lower in PRRKO compared with WT mice. Interestingly, neuronal PRR deletion attenuated the elevation of FBG (127.12±10.46 vs. 167.77±16.57 mg/dl, P=0.039) induced by HFD. Glucose tolerance was significantly improved in PRRKO compared with WT following 16 weeks of HFD (AUC: 20557±894 vs. 29994±2976, P=0.006), while there was no difference in the IST between the groups. We also found that HFD mice had higher levels of plasma (pro)renin (9.95±1.83 vs. 2.74± 0.47 ng/ml, P=0.005) and brain angiotensin II (656.8±94.9 vs. 375.3±32.0 pg/g, P=0.02), as well as higher cardiac (ΔHR to propranolol: -150±6 vs. -82±15 bpm , P=0.0054) and vasomotor (ΔBP to chlorisondamine: -44±3 vs. -22±3 mmHg, P=0.0004) sympathetic tone, suggesting that the HFD-induced rise in BP is sympathetically mediated and associated with elevation of brain angiotensin II. Our data indicates that PRR deletion in the neurons protects against glucose intolerance and BP elevation in HFD mice with no effect on insulin sensitivity or body weight. We conclude that neuronal PRR plays a role in the development of obesity-related metabolic syndrome.

Abstract P316: Angiotensin-(1-7) Contributes to the Insulin-sensitizing Effects of Renin-angiotensin System Blockade in High Fat Fed Mice

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Amy C Arnold
Keyword(s):  
Blood Pressure ◽  
Body Weight ◽  
Insulin Sensitivity ◽  
High Fat Diet ◽  
Renin Angiotensin System ◽  
Ace Inhibition ◽  
Whole Body ◽  
High Fat ◽  
Angiotensin System ◽  
Renin Angiotensin

Angiotensin-converting enzyme (ACE) inhibitors reduce body weight, lower blood pressure, and improve glucose homeostasis in animal models of the cardiometabolic syndrome. These effects are generally attributed to a reduction in angiotensin (Ang) II formation; however, these therapies also increase circulating levels of Ang-(1-7), a peptide with direct anti-hypertensive and insulin-sensitizing effects. In this study, it was hypothesized that endogenous Ang-(1-7) generation contributes to the beneficial cardiometabolic effects of ACE inhibition. To test this hypothesis, diet-induced obesity was produced in adult male C57BL/6J mice by placing them on a 60% high fat diet for 11 weeks. The Ang-(1-7) mas receptor antagonist A779 (400 ng/kg/min) or saline was given after 8 weeks of the high fat diet by subcutaneous osmotic mini-pumps. Immediately following mini-pump implantation, mice received water containing the ACE inhibitor captopril (50 mg/L) or plain tap water. Hyperinsulinemic (4 mU/kg/min) euglycemic clamps were performed in conscious, unrestrained vehicle (n=6), captopril (n=6), or captopril plus A779 (n=13) mice at the end of the 3-week treatment period. Blood pressure was measured via an indwelling carotid artery catheter connected to a transducer on the morning of the clamp. Captopril reduced body weight (28±2 vs. 41±2 g vehicle; p=0.001), lowered blood pressure (systolic: 109±6 vs.144±7 mmHg vehicle; p=0.003), and improved whole-body insulin sensitivity (steady-state glucose infusion rate: 31±4 vs. 16±2 mg/kg/min; p=0.008) in high-fat fed mice. Mas receptor antagonism with A779 attenuated the improvement in insulin sensitivity produced by captopril in high fat fed mice (23±2 mg/kg/min; p=0.042). There was no effect of A779 on the weight loss (32±2 g) or blood pressure lowering effects (111±7 mmHg) of captopril. These findings suggest that the improvement in insulin sensitivity produced by ACE inhibition is at least partly mediated by Ang-(1-7) pathways, and provide new insight into potential mechanisms involved in renin-angiotensin system blockade.

Abstract 404: NLR Family, Pyrin Domain-containing 3 Knockout Rescues Cardiac Dysfunction Induced by High-fat Diet Feeding

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Matthew R Peterson ◽  
Samantha Haller ◽  
Tracy Ta ◽  
Luiza Bosch ◽  
Aspen Smith ◽  
...  
Keyword(s):  
Body Weight ◽  
Blood Glucose ◽  
Inflammatory Response ◽  
Glucose Tolerance ◽  
High Fat Diet ◽  
Fasting Blood Glucose ◽  
Left Ventricular ◽  
Normal Diet ◽  
High Fat ◽  
Pyrin Domain

NLR family, pyrin domain-containing 3 (NLRP3) is a pattern recognition receptor responsible for perpetuating an inflammatory response through production of pro-inflammatory cytokines IL-1β and IL-18. It has been implicated in the sustained inflammatory response in obesity and multiple cardiovascular disease conditions. In order to investigate NLRP3 as a potential therapeutic target in metabolic syndrome, C57BL/6 wild-type (WT) and NLRP3 knockout (NLRP3-\-) mice were fed a normal diet (ND; 12% fat chow) or a high fat diet (HFD; 45% fat chow) for 5 months. At 5 months, echocardiography and glucose tolerance tests (GTTs) were performed. Cardiac function assessed by fractional shortening (FS) was significantly impaired by HFD feeding in the WT group (0.335 HFD vs. 0.456 ND; p<0.05) but not in the NLRP3-\- (0.449 HFD vs. 0.492 ND; p>0.05). FS was higher in NLRP3-\-HFD than in WT-HFD (p<0.05). Two-dimensional analysis shows the FS difference between NLRP3-\-HFD and WT-HFD was primarily explained by the difference in left ventricular end-systolic dimension (0.2716 cm WT vs. 0.1883 cm NLRP3-\-; p<0.05). Glucose tolerance measured by area under the curve (AUC) was significantly impaired by HFD feeding for both WT (23183 ND vs. 57298 HFD; p<0.001) and NLRP3-\- (23197 ND vs. 44626 HFD; p<0.001), but significantly better in the NLRP3-\-HFD than in WT-HFD (p<0.01). HFD feeding increased fasting blood glucose (FBG) for both WT (97.7 mg . dl -1 ND vs. 164.7 mg . dl -1 HFD; p<0.01) and NLRP3-\- (80.50 mg . dl -1 ND vs. 108.8 mg . dl -1 HFD; p<0.05), but significantly less in NLRP3-\- mice (NLRP3-\- vs. WT; p<0.05). For GTTs, body weight was significantly higher in the WT than NLRP3-\- fed HFD (47.93 g vs. 36.5 g; p<0.001). Body weight explained 92% of variation in glucose tolerance (p<0.0001) and 69% of variation in fasting blood glucose (p<0.0001). WT-HFD averaged 1.31X heavier than NLRP3-\-HFD, while the AUC for the IGTT was 1.28X larger for the WT-HFD than NLRP3-\-HFD. Body weights were not significantly different between genotypes at the time of echo. The results suggest that knockout of NLRP3 may be protective against HFD induced cardiovascular dysfunction. A protective effect on glucose tolerance is not strongly supported.

scholarly journals Tpcn2 knockout mice have improved insulin sensitivity and are protected against high-fat diet-induced weight gain

2018 ◽  
Vol 50 (8) ◽  
pp. 605-614
Author(s):  
Hong He ◽  
Katie Holl ◽  
Sarah DeBehnke ◽  
Chay Teng Yeo ◽  
Polly Hansen ◽  
...  
Keyword(s):  
Body Weight ◽  
Weight Gain ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Knockout Mice ◽  
High Fat Diet ◽  
Wild Type ◽  
High Fat ◽  
Male And Female ◽  
Female Mice

Type 2 diabetes is a complex disorder affected by multiple genes and the environment. Our laboratory has shown that in response to a glucose challenge, two-pore channel 2 ( Tpcn2) knockout mice exhibit a decreased insulin response but normal glucose clearance, suggesting they have improved insulin sensitivity compared with wild-type mice. We tested the hypothesis that improved insulin sensitivity in Tpcn2 knockout mice would protect against the negative effects of a high fat diet. Male and female Tpcn2 knockout (KO), heterozygous (Het), and wild-type (WT) mice were fed a low-fat (LF) or high-fat (HF) diet for 24 wk. HF diet significantly increases body weight in WT mice relative to those on the LF diet; this HF diet-induced increase in body weight is blunted in the Het and KO mice. Despite the protection against diet-induced weight gain, however, Tpcn2 KO mice are not protected against HF-diet-induced changes in glucose or insulin area under the curve during glucose tolerance tests in female mice, while HF diet has no significant effect on glucose tolerance in the male mice, regardless of genotype. Glucose disappearance during an insulin tolerance test is augmented in male KO mice, consistent with our previous findings suggesting enhanced insulin sensitivity in these mice. Male KO mice exhibit increased fasting plasma total cholesterol and triglyceride concentrations relative to WT mice on the LF diet, but this difference disappears in HF diet-fed mice where there is increased cholesterol and triglycerides across all genotypes. These data demonstrate that knockout of Tpcn2 may increase insulin action in male, but not female, mice. In addition, both male and female KO mice are protected against diet-induced weight gain, but this protection is likely independent from glucose tolerance, insulin sensitivity, and plasma lipid levels.

scholarly journals The Effect of Angiotensin-Converting Enzyme Inhibition Using Captopril on Energy Balance and Glucose Homeostasis

Endocrinology ◽  
2009 ◽  
Vol 150 (9) ◽  
pp. 4114-4123 ◽  
Author(s):  
Annette D. de Kloet ◽  
Eric G. Krause ◽  
Dong-Hoon Kim ◽  
Randall R. Sakai ◽  
Randy J. Seeley ◽  
...  
Keyword(s):  
Body Weight ◽  
Glucose Tolerance ◽  
Angiotensin Converting Enzyme ◽  
High Fat Diet ◽  
Renin Angiotensin System ◽  
Angiotensin Converting Enzyme Inhibition ◽  
Converting Enzyme ◽  
High Fat ◽  
Angiotensin System ◽  
Converting Enzyme Inhibition

Abstract Increasing evidence suggests that the renin-angiotensin-system contributes to the etiology of obesity. To evaluate the role of the renin-angiotensin-system in energy and glucose homeostasis, we examined body weight and composition, food intake, and glucose tolerance in rats given the angiotensin-converting enzyme inhibitor, captopril (∼40 mg/kg · d). Rats given captopril weighed less than controls when fed a high-fat diet (369.3 ± 8.0 vs. 441.7 ± 8.5 g after 35 d; P &lt; 0.001) or low-fat chow (320.1 ± 4.9 vs. 339.8 ± 5.1 g after 21 d; P &lt; 0.0001). This difference was attributable to reductions in adipose mass gained on high-fat (23.8 ± 2.0 vs. 65.12 ± 8.4 g after 35 d; P &lt; 0.0001) and low-fat diets (12.2 ± 0.7 vs. 17.3 ± 1.3 g after 21 d; P &lt; 0.001). Rats given captopril ate significantly less [3110.3 ± 57.8 vs. 3592.4 ± 88.8 kcal (cumulative 35 d high fat diet intake); P &lt; 0.001] despite increased in neuropeptide-Y mRNA expression in the arcuate nucleus of the hypothalamus and had improved glucose tolerance compared with free-fed controls. Comparisons with pair-fed controls indicated that decreases in diet-induced weight gain and adiposity and improved glucose tolerance were due, primarily, to decreased food intake. To determine whether captopril caused animals to defend a lower body weight, animals in both groups were fasted for 24 h and subsequently restricted to 20% of their intake for 2 d. When free food was returned, captopril and control rats returned to their respective body weights and elicited comparable hyperphagic responses. These results suggest that angiotensin-converting enzyme inhibition protects against the development of diet-induced obesity and glucose intolerance.

scholarly journals Aging Increases Susceptibility to High Fat Diet-Induced Metabolic Syndrome in C57BL/6 Mice: Improvement in Glycemic and Lipid Profile after Antioxidant Therapy

2016 ◽  
Vol 2016 ◽  
pp. 1-17 ◽  
Author(s):  
Valéria Nunes-Souza ◽  
Cheila Juliana César-Gomes ◽  
Lucas José Sá Da Fonseca ◽  
Glaucevane Da Silva Guedes ◽  
Salete Smaniotto ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Metabolic Syndrome ◽  
Lipid Peroxidation ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
High Fat Diet ◽  
High Fat ◽  
Hepatic Lipid ◽  
Hepatic Lipid Peroxidation ◽  
Old Mice

Nonalcoholic fatty liver disease (NAFLD) has been considered a novel component of the metabolic syndrome (MetS), with the oxidative stress participating in its progression. This study aimed to evaluate the metabolic profile in young and old mice with MetS, and the effects of apocynin and tempol on glycemic and lipid parameters. Young and old C57BL/6 mice with high fat diet- (HFD-) induced MetS received apocynin and tempol 50 mg·kg−1/day in their drinking water for 10 weeks. After HFD, the young group showed elevated fasting glucose, worsened lipid profile in plasma, steatosis, and hepatic lipid peroxidation. Nevertheless, the old group presented significant increase in fasting insulin levels, insulin resistance, plasma and hepatic lipid peroxidation, and pronounced steatosis. The hepatic superoxide dismutase and catalase activity did not differ between the groups. Tempol and apocynin seemed to prevent hepatic lipid deposition in both groups. Furthermore, apocynin improved glucose tolerance and insulin sensitivity in old mice. In summary, old mice are more susceptible to HFD-induced metabolic changes than their young counterparts. Also, the antioxidant therapy improved insulin sensitivity and glucose tolerance, and in addition, apocynin seemed to prevent the HFD-induced hepatic fat deposition, suggesting an important role of oxidative stress in the induction of NAFLD.

scholarly journals High-fat diet amplifies renal renin angiotensin system expression, blood pressure elevation, and renal dysfunction caused by Ceacam1 null deletion

2015 ◽  
Vol 309 (9) ◽  
pp. E802-E810 ◽  
Author(s):  
Caixia Li ◽  
Silas A. Culver ◽  
Syed Quadri ◽  
Kelly L. Ledford ◽  
Qusai Y. Al-Share ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Angiotensin Converting Enzyme ◽  
High Fat Diet ◽  
Renin Angiotensin System ◽  
Converting Enzyme ◽  
High Fat ◽  
Angiotensin System ◽  
Collagen Iii ◽  
Renal Expression

Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAMl), a substrate of the insulin receptor tyrosine kinase, regulates insulin action by promoting insulin clearance. Global null mutation of Ceacam1 gene ( Cc1−/−) results in features of the metabolic syndrome, including insulin resistance, hyperinsulinemia, visceral adiposity, elevated blood pressure, and albuminuria. It also causes activation of the renal renin-angiotensin system (RAS). In the current study, we tested the hypothesis that high-fat diet enhances the expression of RAS components. Three-month-old wild-type ( Cc1+/+) and Cc1−/− mice were fed either a regular or a high-fat diet for 8 wk. At baseline under regular feeding conditions, Cc1−/− mice exhibited higher blood pressure, urine albumin-to-creatinine ratio (UACR), and renal expression of angiotensinogen, renin/prorenin, angiotensin-converting enzyme, (pro)renin receptor, angiotensin subtype AT1 receptor, angiotensin II, and elevated PI3K phosphorylation, as detected by p85α (Tyr508) immunostaining, inflammatory response, and the expression of collagen I and collagen III. In Cc1+/+ mice, high-fat diet increased blood pressure, UACR, the expression of angiotensin-converting enzyme and angiotensin II, PI3K phosphorylation, inflammatory response, and the expression of collagen I and collagen III. In Cc1−/− mice, high-fat intake further amplified these parameters. Immunohistochemical staining showed increased p-PI3K p85α (Tyr508) expression in renal glomeruli, proximal, distal, and collecting tubules of Cc1−/− mice fed a high-fat diet. Together, this demonstrates that high-fat diet amplifies the permissive effect of Ceacam1 deletion on renal expression of all RAS components, PI3K phosphorylation, inflammation, and fibrosis.

scholarly journals The neuronal (pro)renin receptor and astrocyte inflammation in the central regulation of blood pressure and blood glucose in mice fed a high-fat diet

2020 ◽  
Vol 318 (5) ◽  
pp. E765-E778 ◽  
Author(s):  
Caleb J. Worker ◽  
Wencheng Li ◽  
Cheng-yuan Feng ◽  
Lucas A. C. Souza ◽  
Ariana Julia B. Gayban ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Blood Glucose ◽  
High Fat Diet ◽  
Critical Role ◽  
Fasting Blood Glucose ◽  
Renin Angiotensin System ◽  
Central Regulation ◽  
Ang Ii ◽  
High Fat ◽  
The Brain

We report here that the neuronal (pro)renin receptor (PRR), a key component of the brain renin-angiotensin system (RAS), plays a critical role in the central regulation of high-fat-diet (HFD)-induced metabolic pathophysiology. The neuronal PRR is known to mediate formation of the majority of angiotensin (ANG) II, a key bioactive peptide of the RAS, in the central nervous system and to regulate blood pressure and cardiovascular function. However, little is known about neuronal PRR function in overnutrition-related metabolic physiology. Here, we show that PRR deletion in neurons reduces blood pressure, neurogenic pressor activity, and fasting blood glucose and improves glucose tolerance without affecting food intake or body weight following a 16-wk HFD. Mechanistically, we found that a HFD increases levels of the PRR ligand (pro)renin in the circulation and hypothalamus and of ANG II in the hypothalamus, indicating activation of the brain RAS. Importantly, PRR deletion in neurons reduced astrogliosis and activation of the astrocytic NF-κB p65 (RelA) in the arcuate nucleus and the ventromedial nucleus of the hypothalamus. Collectively, our findings indicate that the neuronal PRR plays essential roles in overnutrition-related metabolic pathophysiology.

scholarly journals Partial Deficiency of Zfp217 Resists High-Fat Diet-Induced Obesity by Increasing Energy Metabolism in Mice

2021 ◽  
Vol 22 (10) ◽  
pp. 5390
Author(s):  
Qianhui Zeng ◽  
Nannan Wang ◽  
Yaru Zhang ◽  
Yuxuan Yang ◽  
Shuangshuang Li ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Weight Gain ◽  
Insulin Sensitivity ◽  
Energy Metabolism ◽  
Glucose Tolerance ◽  
High Fat Diet ◽  
Chow Diet ◽  
High Fat ◽  
Glycolipid Metabolism ◽  
Partial Deficiency

Obesity-induced adipose tissue dysfunction and disorders of glycolipid metabolism have become a worldwide research priority. Zfp217 plays a crucial role in adipogenesis of 3T3-L1 preadipocytes, but about its functions in animal models are not yet clear. To explore the role of Zfp217 in high-fat diet (HFD)-induced obese mice, global Zfp217 heterozygous knockout (Zfp217+/−) mice were constructed. Zfp217+/− mice and Zfp217+/+ mice fed a normal chow diet (NC) did not differ significantly in weight gain, percent body fat mass, glucose tolerance, or insulin sensitivity. When challenged with HFD, Zfp217+/− mice had less weight gain than Zfp217+/+ mice. Histological observations revealed that Zfp217+/− mice fed a high-fat diet had much smaller white adipocytes in inguinal white adipose tissue (iWAT). Zfp217+/− mice had improved metabolic profiles, including improved glucose tolerance, enhanced insulin sensitivity, and increased energy expenditure compared to the Zfp217+/+ mice under HFD. We found that adipogenesis-related genes were increased and metabolic thermogenesis-related genes were decreased in the iWAT of HFD-fed Zfp217+/+ mice compared to Zfp217+/− mice. In addition, adipogenesis was markedly reduced in mouse embryonic fibroblasts (MEFs) from Zfp217-deleted mice. Together, these data indicate that Zfp217 is a regulator of energy metabolism and it is likely to provide novel insight into treatment for obesity.

scholarly journals Vagotomy Reduces Insulin Clearance in Obese Mice Programmed by Low-Protein Diet in the Adolescence

2017 ◽  
Vol 2017 ◽  
pp. 1-7 ◽  
Author(s):  
Camila Lubaczeuski ◽  
Luciana Mateus Gonçalves ◽  
Jean Franciesco Vettorazzi ◽  
Mirian Ayumi Kurauti ◽  
Junia Carolina Santos-Silva ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
High Fat Diet ◽  
Insulin Clearance ◽  
Protein Diet ◽  
Low Protein Diet ◽  
High Fat ◽  
Insulin Degrading Enzyme ◽  
Low Protein

The aim of this study was to investigate the effect of subdiaphragmatic vagotomy on insulin sensitivity, secretion, and degradation in metabolic programmed mice, induced by a low-protein diet early in life, followed by exposure to a high-fat diet in adulthood. Weaned 30-day-old C57Bl/6 mice were submitted to a low-protein diet (6% protein). After 4 weeks, the mice were distributed into three groups: LP group, which continued receiving a low-protein diet; LP + HF group, which started to receive a high-fat diet; and LP + HFvag group, which underwent vagotomy and also was kept at a high-fat diet. Glucose-stimulated insulin secretion (GSIS) in isolated islets, ipGTT, ipITT, in vivo insulin clearance, and liver expression of the insulin-degrading enzyme (IDE) was accessed. Vagotomy improved glucose tolerance and reduced insulin secretion but did not alter adiposity and insulin sensitivity in the LP + HFvag, compared with the LP + HF group. Improvement in glucose tolerance was accompanied by increased insulinemia, probably due to a diminished insulin clearance, as judged by the lower C-peptide : insulin ratio, during the ipGTT. Finally, vagotomy also reduced liver IDE expression in this group. In conclusion, when submitted to vagotomy, the metabolic programmed mice showed improved glucose tolerance, associated with an increase of plasma insulin concentration as a result of insulin clearance reduction, a phenomenon probably due to diminished liver IDE expression.

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