Adipocyte-specific deficiency of angiotensinogen decreases plasma angiotensinogen concentration and systolic blood pressure in mice

Yiannikouris, Frédérique; Karounos, Michael; Charnigo, Richard; English, Victoria; Rateri, Debra L.; Daugherty, Alan; Cassis, Lisa A.

doi:10.1152/ajpregu.00323.2011

Cited by 91 publications

(89 citation statements)

References 36 publications

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“…Frozen sections were stained with ORO (Sigma-Aldrich) for lipid deposition using standard methods. Adipocyte size was measured as described previously 38 . Briefly, sections of epididymal adipose tissue from each mouse were photographed under ×100 magnification.…”

Section: Methodsmentioning

confidence: 99%

An obligatory role for neurotensin in high-fat-diet-induced obesity

Song

Zaytseva

et al. 2016

Nature

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227

237

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Obesity and its associated comorbidities (e.g., diabetes mellitus and hepatic steatosis) contribute to approximately 2.5 million deaths annually1 and are among the most prevalent and challenging conditions confronting the medical profession2,3. Neurotensin (NT), a 13-amino acid peptide predominantly localized in specialized enteroendocrine (EE) cells of the small bowel4 and released by fat ingestion5, facilitates fatty acid (FA) translocation in rat intestine6, and stimulates growth of various cancers7; the effects of NT are mediated through three known NT receptors (NTR1, 2 and 3)8. Increased fasting plasma levels of pro-NT (a stable NT precursor fragment produced in equimolar amounts relative to NT) are associated with increased risk of diabetes, cardiovascular disease and mortality9; however, a role for NT as a causative factor in these diseases is unknown. Here, we show that NT-deficient mice demonstrate significantly reduced intestinal fat absorption and are protected from obesity, hepatic steatosis and insulin resistance associated with high fat consumption. We further demonstrate that NT attenuates the activation of AMP-activated protein kinase (AMPK) and stimulates FA absorption in mice and in cultured intestinal cells, and that this occurs through a mechanism involving NTR1 and NTR3/sortilin. Consistent with the findings in mice, expression of NT in Drosophila midgut EE cells results in increased lipid accumulation in the midgut, fat body, and oenocytes (specialized hepatocyte-like cells) and decreased AMPK activation. Remarkably, in humans, we show that both obese and insulin-resistant subjects have elevated plasma concentrations of pro-NT, and in longitudinal studies among non-obese subjects, high levels of pro-NT denote a doubling of the risk of developing obesity later in life. Our findings directly link NT with increased fat absorption and obesity and suggest that NT may provide a prognostic marker of future obesity and a potential target for prevention and treatment.

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Section: Methodsmentioning

confidence: 99%

An obligatory role for neurotensin in high-fat-diet-induced obesity

Song

Zaytseva

et al. 2016

Nature

Self Cite

227

237

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“…By contrast, in WT mice, the transgenic overexpression of adipocyte Agt not only increased circulating Agt concentration but also increased BP. By contrast, mice with deleted adipocyte Agt had a lower BP than their WT counterparts (Yiannikouris et al 2012a). Not surprisingly, Agt mRNA expression levels were higher in visceral adipose tissue of Sprague-Dawley rats with dietinduced obesity and hypertension (Boustany et al 2004).…”

Section: Renin-angiotensin Systemmentioning

confidence: 96%

Obesity-related hypertension: possible pathophysiological mechanisms

Vaněčková¹,

Maletı́nská²,

Behuliak³

et al. 2014

Journal of Endocrinology

129

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Hypertension is one of the major risk factors of cardiovascular diseases, but despite a century of clinical and basic research, the discrete etiology of this disease is still not fully understood. The same is true for obesity, which is recognized as a major global epidemic health problem nowadays. Obesity is associated with an increasing prevalence of the metabolic syndrome, a cluster of risk factors including hypertension, abdominal obesity, dyslipidemia, and hyperglycemia. Epidemiological studies have shown that excess weight gain predicts future development of hypertension, and the relationship between BMI and blood pressure (BP) appears to be almost linear in different populations. There is no doubt that obesity-related hypertension is a multifactorial and polygenic trait, and multiple potential pathogenetic mechanisms probably contribute to the development of higher BP in obese humans. These include hyperinsulinemia, activation of the renin-angiotensin-aldosterone system, sympathetic nervous system stimulation, abnormal levels of certain adipokines such as leptin, or cytokines acting at the vascular endothelial level. Moreover, some genetic and epigenetic mechanisms are also in play. Although the full manifestation of both hypertension and obesity occurs predominantly in adulthood, their roots can be traced back to early ontogeny. The detailed knowledge of alterations occurring in the organism of experimental animals during particular critical periods (developmental windows) could help to solve this phenomenon in humans and might facilitate the age-specific prevention of human obesity-related hypertension. In addition, better understanding of particular pathophysiological mechanisms might be useful in so-called personalized medicine. Key Words" obesity " hypertension " sympathetic nervous system " renin-angiotensin system " critical developmental periods " epigenetics " rat

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“…Targeting the intracellular renin-angiotensin system achieved beneficial effect on cardiac protection in type1 diabetes mellitus and hyperglycemia-induced cardiac dysfunction (Kumar et al 2012). Taken together, with the elevated gene expression of angiotensinogen by hyperglycemia, existence of intracellular angiotensin system in various tissues, expansion of adipose tissue and elevated blood pressure of animals with obesity and T2D (Su et al 2008, Yiannikouris et al 2012, we expect that failure of suppression of angiotensinogen for the production of Ang II by insulin resistance may have a significant impact 233:3 on the development of hypertension and associated cardiovascular dysfunction in humans.…”

Section: Crosstalk Between Insulin Signaling and Renin-angiotensin Symentioning

confidence: 98%

“…Angiotensinogen is largely expressed in the liver and in the adipose tissue particularly in obese populations (Yiannikouris et al 2012). The components of renin-angiotensin signaling are also minimally expressed in the heart and enhanced by hyperglycemia, which promotes myocardial death and diabetic cardiomyopathy (Singh et al 2008).…”

Section: Crosstalk Between Insulin Signaling and Renin-angiotensin Symentioning

confidence: 99%

Insulin receptor substrate signaling controls cardiac energy metabolism and heart failure

Guo

2017

Journal of Endocrinology

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The heart is an insulin-dependent and energy-consuming organ in which insulin and nutritional signaling integrates to the regulation of cardiac metabolism, growth and survival. Heart failure is highly associated with insulin resistance, and heart failure patients suffer from the cardiac energy deficiency and structural and functional dysfunction. Chronic pathological conditions, such as obesity and type 2 diabetes mellitus, involve various mechanisms in promoting heart failure by remodeling metabolic pathways, modulating cardiac energetics and impairing cardiac contractility. Recent studies demonstrated that insulin receptor substrates 1 and 2 (IRS-1,-2) are major mediators of both insulin and insulin-like growth factor-1 (IGF-1) signaling responsible for myocardial energetics, structure, function and organismal survival. Importantly, the insulin receptor substrates (IRS) play an important role in the activation of the phosphatidylinositide-3-dependent kinase (PI-3K) that controls Akt and Foxo1 signaling cascade, regulating the mitochondrial function, cardiac energy metabolism and the renin-angiotensin system. Dysregulation of this branch in signaling cascades by insulin resistance in the heart through the endocrine system promotes heart failure, providing a novel mechanism for diabetic cardiomyopathy. Therefore, targeting this branch of IRS→PI-3K→Foxo1 signaling cascade and associated pathways may provide a fundamental strategy for the therapeutic and nutritional development in control of metabolic and cardiovascular diseases. In this review, we focus on insulin signaling and resistance in the heart and the role energetics play in cardiac metabolism, structure and function.

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Adipocyte-specific deficiency of angiotensinogen decreases plasma angiotensinogen concentration and systolic blood pressure in mice

Cited by 91 publications

References 36 publications

An obligatory role for neurotensin in high-fat-diet-induced obesity

An obligatory role for neurotensin in high-fat-diet-induced obesity

Obesity-related hypertension: possible pathophysiological mechanisms

Insulin receptor substrate signaling controls cardiac energy metabolism and heart failure

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