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Increased angiotensin II (Ang II) signaling contributes to insulin resistance and liver steatosis. In addition to ameliorating hypertension, angiotensin receptor blockers (ARBs) improve lipid metabolism and hepatic steatosis, which are impaired with metabolic syndrome (MetS). Chronic blockade of the Ang II receptor type 1 (AT1) increases plasma angiotensin 1-7 (Ang 1-7), which mediates mechanisms counterregulatory to AT1 signaling. Elevated plasma Ang 1-7 is associated with decreased plasma triacylglycerol (TAG), cholesterol, glucose, and insulin; however, the benefits of RAS modulation to prevent non-alcoholic fatty liver disease (NAFLD) are not fully investigated. To better address the relationships among chronic ARB treatment, plasma Ang 1-7, and hepatic steatosis, three groups of 10-week-old-rats were studied: (1) untreated lean Long Evans Tokushima Otsuka (LETO), (2) untreated Otsuka Long Evans Tokushima Fatty (OLETF), and (3) OLETF + ARB (ARB; 10 mg olmesartan/kg/d × 6 weeks). Following overnight fasting, rats underwent an acute glucose load to better understand the dynamic metabolic responses during hepatic steatosis and early MetS. Tissues were collected at baseline (pre-load; T0) and 1 and 2 h post-glucose load. AT1 blockade increased plasma Ang 1-7 and decreased liver lipids, which was associated with decreased fatty acid transporter 5 (FATP5) and fatty acid synthase (FASN) expression. AT1 blockade decreased liver glucose and increased glucokinase (GCK) expression. These results demonstrate that during MetS, overactivation of AT1 promotes hepatic lipid deposition that is stimulated by an acute glucose load and lipogenesis genes, suggesting that the chronic hyperglycemia associated with MetS contributes to fatty liver pathologies via an AT1-mediated mechanism.

PurposeAngiotensin receptor blockers (ARBs) can ameliorate metabolic syndrome (MetS)-associated dyslipidemia, hepatic steatosis, and glucose intolerance, suggesting that angiotensin receptor (AT1) over-activation contributes to impaired lipid and glucose metabolism, which is characteristic of MetS. The aim of this study was to evaluate changes in the lipid profile and proteins of fatty acid uptake, triacylglycerol (TAG) synthesis, and β-oxidation to better understand the links between AT1 overactivation and non-alcoholic fatty liver disease (NAFLD) during MetS.MethodsFour groups of 25-week-old-rats were used: (1) untreated LETO, (2) untreated OLETF, (3) OLETF + angiotensin receptor blocker (ARB; 10 mg olmesartan/kg/d × 8 weeks) and (4) OLETF ± ARB (MINUS; 10 mg olmesartan/kg/d × 4 weeks, then removed until dissection). To investigate the dynamic shifts in metabolism, animals were dissected after an oral glucose challenge (fasting, 3 and 6 h post-glucose).ResultsCompared to OLETF, plasma total cholesterol and TAG remained unchanged in ARB. However, liver TAG was 55% lesser in ARB than OLETF, and remained lower throughout the challenge. Basal CD36 and ApoB were 28% and 29% lesser, respectively, in ARB than OLETF. PRDX6 abundance in ARB was 45% lesser than OLETF, and it negatively correlated with liver TAG in ARB.ConclusionsChronic blockade of AT1 protects the liver from TAG accumulation during glucose overload. This may be achieved by modulating NEFA uptake and increasing TAG export via ApoB. Our study highlights the contributions of AT1 signaling to impaired hepatic substrate metabolism and the detriments of a high-glucose load and its potential contribution to steatosis during MetS.

The onset of type II diabetes increases the heart's susceptibility to oxidative damage because of the associated inflammation and diminished antioxidant response. Transcription factor NF-κB initiates inflammation while Nrf2 controls antioxidant defense. Current evidence suggests crosstalk between these transcription factors that may become dysregulated during type II diabetes mellitus (T2DM) manifestation. The objective of this study was to examine the dynamic changes that occur in both transcription factors and target genes during the progression of T2DM in the heart. Novel UC Davis T2DM (UCD-T2DM) rats at the following states were utilized: (1) lean, control Sprague-Dawley (SD; n = 7), (2) insulin-resistant pre-diabetic UCD-T2DM (Pre; n = 9), (3) 2-week recently diabetic UCD-T2DM (2Wk; n = 9), (4) 3-month diabetic UCD-T2DM (3Mo; n = 14), and (5) 6-month diabetic UCD-T2DM (6Mo; n = 9). NF-κB acetylation increased 2-fold in 3Mo and 6Mo diabetic animals compared to SD and Pre animals. Nox4 protein increased 4-fold by 6Mo compared to SD. Nrf2 translocation increased 82% in Pre compared to SD but fell 47% in 6Mo animals. GCLM protein fell 35% in 6Mo animals compared to Pre. Hmox1 mRNA decreased 45% in 6Mo animals compared to SD. These data suggest that during the progression of T2DM, NF-κB related genes increase while Nrf2 genes are suppressed or unchanged, perpetuating inflammation and a lesser ability to handle an oxidant burden altering the heart's redox state. Collectively, these changes likely contribute to the diabetes-associated cardiovascular complications.

Non-alcoholic fatty liver disease (NAFLD) affects up to 20% of the world's population. Overactivation of the angiotensin receptor type 1 (AT1) contributes to metabolic dysfunction and increased oxidant production, which are associated with NAFLD and impaired hepatic lipid metabolism. Nuclear factor erythroid-2-related factor 2 (Nrf2) regulates the expression of antioxidant phase II genes by binding to the antioxidant response element (ARE); however, the mechanisms by which AT1 contributes to this pathway during the progression of NAFLD remain unresolved. To investigate hepatic Nrf2 response to a hyperglycemic challenge, we studied three groups of rats (male, 10-weeks-old): (1) untreated, lean Long Evans Tokushima Otsuka (LETO), (2) untreated, obese Otsuka Long Evans Tokushima Fatty (OLETF), and (3) OLETF + angiotensin receptor blocker (OLETF + ARB; 10 mg olmesartan/kg/d × 6 weeks). Livers were collected after overnight fasting (T0; baseline), and 1 h and 2 h post-oral glucose load. At baseline, chronic AT1 blockade increased nuclear Nrf2 content, reduced expression of glutamate-cysteine ligase catalytic (GCLC) subunit, glutathione peroxidase 1 (GPx1), and superoxide dismutase 2 (SOD2), mitochondrial catalase activity, and hepatic 4-hydroxy-2-nonenal (4-HNE) content. The expression of hepatic interleukin-1 beta (IL-1β) and collagen type IV, which are associated with liver fibrosis, were decreased with AT1 blockade. Glucose increased Nrf2 translocation in OLETF but was reduced in ARB, suggesting that glucose induces the need for antioxidant defense that is ameliorated with ARB. These results suggest that overactivation of AT1 promotes oxidant damage by suppressing Nrf2 and contributing to hepatic fibrosis associated with NAFLD development.

Inappropriate activation of the renin-angiotensin system decreases glucose uptake in peripheral tissues. Chronic angiotensin receptor type 1 (AT1) blockade (ARB) increases glucose uptake in skeletal muscle and decreases the abundance of large adipocytes and macrophage infiltration in adipose. However, the contributions of each tissue to the improvement in hyperglycemia in response to AT1 blockade are not known. Therefore, we determined the static and dynamic responses of soleus muscle, liver, and adipose to an acute glucose challenge following the chronic blockade of AT1. We measured adipocyte morphology along with TNF-α expression, F4/80- and CD11c-positive cells in adipose and measured insulin receptor (IR) phosphorylation and AKT phosphorylation in soleus muscle, liver, and retroperitoneal fat before (T0), 60 (T60) and 120 (T120) min after an acute glucose challenge in the following groups of male rats: 1) Long-Evans Tokushima Otsuka (LETO; lean control; n = 5/time point), 2) obese Otsuka Long Evans Tokushima Fatty (OLETF; n = 7 or 8/time point), and 3) OLETF + ARB (ARB; 10 mg olmesartan/kg/day; n = 7 or 8/time point). AT1 blockade decreased adipocyte TNF-α expression and F4/80- and CD11c-positive cells. In retroperitoneal fat at T60, IR phosphorylation was 155% greater in ARB than in OLETF. Furthermore, in retroperitoneal fat AT1 blockade increased glucose transporter-4 (GLUT4) protein expression in ARB compared with OLETF. IR phosphorylation and AKT phosphorylation were not altered in the liver of OLETF, but AT1 blockade decreased hepatic Pck1 and G6pc1 mRNA expressions. Collectively, these results suggest that chronic AT1 blockade improves obesity-associated hyperglycemia in OLETF rats by improving adipocyte function and by decreasing hepatic glucose production via gluconeogenesis.NEW & NOTEWORTHY Inappropriate activation of the renin-angiotensin system increases adipocyte inflammation contributing to the impairment in adipocyte function and increases hepatic Pck1 and G6pc1 mRNA expression in response to a glucose challenge. Ultimately, these effects may contribute to the development of glucose intolerance.

PurposeAngiotensin receptor blockers (ARBs) can ameliorate metabolic syndrome (MetS)-associated dyslipidemia, hepatic steatosis, and glucose intolerance, suggesting that angiotensin receptor (AT1) over-activation contributes to impaired lipid and glucose metabolism, which is characteristic of MetS. The aim of this study was to evaluate changes in the lipid profile and proteins of fatty acid uptake, triacylglycerol (TAG) synthesis, and β-oxidation to better understand the links between AT1 overactivation and non-alcoholic fatty liver disease (NAFLD) during MetS.MethodsFour groups of 25-week-old-rats were used: (1) untreated LETO, (2) untreated OLETF, (3) OLETF + angiotensin receptor blocker (ARB; 10 mg olmesartan/kg/d × 8 weeks) and (4) OLETF ± ARB (MINUS; 10 mg olmesartan/kg/d × 4 weeks, then removed until dissection). To investigate the dynamic shifts in metabolism, animals were dissected after an oral glucose challenge (fasting, 3 and 6 h post-glucose).ResultsCompared to OLETF, plasma total cholesterol and TAG remained unchanged in ARB. However, liver TAG was 55% lesser in ARB than OLETF, and remained lower throughout the challenge. Basal CD36 and ApoB were 28% and 29% lesser, respectively, in ARB than OLETF. PRDX6 abundance in ARB was 45% lesser than OLETF, and it negatively correlated with liver TAG in ARB.ConclusionsChronic blockade of AT1 protects the liver from TAG accumulation during glucose overload. This may be achieved by modulating NEFA uptake and increasing TAG export via ApoB. Our study highlights the contributions of AT1 signaling to impaired hepatic substrate metabolism and the detriments of a high-glucose load and its potential contribution to steatosis during MetS.

Insulin resistance increases renal oxidant production by upregulating NADPH oxidase 4 (Nox4) expression contributing to oxidative damage and ultimately albuminuria. Inhibition of the renin-angiotensin system (RAS) and activation of glucagon-like peptide-1 (GLP-1) receptor signalling may reverse this effect. However, whether angiotensin receptor type 1 (AT1) blockade and GLP-1 receptor activation improve oxidative damage and albuminuria through different mechanisms is not known. Using insulin-resistant Otsuka Long-Evans Tokushima Fatty (OLETF) rats, we tested the hypothesis that simultaneous blockade of AT1 and activation of GLP-1r additively decrease oxidative damage and urinary albumin excretion (Ualb V) in the following groups: (a) untreated, lean LETO (n = 7), (b) untreated, obese OLETF (n = 9), (c) OLETF + angiotensin receptor blocker (ARB; 10 mg olmesartan/kg/d; n = 9), (d) OLETF + GLP-1 mimetic (EXE; 10 µg exenatide/kg/d; n = 7) and (e) OLETF + ARB +exenatide (Combo; n = 6). Mean kidney Nox4 protein expression and nitrotyrosine (NT) levels were 30% and 46% greater, respectively, in OLETF compared with LETO. Conversely, Nox4 protein expression and NT were reduced to LETO levels in ARB and EXE, and Combo reduced Nox4, NT and 4-hydroxy-2-nonenal levels by 21%, 27% and 27%, respectively. At baseline, Ualb V was nearly double in OLETF compared with LETO and increased to nearly 10-fold greater levels by the end of the study. Whereas ARB (45%) and EXE (55%) individually reduced Ualb V, the combination completely ameliorated the albuminuria. Collectively, these data suggest that AT1 blockade and GLP-1 receptor activation reduce renal oxidative damage similarly during insulin resistance, whereas targeting both signalling pathways provides added benefit in restoring and/or further ameliorating albuminuria in a model of diet-induced obesity.

Diabetic hearts are susceptible to damage from inappropriate activation of the renin angiotensin system (RAS) and hyperglycemic events both of which contribute to increased oxidant production. Prolonged elevation of oxidants impairs mitochondrial enzyme function, further contributing to metabolic derangement. Nuclear factor erythriod-2-related factor 2 (Nrf2) induces antioxidant genes including those for glutathione (GSH) synthesis following translocation to the nucleus. We hypothesized that an acute elevation in glucose impairs Nrf2-related gene expression in diabetic hearts, while AT1 antagonism would aid in Nrf2-mediated antioxidant production and energy replenishment. We used four groups (n = 6-8/group) of 25-week-old rats: 1) LETO (lean strain-control), 2) type II diabetic OLETF, 3) OLETF + angiotensin receptor blocker (ARB; 10 mg olmesartan/kg/d × 8 wks), and 4) ARBM (4 weeks on ARB, 4 weeks off) to study the effects of acutely elevated glucose on cardiac mitochondrial function and Nrf2 signaling in the diabetic heart. Animals were gavaged with a glucose bolus (2 g/kg) and groups were dissected at T0, T180, and T360 minutes. Nrf2 mRNA was 32% lower in OLETF rats compared to LETO and remained suppressed in response to glucose. LETO Nrf2 mRNA increased 25% at T360 in response to glucose while no changes were observed in diabetic hearts. GCLC and GCLM mRNA decreased in diabetic hearts 33% and 44% respectively and remained suppressed in response to glucose while ARB treatment increased GCLM transcripts 90% at T180. These data illustrate that during T2DM and in response to glucose, cardiac Nrf2's adaptive response to environmental stressors such as glucose is impaired in diabetic hearts and that ARB treatment may aid Nrf2's impaired dynamic response.

Obesity is associated with an inappropriately activated renin-angiotensin-aldosterone system, suppressed glucagon-like peptide-1 (GLP-1), increased renal Na+ reabsorption, and hypertension. To assess the link between GLP-1 and angiotensin receptor type 1 (AT1) signaling on obesity-associated impairment of urinary Na+ excretion (UNaV) and elevated arterial pressure, we measured mean arterial pressure (MAP) and heart rate by radiotelemetry and metabolic parameters for 40 days. We tested the hypothesis that stimulation of GLP-1 signaling provides added benefit to blockade of AT1 by increasing UNaV and further reducing arterial pressure in the following groups: (1) untreated Long-Evans Tokushima Otsuka (LETO) rats (n = 7); (2) untreated Otsuka Long-Evans Tokushima Fatty (OLETF) rats (n = 9); (3) OLETF + ARB (ARB; 10 mg olmesartan/kg/day; n = 9); (4) OLETF + GLP-1 receptor agonist (EXE; 10 µg exenatide/kg/day; n = 7); and (5) OLETF + ARB + EXE (Combo; n = 6). On day 2, UNaV was 60% and 62% reduced in the EXE and Combo groups, respectively, compared with that in the OLETF rats. On day 40, UNaV was increased 69% in the Combo group compared with that in the OLETF group. On day 40, urinary angiotensinogen was 4.5-fold greater in the OLETF than in the LETO group and was 56%, 62%, and 58% lower in the ARB, EXE, and Combo groups, respectively, than in the OLETF group. From day 2 to the end of the study, MAP was lower in the ARB and Combo groups than in the OLETF rats. These results suggest that GLP-1 receptor activation may reduce intrarenal angiotensin II activity, and that simultaneous blockade of AT1 increases UNaV in obesity; however, these beneficial effects do not translate to a further reduction in MAP.

Inappropriate activation of the renin-angiotensin system decreases glucose uptake in peripheral tissues. Chronic angiotensin receptor type 1 (AT1) blockade (ARB) increases glucose uptake in skeletal muscle and decreases the abundance of large adipocytes and macrophage infiltration in adipose. However, the contributions of each tissue to the improvement in hyperglycemia in response to AT1 blockade are not known. Therefore, we determined the static and dynamic responses of soleus muscle, liver, and adipose to an acute glucose challenge following the chronic blockade of AT1. We measured adipocyte morphology along with TNF-a expression, F4/80- and CD11c-positive cells in adipose and measured insulin receptor (IR) phosphorylation and AKT phosphorylation in soleus muscle, liver, and retroperitoneal fat before (T0), 60 (T60) and 120 (T120) min after an acute glucose challenge in the following groups of male rats: 1) Long-Evans Tokushima Otsuka (LETO; lean control; n = 5/time point), 2) obese Otsuka Long Evans Tokushima Fatty (OLETF; n = 7 or 8/time point), and 3) OLETF þ ARB (ARB; 10 mg olmesartan/kg/day; n = 7 or 8/time point). AT1 blockade decreased adipocyte TNF-a expression and F4/80- and CD11c-positive cells. In retroperitoneal fat at T60, IR phosphorylation was 155% greater in ARB than in OLETF. Furthermore, in retroperitoneal fat AT1 blockade increased glucose transporter-4 (GLUT4) protein expression in ARB compared with OLETF. IR phosphorylation and AKT phosphorylation were not altered in the liver of OLETF, but AT1 blockade decreased hepatic Pck1 and G6pc1 mRNA expressions. Collectively, these results suggest that chronic AT1 blockade improves obesity-associated hyperglycemia in OLETF rats by improving adipocyte function and by decreasing hepatic glucose production via gluconeogenesis. [ABSTRACT FROM AUTHOR]

Introduction: Chronic air pollution (AirPoll) is associated with accelerated cognitive decline and risk of Alzheimer's disease (AD). Correspondingly, wild-type and AD-transgenic rodents exposed to AirPoll have increased amyloid peptides and behavioral impairments., Methods: We examined the γ-secretase modulator GSM-15606 for potential AirPoll protection by its attenuating of amyloid beta (Aβ)42 peptide production. Male and female wild-type mice were fed GSM-15606 during an 8-week inhalation exposure to AirPoll subfractions, ambient nanoparticulate matter (nPM), and diesel exhaust particles (DEP)., Results: GSM-15606 decreased Aβ42 during nPM and DEP exposure without changing beta- or gamma-secretase activity or BACE1 and PS1 protein levels. DEP increased lateral ventricle volume by 25%., Discussion: These enzyme responses are relevant to AD drug treatments, as well as to the physiological functions of the Aβ42 peptide. GSM-15606 attenuation of Aβ42 may benefit human exposure to AirPoll., Highlights: Gamma-secretase modulator (GSM-15606) attenuates the amyloidogenic amyloid beta (Aβ)42 peptide during exposure to air pollution, which may be a mechanism by which air pollution increases Alzheimer's disease (AD) risk. AD drug treatments may also consider Aβ homeostasis among the chronic effects of GSM-15606 and other amyloid reduction treatments on secretase enzymes., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Deferoxamine (DFO) and other iron chelators are clinically used for cancer and stroke. They may also be useful for Alzheimers disease (AD) to diminish iron from microbleeds. DFO may also stimulate antioxidant membrane repair which is impaired during AD. DFO, and other chelators do enter the brain despite some contrary reports., Objective: Low dose, oral DFO was given in lab chow to wildtype (WT) C57BL/6 mice to evaluate potential impact on iron levels, iron-signaling and storage proteins, and amyloid precursor protein (APP) and processing enzymes. Young WT mice do not have microbleeds or disrupted blood-brain barrier of AD mice., Methods: Iron was measured by MRI and chemically after two weeks of dietary DFO. Cerebral cortex was examined for changes in iron metabolism, antioxidant signaling, and APP processing by Western blot., Results: DFO decreased brain iron by 18% (MRI) and decreased seven major proteins that mediate iron metabolism by at least 25%. The iron storage proteins ferritin light and heavy chain decreased by at least 30%. APP and secretase enzymes also decreased by 30%., Conclusions: WT mice respond to DFO with decreased APP, amyloid processing enzymes, and antioxidant repair. Potential DFO treatment for early-stage AD by DFO should consider the benefits of lowered APP and secretase enzymes.

Iron-mediated cell death (ferroptosis) is a proposed mechanism of Alzheimers disease (AD) pathology. While iron is essential for basic biological functions, its reactivity generates oxidants which contribute to cell damage and death. To further resolve mechanisms of iron-mediated toxicity in AD, we analyzed postmortem human brain and ApoEFAD mice. AD brains had decreased antioxidant enzymes, including those mediated by glutathione (GSH). Subcellular analyses of AD brains showed greater oxidative damage and lower antioxidant enzymes in lipid rafts, the site of amyloid processing, than in the non-raft membrane fraction. ApoE4 carriers had lower lipid raft yield with greater membrane oxidation. The hypothesized role of iron to AD pathology was tested in ApoEFAD mice by iron chelation with deferoxamine, which decreased fibrillar amyloid and lipid peroxidation, together with increased GSH-mediated antioxidants. These novel molecular pathways in iron mediated damage during AD.

Inappropriate activation of the renin-angiotensin system decreases glucose uptake in peripheral tissues. Chronic angiotensin receptor type 1 (AT 1 ) blockade (ARB) increases glucose uptake in skeletal muscle and decreases the abundance of large adipocytes and macrophage infiltration in adipose. However, the contributions of each tissue to the improvement in hyperglycemia in response to AT 1 blockade are not known. Therefore, we determined the static and dynamic responses of soleus muscle, liver, and adipose to an acute glucose challenge following the chronic blockade of AT 1 . We measured adipocyte morphology along with TNF-α expression, F4/80- and CD11c-positive cells in adipose and measured insulin receptor (IR) phosphorylation and AKT phosphorylation in soleus muscle, liver, and retroperitoneal fat before ( T0 ), 60 ( T60 ) and 120 ( T120 ) min after an acute glucose challenge in the following groups of male rats: 1 ) Long-Evans Tokushima Otsuka (LETO; lean control; n = 5/time point), 2 ) obese Otsuka Long Evans Tokushima Fatty (OLETF; n = 7 or 8/time point), and 3 ) OLETF + ARB (ARB; 10 mg olmesartan/kg/day; n = 7 or 8/time point). AT 1 blockade decreased adipocyte TNF-α expression and F4/80- and CD11c-positive cells. In retroperitoneal fat at T60 , IR phosphorylation was 155% greater in ARB than in OLETF. Furthermore, in retroperitoneal fat AT 1 blockade increased glucose transporter-4 (GLUT4) protein expression in ARB compared with OLETF. IR phosphorylation and AKT phosphorylation were not altered in the liver of OLETF, but AT 1 blockade decreased hepatic Pck1 and G6pc1 mRNA expressions. Collectively, these results suggest that chronic AT 1 blockade improves obesity-associated hyperglycemia in OLETF rats by improving adipocyte function and by decreasing hepatic glucose production via gluconeogenesis. NEW & NOTEWORTHY Inappropriate activation of the renin-angiotensin system increases adipocyte inflammation contributing to the impairment in adipocyte function and increases hepatic Pck1 and G6pc1 mRNA expression in response to a glucose challenge. Ultimately, these effects may contribute to the development of glucose intolerance.