scholarly journals Maternal high-fat diet acts on the brain to induce baroreflex dysfunction and sensitization of angiotensin II-induced hypertension in adult offspring

2018 ◽  
Vol 314 (5) ◽  
pp. H1061-H1069 ◽  
Author(s):  
Yu-Ping Zhang ◽  
Yan-Li Huo ◽  
Zhi-Qin Fang ◽  
Xue-Fang Wang ◽  
Jian-Dong Li ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Proinflammatory Cytokines ◽  
High Fat Diet ◽  
Control Diet ◽  
Renin Angiotensin System ◽  
Adult Offspring ◽  
Ang Ii ◽  
High Fat ◽  
Pressor Responses ◽  
The Brain

Accumulating evidence indicates that maternal high-fat diet (HFD) is associated with metabolic syndrome and cardiovascular disease in adult offspring. The present study tested the hypothesis that maternal HFD modulates the brain renin-angiotensin system (RAS), oxidative stress, and proinflammatory cytokines that alter angiotensin II (ANG II) and TNF-α actions and sensitize the ANG II-elicited hypertensive response in adult offspring. All offspring were cross fostered by dams on the same or opposite diet to yield the following four groups: offspring from normal-fat control diet-fed dams suckled by control diet-fed dams (OCC group) or by HFD-fed dams (OCH group) and offspring from HFD-fed dams fed a HFD suckled by control diet-fed dams (OHC group) or by HFD-fed dams (OHH group). RT-PCR analyses of the lamina terminalis and paraventricular nucleus indicated upregulation of mRNA expression of several RAS components, NADPH oxidase, and proinflammatory cytokines in 10-wk-old male offspring of dams fed a HFD during either pregnancy, lactation, or both (OHC, OCH, and OHH groups). These offspring also showed decreased cardiac baroreflex sensitivity and increased pressor responses to intracerebroventricular microinjection of either ANG II or TNF-α. Furthermore, chronic systemic infusion of ANG II resulted in enhanced upregulation of mRNA expression of RAS components, NADPH oxidase, and proinflammatory cytokines in the lamina terminalis and paraventricular nucleus and an augmented hypertensive response in the OHC, OCH, and OHH groups compared with the OCC group. The results suggest that maternal HFD blunts cardiac baroreflex function and enhances pressor responses to ANG II or proinflammatory cytokines through upregulation of the brain RAS, oxidative stress, and inflammation. NEW & NOTEWORTHY The results of our study indicate that a maternal high-fat diet during either pregnancy or lactation is sufficient for perinatal programming of sensitization for hypertension, which is associated with hyperreactivity of central cardiovascular nuclei that, in all likelihood, involves elevated expression of the renin-angiotensin system, NADPH oxidase, and proinflammatory cytokines. The present study demonstrates, for the first time, the central mechanism underlying maternal high-fat diet sensitization of the hypertensive response in adult offspring.

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 Effect of selective expression of dominant-negative PPARγ in pro-opiomelanocortin neurons on the control of energy balance

2016 ◽  
Vol 48 (7) ◽  
pp. 491-501 ◽  
Author(s):  
Madeliene Stump ◽  
Deng-Fu Guo ◽  
Ko-Ting Lu ◽  
Masashi Mukohda ◽  
Xuebo Liu ◽  
...  
Keyword(s):  
Body Weight ◽  
Weight Gain ◽  
Energy Balance ◽  
High Fat Diet ◽  
Control Diet ◽  
Cre Recombinase ◽  
Dominant Negative ◽  
High Fat ◽  
Pparγ Agonist ◽  
The Brain

Peroxisome proliferator-activated receptor-γ (PPARγ), a master regulator of adipogenesis, was recently shown to affect energy homeostasis through its actions in the brain. Deletion of PPARγ in mouse brain, and specifically in the pro-opiomelanocortin (POMC) neurons, results in resistance to diet-induced obesity. To study the mechanisms by which PPARγ in POMC neurons controls energy balance, we constructed a Cre-recombinase-dependent conditionally activatable transgene expressing either wild-type (WT) or dominant-negative (P467L) PPARγ and the tdTomato reporter. Inducible expression of both forms of PPARγ was validated in cells in culture, in liver of mice infected with an adenovirus expressing Cre-recombinase (AdCre), and in the brain of mice expressing Cre-recombinase either in all neurons (NESCre/PPARγ-P467L) or selectively in POMC neurons (POMCCre/PPARγ-P467L). Whereas POMCCre/PPARγ-P467L mice exhibited a normal pattern of weight gain when fed 60% high-fat diet, they exhibited increased weight gain and fat mass accumulation in response to a 10% fat isocaloric-matched control diet. POMCCre/PPARγ-P467L mice were leptin sensitive on control diet but became leptin resistant when fed 60% high-fat diet. There was no difference in body weight between POMCCre/PPARγ-WT mice and controls in response to 60% high-fat diet. However, POMCCre/PPARγ-WT, but not POMCCre/PPARγ-P467L, mice increased body weight in response to rosiglitazone, a PPARγ agonist. These observations support the concept that alterations in PPARγ-driven mechanisms in POMC neurons can play a role in the regulation of metabolic homeostasis under certain dietary conditions.

scholarly journals Blockade of angiotensin-converting enzyme or tumor necrosis factor-α reverses maternal high-fat diet-induced sensitization of angiotensin II hypertension in male rat offspring

2020 ◽  
Vol 318 (2) ◽  
pp. R351-R359 ◽  
Author(s):  
Xue-Fang Wang ◽  
Jian-Dong Li ◽  
Yan-Li Huo ◽  
Yu-Ping Zhang ◽  
Zhi-Qin Fang ◽  
...  
Keyword(s):  
High Fat Diet ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Adult Offspring ◽  
Ang Ii ◽  
Converting Enzyme ◽  
High Fat ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor

Maternal high-fat diet (HFD) is associated with metabolic syndrome and cardiovascular diseases in adult offspring. Our previous study demonstrated that maternal HFD enhances pressor responses to ANG II or a proinflammatory cytokine (PIC), which is associated with increased expression of brain renin-angiotensin system (RAS) components and PICs in adult offspring. The present study further investigated whether inhibition of angiotensin-converting enzyme (ACE) or tumor necrosis factor-α (TNF-α) blocks sensitization of ANG II hypertension in offspring of HFD dams. All offspring were bred from dams with normal fat diet (NFD) or HFD starting two weeks before mating and maintained until weaning of the offspring. Then the weaned offspring were treated with an ACE inhibitor (captopril) or a TNF-α inhibitor (pentoxifylline) in the drinking water through the end of testing with a slow-pressor dose of ANG II. RT-PCR analyses of the lamina terminalis and paraventricular nucleus revealed upregulation of mRNA expression of several RAS components and PICs in male offspring of HFD dams when compared with age-matched offspring of NFD dams. The enhanced gene expression was attenuated by blockade of either RAS or PICs. Likewise, ANG II administration produced an augmented pressor response in offspring of HFD dams. This was abolished by either ACE or TNF-α inhibitor. Taken together, this study provides mechanistic evidence and a therapeutic strategy that systemic inhibition of the RAS and PICs can block maternal HFD-induced sensitization of ANG II hypertension, which is associated with attenuation of brain RAS and PIC expression in offspring.

scholarly journals Maternal high-fat diet programs cerebrovascular remodeling in adult rat offspring

2017 ◽  
Vol 38 (11) ◽  
pp. 1954-1967 ◽  
Author(s):  
ChengCheng Lin ◽  
XiaoYun Wu ◽  
YuLei Zhou ◽  
Bei Shao ◽  
XiaoTing Niu ◽  
...  
Keyword(s):  
High Fat Diet ◽  
Maternal Diet ◽  
Control Diet ◽  
Endothelial Damage ◽  
Adult Offspring ◽  
High Fat ◽  
Adult Rat ◽  
Transmission Electron ◽  
Pregnancy And Lactation ◽  
And Function

Maternal environmental factors such as diet have consequences on later health of the offspring. We found that maternal high-fat diet (HFD) exposure renders adult offspring brain more susceptible to ischemic injury. The present study was further to investigate whether HFD consumption during rat pregnancy and lactation influences the cerebral vasculature in adult male offspring. Besides the endothelial damage observed in the transmission electron microscopy, the MCAs of offspring from fat-fed dams fed with control diet (HFD/C) also displayed increased wall thickness and media/lumen ratio, suggesting that cerebrovascular hypertrophy or hyperplasia occurs. Moreover, smaller lumen diameter and elevated myogenic tone of the MCAs over a range of intralumenal pressures indicate inward cerebrovascular remodeling in HFD/C rats, with a concomitant increase in vessel stiffness. More importantly, both wire and pressure myography demonstrated that maternal HFD intake also enhanced the MCAs contractility to ET-1, accompanied by increases in ET types A receptor (ETAR) but not B (ETBR) density in the arteries. Furthermore, ETAR antagonism but not ETBR antagonism restored maternal HFD-induced cerebrovascular dysfunction in adult offspring. Taken together, maternal diet can substantially influence adult offspring cerebrovascular health, through remodeling of both structure and function, at least partially in an ET-1 manner.

scholarly journals Maternal Angiotensin II–Induced Hypertension Sensitizes Postweaning High‐Fat Diet–Elicited Hypertensive Response Through Increased Brain Reactivity in Rat Offspring

2021 ◽  
Author(s):  
Baojian Xue ◽  
Yang Yu ◽  
Terry G. Beltz ◽  
Fang Guo ◽  
Robert B. Felder ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Mean Arterial Pressure ◽  
Arterial Pressure ◽  
Proinflammatory Cytokines ◽  
High Fat Diet ◽  
Renin Angiotensin System ◽  
Sympathetic Tone ◽  
High Fat ◽  
Angiotensin System ◽  
Induced Hypertension

Background Prenatal and postnatal insults can induce a physiological state that leaves offspring later in life vulnerable to subsequent challenges (stressors) eliciting cardiometabolic diseases including hypertension. In this study, we investigated whether maternal angiotensin II–induced hypertension in rats sensitizes postweaning high‐fat diet (HFD)‐elicited hypertensive response and whether this is associated with autonomic dysfunction and altered central mechanisms controlling sympathetic tone in offspring. Methods and Results When eating a low‐lard‐fat diet, basal mean arterial pressure of male offspring of normotensive or hypertensive dams were comparable. However, HFD feeding significantly increased mean arterial pressure in offspring of normotensive and hypertensive dams, but the elevated mean arterial pressure induced by HFD was greater in offspring of hypertensive dams, which was accompanied by greater sympathetic tone and enhanced pressor responses to centrally administrated angiotensin II or leptin. HFD feeding also produced comparable elevations in cardiac sympathetic activity and plasma levels of angiotensin II, interleukin‐6, and leptin in offspring of normotensive and hypertensive dams. Reverse transcriptase polymerase chain reaction analyses in key forebrain regions implicated in the control of sympathetic tone and blood pressure indicated that HFD feeding led to greater increases in mRNA expression of leptin, several components of the renin‐angiotensin system and proinflammatory cytokines in offspring of hypertensive dams when compared with offspring of normotensive dams. Conclusions The results indicate that maternal hypertension sensitized male adult offspring to HFD‐induced hypertension. Increased expression of renin‐angiotensin system components and proinflammatory cytokines, elevated brain reactivity to pressor stimuli, and augmented sympathetic drive to the cardiovascular system likely contributed.

Abstract 082: Chronic Angiotensin-(1-7) Attenuates the Development of Obesity in Mice by Enhancing Energy Expenditure

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Amy C Arnold ◽  
Charlene Finney ◽  
Italo Biaggioni
Keyword(s):  
Insulin Resistance ◽  
Oxygen Consumption ◽  
Energy Expenditure ◽  
Water Intake ◽  
High Fat Diet ◽  
Renin Angiotensin System ◽  
Ang Ii ◽  
High Fat ◽  
Angiotensin System ◽  
Obesity In Mice

Activation of the renin-angiotensin system, and in particular angiotensin (Ang) II, is observed in obese patients and closely correlates with insulin resistance. Obesity is also associated with deficiency of Ang-(1-7), a vasodilatory peptide that mitigates Ang II actions. Accumulating evidence suggests that Ang-(1-7) has direct positive metabolic effects including reducing adiposity and reversing whole-body glucose intolerance and insulin resistance in animal models of cardiometabolic syndrome. In this study, we tested the hypothesis that chronic Ang-(1-7) administration would prevent high fat diet-induced obesity in mice, and determined potential mechanisms underlying this effect. To test this hypothesis, adult male C57BL/6J mice received a 12-week systemic infusion of Ang-(1-7) (400 ng/kg/min; n=7) or saline (n=6) via subcutaneous osmotic mini-pumps. Immediately following mini-pump implantation, mice were placed on a 60% high fat diet, with body mass measured weekly. Body composition (mq10 nuclear magnetic resonance analyzer), food and water intake, and energy expenditure (indirect calorimetry) were measured during the last week of treatment. Ang-(1-7) attenuated high fat diet-induced weight gain [39.7±1.3 Ang-(1-7) vs. 43.9±0.7 g saline at 12 weeks; p=0.023) and adiposity [32±1 Ang-(1-7) vs. 29±1% saline; p=0.050). The reduced gain in body weight following Ang-(1-7) was associated with increased average energy expenditure [0.55±0.02 Ang-(1-7) vs. 0.42±0.06 kcal/hour saline, p=0.038] and oxygen consumption [1.84±0.07 Ang-(1-7) vs. 1.39±0.23 ml/min saline, p=0.049] during the dark cycle, with no effect on locomotor activity. A similar trend for Ang-(1-7) to increase energy expenditure and oxygen consumption was observed during the light cycle. There were no significant differences in food or water intake following chronic Ang-(1-7) versus saline infusion. These findings suggest that targeting of Ang-(1-7) may be a novel strategy to prevent the development of obesity by enhancing energy expenditure, and further highlight the importance of the renin-angiotensin system in metabolic regulation.

Sympathoexcitatory and pressor responses to increased brain sodium and ouabain are mediated via brain ANG II

1996 ◽  
Vol 270 (1) ◽  
pp. H275-H280 ◽  
Author(s):  
B. S. Huang ◽  
F. H. Leenen
Keyword(s):  
Pressor Response ◽  
Renin Angiotensin System ◽  
Sodium Concentration ◽  
Ang Ii ◽  
Angiotensin System ◽  
Renal Sympathetic Nerve Activity ◽  
Fab Fragments ◽  
Pressor Responses ◽  
Before And After ◽  
The Brain

Intracerebroventricular administration of hypertonic saline, ouabain, brain ouabainlike activity (OLA), or angiotensin II (ANG II) causes sympathoexcitatory and pressor effects in rats. To clarify the possible interaction between increased brain sodium, brain OLA, and the brain renin-angiotensin system (RAS), increases in mean arterial pressure, heart rate (HR), and renal sympathetic nerve activity (RSNA) in response to intracerebroventricular 0.3 M NaCl, ouabain, and ANG II were recorded in conscious Wistar rats before and after intracerebroventricular pretreatment with the angiotensin-receptor (AT1) blocker losartan, antibody Fab fragments (Digibind), or, as control, gamma-globulins. These Fab fragments bind ouabain and brain OLA with high affinity. The arginine vasopressin (AVP) antagonist [d(CH2)5Tyr(Me)]AVP (30 micrograms/ kg) was injected intravenously before each intracerebroventricular injection. Intracerebroventricularly administered 0.3 M NaCl (3.8 mul/min for 10 min), ouabain (0.3 and 0.6 microgram), and ANG II (10 and 30 ng) caused similar pressor responses. However, the extent of HR and RSNA responses to ANG II was smaller than those to 0.3 M NaCl and ouabain. Intracerebroventricular losartan (10 and 20 micrograms) blocked responses to ANG II and 0.3 M NaCl and significantly attenuated the responses to ouabain (pressor response by 50-70%; RSNA and HR by 60-80%). In contrast, intracerebroventricular Fab fragments (66 micrograms) blocked only the responses to 0.3 M NaCl and ouabain and did not affect the responses to ANG II. These results suggest that an acute rise in brain sodium concentration increases brain OLA and the latter exerts its sympathoexcitatory and pressor effects at least partly via activation of the brain RAS.

scholarly journals Leptin and Melanocortin Signaling Mediates Hypertension in Offspring From Female Rabbits Fed a High-Fat Diet During Gestation and Lactation

2021 ◽  
Vol 12 ◽  
Author(s):  
Kyungjoon Lim ◽  
Sandra L. Burke ◽  
Francine Z. Marques ◽  
Kristy L. Jackson ◽  
Cindy Gueguen ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
High Fat Diet ◽  
Leptin Receptor ◽  
Control Diet ◽  
Ventromedial Hypothalamus ◽  
Melanocortin Receptor ◽  
Residual Body ◽  
Adult Offspring ◽  
High Fat ◽  
Melanocyte Stimulating Hormone

Maternal high-fat diet in rabbits leads to hypertension and elevated renal sympathetic nerve activity (RSNA) in adult offspring but whether this is due to adiposity or maternal programming is unclear. We gave intracerebroventricular (ICV) and ventromedial hypothalamus (VMH) administration of leptin-receptor antagonist, α-melanocyte-stimulating hormone (αMSH), melanocortin-receptor antagonist (SHU9119), or insulin-receptor (InsR) antagonist to conscious adult offspring from mothers fed a high-fat diet (mHFD), control diet (mCD), or mCD offspring fed HFD for 10d (mCD10d, to deposit equivalent fat but not during development). mHFD and mCD10d rabbits had higher mean arterial pressure (MAP, +6.4 mmHg, +12.1 mmHg, p < 0.001) and RSNA (+2.3 nu, +3.2 nu, p < 0.01) than mCD, but all had similar plasma leptin. VMH leptin-receptor antagonist reduced MAP (−8.0 ± 3.0 mmHg, p < 0.001) in mCD10d but not in mHFD or mCD group. Intracerebroventricular leptin-receptor antagonist reduced MAP only in mHFD rabbits (p < 0.05). Intracerebroventricular SHU9119 reduced MAP and RSNA in mHFD but only reduced MAP in the mCD10d group. VMH αMSH increased RSNA (+85%, p < 0.001) in mHFD rabbits but ICV αMSH increased RSNA in both mHFD and mCD10d rabbits (+45%, +51%, respectively, p < 0.001). The InsR antagonist had no effect by either route on MAP or RSNA. Hypothalamic leptin receptor and brain-derived neurotrophic factor (BDNF) mRNA were greater in mHFD compared with mCD rabbits and mCD10d rabbits. In conclusion, the higher MAP in mHFD and mCD10d offspring was likely due to greater central leptin signaling at distinct sites within the hypothalamus while enhanced melanocortin contribution was common to both groups suggesting that residual body fat was mainly responsible. However, the effects of SHU9119 and αMSH on RSNA pathways only in mHFD suggest a maternal HFD may program sympatho-excitatory capacity in these offspring and that this may involve increased leptin receptor and BDNF expression.

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