Oral Angiotensin-(1–7) prevented obesity and hepatic inflammation by inhibition of resistin/TLR4/MAPK/NF-κB in rats fed with high-fat diet

Santos, Sérgio Henrique Sousa; Andrade, João Marcus Oliveira; Fernandes, Liliam; Sinisterra, Rubén D.; Sousa, Frederico B. De; Feltenberger, John David; Alvarez-Leite, Jacqueline I.; Santos, Robson Augusto Souza

doi:10.1016/j.peptides.2013.05.010

Cited by 117 publications

(75 citation statements)

References 30 publications

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“…This alludes to an adaptation, which is lost upon repeated and/or sustained exposure to hepatotoxic stimuli leading to NAFLD and steatohepatitis. Furthermore, the constitutive activation of NF-κB has been associated with severe hepatic and moderate peripheral insulin resistance (53). The present data suggest that a single PO challenge promotes pathways of LPSand TLR4-mediated inflammation and cytotoxicity, which are buffered by the activation of NF-κB, which in turn contributes to insulin resistance.…”

Section: Figure 2 Time Courses Of Circulating Metabolites and Hormonmentioning

confidence: 54%

Acute dietary fat intake initiates alterations in energy metabolism and insulin resistance

Hernández¹,

Kahl²,

Seelig³

et al. 2017

Journal of Clinical Investigation

159

130

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H and ex vivo2 H magnetic resonance spectroscopy before and during hyperinsulinemiceuglycemic clamps with isotope dilution. Mice underwent identical clamp procedures and hepatic transcriptome analyses.RESULTS. PO administration decreased whole-body, hepatic, and adipose tissue insulin sensitivity by 25%, 15%, and 34%, respectively. Hepatic triglyceride and ATP content rose by 35% and 16%, respectively. Hepatic gluconeogenesis increased by 70%, and net glycogenolysis declined by 20%. Mouse transcriptomics revealed that PO differentially regulates predicted upstream regulators and pathways, including LPS, members of the TLR and PPAR families, NF-κB, and TNF-related weak inducer of apoptosis (TWEAK). CONCLUSION.Saturated fat ingestion rapidly increases hepatic lipid storage, energy metabolism, and insulin resistance. This is accompanied by regulation of hepatic gene expression and signaling that may contribute to development of NAFLD. PO results in increased circulating TG, glucagon, and incretins. After PO administration, TG in plasma rose by 59% (area under the time curve [AUC], P < 0.001) and by 156% in chylomicrons (AUC, P = 0.009) (Figure 2A). The AUC for plasma free fatty acids (FFA) ( Figure 2B) and insulin concentrations ( Figure 2C) was unchanged, while the AUC for plasma C-peptide was 28% higher after PO ingestion versus VCL (P < 0.005, Figure 2D). Of note, FFA were increased at 300, 420, and 480 minutes. Blood glucose levels were not different between PO-and VCL-treated groups ( Figure 2E). Plasma glucagon rose by 41% (AUC, P < 0.0001) only after PO ingestion ( Figure 2F). Also, glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP) levels were markedly increased and remained elevated after PO ingestion (both P < 0.005) (Supplemental Figure 2; supplemental material available online with this article; https://doi.org/10.1172/ JCI89444DS1). Circulating levels of TNF-α, IL-6, fetuin-A, chemerin, omentin, and cortisol were not different between PO and VCL groups (P > 0.5 for all) (Supplemental Table 1). REGISTRATION. The Journal of Clinical Investigation C L I N I C A L M E D I C I N EPO induces insulin resistance at whole-body, liver, and adipose tissue levels. Insulin sensitivity was measured using hyperinsulinemic-euglycemic clamp tests in healthy humans. Steady state was reached (Supplemental Figure 1), and pertinent parameters were analyzed during this time. PO ingestion reduced WBIS by 25% compared with VCL treatment (P = 0.0005, Figure 3A). Furthermore, after PO, volunteers also showed a decrease of 22% (P = 0.002) in the rate of glucose disappearance (Rd), mostly due to a 33% (P = 0.01) reduction in glucose oxidation (GOX), while the rate of nonoxidative glucose disposal remained unchanged

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Section: Figure 2 Time Courses Of Circulating Metabolites and Hormonmentioning

confidence: 54%

Acute dietary fat intake initiates alterations in energy metabolism and insulin resistance

Hernández¹,

Kahl²,

Seelig³

et al. 2017

Journal of Clinical Investigation

159

130

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“…Like ACE inhibitors or AT 1 receptor blockers, ANG-(1-7) attenuates the characteristics of metabolic syndrome (49). Oral formulation of ANG-(1-7) improves metabolism, and decreases the proinflammatory profile and fat deposition in HFD-fed mice as well as hypertensive rats (50,51). Prolonged ANG-(1-7) treatment has also been shown to improve endothelial dysfunction and oxidative stress in a mouse model of obesity (52).…”

Section: Discussionmentioning

confidence: 99%

Heat Shock Prevents Insulin Resistance–Induced Vascular Complications by Augmenting Angiotensin-(1-7) Signaling

Karpe

Tikoo

2014

Diabetes

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We have investigated the role of heat shock (HS) in preventing insulin resistance-induced endothelial dysfunction. To the best of our knowledge, we report here for the first time that insulin resistance inhibits vascular HS protein (HSP) 72 expression. HS treatment (41°C for 20 min) restored the HSP72 expression. High-fat diet (HFD)-fed, insulin-resistant rats show attenuated angiotensin (ANG)-(1-7)-induced vasodilator effect, endothelial nitric oxide synthase (eNOS) phosphorylation, AMP-activated protein kinase phosphorylation, and sirtuin 1 (SIRT1) expression. Interestingly, HS prevented this attenuation. We also provide the first evidence that HFD-fed rats show increased vascular DNA methyltransferase 1 (DNMT1) expression and that HS prevented this increase. Our data show that in HFD-fed rats HS prevented loss in the expression of ANG-(1-7) receptor Mas and ACE2, which were responsible for vascular complications. Further, the inhibition of eNOS (L-N G -nitro-L-arginine methyl ester), Mas (A-779), and SIRT1 (nicotinamide) prevented the favorable effects of HS. This suggests that HS augmented ANG-(1-7) signaling via the Mas/eNOS/SIRT1 pathway. Our study, for the first time, suggests that induction of intracellular HSP72 alters DNMT1 expression, and may function as an epigenetic regulator of SIRT1 and eNOS expression. We propose that induction of HSP72 is a novel approach to prevent insulin resistance-induced vascular complications. Insulin resistance is a prominent component of metabolic syndrome, which is characterized by obesity, hypertension, and atherosclerosis. A reciprocal relationship has been established between insulin resistance and endothelial dysfunction, which may lead to cardiovascular disorders (1). Apart from the metabolic actions, insulin performs various important hemodynamic functions such as peripheral vasodilation and increased regional blood flow via stimulation of nitric oxide (NO). Therefore, anything that impairs insulin action is expected to result in endothelial dysfunction and vice versa (2). Insulin has been shown to induce endothelial-dependent vasodilation without affecting endothelium-independent vasodilation. We and others (3,4) have reported that insulin resistance impairs endothelium-dependent vasodilation.Several studies have pointed out active involvement of renin-angiotensin system (RAS) in cardiovascular disorders and insulin resistance (5,6). RAS further splits in two, as follows: angiotensin (ANG) II/ACE1 and ANG-(1-7)/ACE2 axis. ANG-(1-7), acting through receptor Mas (G-protein-coupled), counter-regulates the actions of ANG II. Mas receptor dimerizes with AT 1 receptor and COMPLICATIONS inhibits ANG II signaling, suggesting direct interaction of ANG II and the ANG-(1-7) axis (7). ANG-(1-7) promotes vasodilation and inhibits cell proliferation thrombosis, hence opposing the effects of ANG II (8,9). In endothelial cells, ANG-(1-7) inhibited ANG II-induced c-Src, extracellular signal-related kinase 1/2, and NADPH oxidase by activating SHP-2 phosphatase (10). ANG-(1-7) als...

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“…Diverging from many reports describing Mas-mediated anti-inflammatory effects in different tissues (Al-Maghrebi et al, 2009;da Silveira et al, 2010;El-Hashim et al, 2012;Giani et al, 2012;Jiang et al, 2012;Santos et al, 2012;Souza and Costa-Neto, 2012;Sukumaran et al, 2012;Chen et al, 2013;Feltenberger et al, 2013;Moore et al, 2013;Regenhardt et al, 2013;Wagenaar et al, 2013;Wang et al, 2013c;Acuna et al, 2014;Meng et al, 2014), in the kidney, a proinflammatory role for Ang-(1-7) and Mas was reported by using a model of unilateral ureteral obstruction in mice (Esteban et al, 2009). In contrast, anti-inflammatory and beneficial effects of Ang-(1-7) were observed in other models of kidney injury (Singh et al, 2010b;Moon et al, 2011;Bernardi et al, 2012;Giani et al, 2012;Harris, 2012;Chou et al, 2013;Santos et al, 2013b;Zhang et al, 2014). Interestingly, the outcome of adriamycin-induced nephropathy was similar in Mas-KO and wild-type mice.…”

Section: Mas-related G Protein-coupled Receptors and Mas In Cardiomentioning

confidence: 96%

Mas and Its Related G Protein–Coupled Receptors, Mrgprs

et al. 2014

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Oral Angiotensin-(1–7) prevented obesity and hepatic inflammation by inhibition of resistin/TLR4/MAPK/NF-κB in rats fed with high-fat diet

Cited by 117 publications

References 30 publications

Acute dietary fat intake initiates alterations in energy metabolism and insulin resistance

Acute dietary fat intake initiates alterations in energy metabolism and insulin resistance

Heat Shock Prevents Insulin Resistance–Induced Vascular Complications by Augmenting Angiotensin-(1-7) Signaling

Mas and Its Related G Protein–Coupled Receptors, Mrgprs

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