Uncoupling the mechanisms of obesity and hypertension by targeting hypothalamic IKK-β and NF-κB

Purkayastha, Sudarshana; Guo, Zhen; Cai, Dongsheng

doi:10.1038/nm.2372

Cited by 210 publications

(254 citation statements)

References 40 publications

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“…Overnutritionrelated metabolic inflammation in the hypothalamus, specifically in the POMC neurons, was found to be associated with the development of hypertension in obese mice (Purkayastha et al, 2011). In this study, the signal transducing genes HCRTR1, OR4C45, and RXFP2, involved in neuroactive ligand-receptor interaction in the hypothalamus, were found to undergo polymorphisms, affecting the regulation of food intake (Kong et al, 2010;Flores et al, 2013).…”

Section: Family the Expression Of Variants Of Genes Identified By Gwmentioning

confidence: 61%

Exome sequencing in Thai patients with familial obesity

et al. 2016

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Section: Family the Expression Of Variants Of Genes Identified By Gwmentioning

confidence: 61%

Exome sequencing in Thai patients with familial obesity

et al. 2016

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“…37 Furthermore, overnutrition evokes activation of the IKKβ/NF-κB pathway in the hypothalamus leading to inflammation and the disruption of central insulin and leptin signaling, thus resulting in impaired central nervous system's control of food intake and promoting body weight gain. 38,39 Consequently, inhibition of IKKβ activation was also identified as a potential therapeutic target to reverse inflammation in obesity-associated type 2 diabetes. 40 Meanwhile, some rare homozygous null mutations in IKBKB have been reported in patients with severe combined immunodeficiency, which result in IKKβ loss of expression and therefore impairment of immune activation.…”

Section: Discussionmentioning

confidence: 99%

Rare variant associations with waist-to-hip ratio in European-American and African-American women from the NHLBI-Exome Sequencing Project

et al. 2016

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Waist-to-hip ratio (WHR), a relative comparison of waist and hip circumferences, is an easily accessible measurement of body fat distribution, in particular central abdominal fat. A high WHR indicates more intra-abdominal fat deposition and is an established risk factor for cardiovascular disease and type 2 diabetes. Recent genome-wide association studies have identified numerous common genetic loci influencing WHR, but the contributions of rare variants have not been previously reported. We investigated rare variant associations with WHR in 1510 European-American and 1186 African-American women from the National Heart, Lung, and Blood Institute-Exome Sequencing Project. Association analysis was performed on the gene level using several rare variant association methods. The strongest association was observed for rare variants in IKBKB (P = 4.0 × 10 − 8 ) in EuropeanAmericans, where rare variants in this gene are predicted to decrease WHRs. The activation of the IKBKB gene is involved in inflammatory processes and insulin resistance, which may affect normal food intake and body weight and shape. Meanwhile, aggregation of rare variants in COBLL1, previously found to harbor common variants associated with WHR and fasting insulin, were nominally associated (P = 2.23 × 10 − 4 ) with higher WHR in European-Americans. However, these significant results are not shared between African-Americans and European-Americans that may be due to differences in the allelic architecture of the two populations and the small sample sizes. Our study indicates that the combined effect of rare variants contribute to the interindividual variation in fat distribution through the regulation of insulin response.

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“…NF-κB activation within the vascular endothelium drives hypertensive renal damage without measurable effects on blood pressure suggesting a direct role in end-organ damage (68). Within cardiovascular control centers in the brain, NF-κB activation potently enhances sympathetic outflow (69)(70)(71), which could potentially promote sodium retention in the kidney via stimulation of renal sympathetic nerves. Within kidney parenchymal cells, induction of oxidative stress leads to NF-κB nuclear translocation, impaired sodium excretion, and blood pressure elevation by disrupting D1 dopamine receptor function (72).…”

Section: Immune Mechanisms In Hypertensionmentioning

confidence: 99%

The inextricable role of the kidney in hypertension

Coffman¹

2014

J. Clin. Invest.

139

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An essential link between the kidney and blood pressure control has long been known. Here, we review evidence supporting the premise that an impaired capacity of the kidney to excrete sodium in response to elevated blood pressure is a major contributor to hypertension, irrespective of the initiating cause. In this regard, recent work suggests that novel pathways controlling key sodium transporters in kidney epithelia have a critical impact on hypertension pathogenesis, supporting a model in which impaired renal sodium excretion is a final common pathway through which vascular, neural, and inflammatory responses raise blood pressure. We also address recent findings calling into question long-standing notions regarding the relationship between sodium intake and changes in body fluid volume. Expanded understanding of the role of the kidney as both a cause and target of hypertension highlights key aspects of pathophysiology and may lead to identification of new strategies for prevention and treatment. IntroductionHypertension is one of the most common chronic diseases of humankind, affecting more than 1 billion people worldwide (1). Although elevated blood pressure per se does not typically cause overt symptoms, the consequences of chronic hypertension, including cardiac hypertrophy, heart failure, stroke, and kidney disease, are responsible for substantial morbidity and mortality (2). Treatments that effectively reduce blood pressure can prevent these complications (2-4). However, in a recent analysis of data from the National Health and Nutrition Examination Survey (NHANES) covering the period from 2009 to 2010, blood pressures were reduced to target levels in less than 50% of patients receiving hypertension treatment, and this rate was under 40% in individuals who also had chronic kidney disease (CKD) (5). The reasons for these poor outcomes are complex and include health services issues around processes of care, compliance, and patient education. Moreover, the precise cause of hypertension is not apparent in the vast majority of patients with hypertension. Limitations in our understanding of hypertension pathogenesis in individual patients are an obstacle to applying individualized approaches for prevention and treatment and to identifying new, specific therapies.

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Uncoupling the mechanisms of obesity and hypertension by targeting hypothalamic IKK-β and NF-κB

Cited by 210 publications

References 40 publications

Exome sequencing in Thai patients with familial obesity

Exome sequencing in Thai patients with familial obesity

Rare variant associations with waist-to-hip ratio in European-American and African-American women from the NHLBI-Exome Sequencing Project

The inextricable role of the kidney in hypertension

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