ACE2 activation by xanthenone prevents leptin-induced increases in blood pressure and proteinuria during pregnancy in Sprague-Dawley rats

Ibrahim, Hisham; Froemming, Gabriele Ruth Anisah; Omar, Effat; Singh, Harbindar Jeet Singh Gurcharan

doi:10.1016/j.reprotox.2014.08.006

Cited by 28 publications

(13 citation statements)

References 63 publications

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“…The choice of the dose of leptin was based on our previous studies investigating the effect of leptin on blood pressure, blood pressure and proteinuria during pregnancy, and on sperm parameters in the rat, where it was found to show significant adverse effects but little effect on body weight. [11][12][13] The duration of treatment was based on the N-Methyl-N'-Nitro-N-Nitrosoguanidine (MNNG) model of gastric adenocarcinoma. 14 Rats were fasted for 24 h before they were euthanized at 40 weeks.…”

Section: Experimental Animals and Groupingmentioning

confidence: 99%

Leptin induces the expression of tumorigenic genes in the gastric mucosa of male Sprague-Dawley rats

Isyraqiah

Kutty

Durairajanayagam

et al. 2018

Exp Biol Med (Maywood)

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Leptin promotes the growth of gastric cancer cells in vitro. It is, however, unknown if leptin induces gastric cancer in vivo. This study therefore investigated the effect of leptin on the histology and expression of tumorigenic genes in the stomach of rats following 40 weeks of leptin treatment. Male Sprague-Dawley rats, aged 6 weeks, were randomized into control and experimental groups ( n = 8 per group). The experimental group was given intraperitoneal injections of leptin (60 µg/kg/day) once daily for 40 weeks, whereas the control group received intraperitoneal injection of an equal volume of normal saline daily. Rats were housed in polypropylene cages for the duration of the study. Body weight was measured weekly. Upon completion of treatment, rats were euthanized and their stomachs were collected for histopathological examination, microarray, and RT-qPCR. Data were analyzed using one-way ANOVA and Fisher’s exact test. On histology, one rat (12.5%) in the leptin-treated group had a large red-colored tumor nodule at the pyloric antrum of the stomach. Microscopically, stomachs of two leptin-treated rats (25%) showed hyperplasia or dysplasia. Microarray analysis revealed significant upregulation of a number of genes in the stomachs of leptin-treated rats that have been shown to be associated with tumorigenesis in other tissues, including Furin (protein maturation), Eef1a1 and Eif4g2 (translation factors), Tmed2 (vesicular trafficking), Rab7a (plasma membrane trafficking), Rfwd2 (protein degradation), Fth1 and Ftl1 (oxygen transport), Tspan8, Tspan1, Fxyd3, and Rack1 (cell migration), Pde4d (signal transduction), Nupr1 and Ybx1 (transcription factors), Ptma and Tmem134 (oncogenes), Srsf2 (mRNA maturation), and Reep5 (cell proliferation). None of the known oncogenes were, however, significantly up-regulated. In conclusion, although the overall effect of leptin on gastric carcinogenesis seems inconclusive, the findings of dysplasia and the up-regulation of some of the cancer-related genes nevertheless warrant further scrutiny on the role of leptin in gastric cancer. Impact statement Gastric cancer is the third most common cause of death due to cancer in the world. Obese individuals are at risk of developing gastric cancer, and the reason for this is unknown. Serum leptin levels are high in obese individuals and leptin is known to induce proliferation of gastric cancer cells in vitro. However, to date, no reports exist on the tumorigenic effects of leptin on the stomach in vivo. This study therefore determines if chronic leptin administration induces gastric carcinogenesis in non-obese rats, which might serve as a useful animal model for future studies. Although the findings are somewhat inconclusive, to our knowledge, however, this is the first study to show the up-regulation of numerous potential driver genes that highlight the potential role of leptin in the higher prevalence of gastric cancer among obese individuals. The findings certainly necessitate further scrutiny of leptin gastric cancer.

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Section: Experimental Animals and Groupingmentioning

confidence: 99%

Leptin induces the expression of tumorigenic genes in the gastric mucosa of male Sprague-Dawley rats

Isyraqiah

Kutty

Durairajanayagam

et al. 2018

Exp Biol Med (Maywood)

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“…Adipose tissue produce the proinflammatory adipokine leptin. A reduction in ACE2 is associated with more ATII and also with higher leptin levels [ 15 ]. Leptin regulates the normal development of hematopoiesis, angiogenesis, and innate and adaptive immunity [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

Leptin levels in SARS-CoV-2 infection related respiratory failure: A cross-sectional study and a pathophysiological framework on the role of fat tissue

Voort

Moser

Zandstra

et al. 2020

Heliyon

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Obesity is a risk factor for SARS-CoV-2 infected patients to develop respiratory failure. Leptin produced in visceral fat might play a role in the deterioration to mechanical ventilation. A cross sectional study was performed. The mean BMI was 31 kg/m 2 (range 24.8–48.4) for the 31 SARS-CoV-2 ventilated patients and 26 kg/m 2 (range 22.4–33.5) for 8 critically ill non-infected control patients. SARS-CoV-2 infected patients with a similar BMI as control patients appear to have significantly higher levels of serum leptin. The mean leptin level was 21.2 (6.0–85.2) vs 5.6 (2.4–8.2) ug/L for SARS-CoV-2 and controls respectively (p = 0.0007). With these findings we describe a clinical and biological framework that may explain these clinical observations. The ACE2 utilization by the virus leads to local pulmonary inflammation due to ACE2-ATII disbalance. This might be enhanced by an increase in leptin production induced by SARS-CoV-2 infection of visceral fat. Leptin receptors in the lungs are now more activated to enhance local pulmonary inflammation. This adds to the pre-existent chronic inflammation in obese patients. Visceral fat, lung tissue and leptin production play an interconnecting role. This insight can lead the way to further research and treatment.

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“…Although adipocytes also produce many other adipokines, studies suggest that leptin may be an important link between obesity and obesity-related diseases. In this regard, leptin administration has been shown to increase blood pressure in pregnant and nonpregnant female rats, increase urinary protein excretion, interfere with glucose metabolism, and activate endothelial cells 8687. When administered to nonobese male rats, leptin decreases sperm count and increases sperm abnormalities.…”

Section: Discussionmentioning

confidence: 99%

Leptin and its actions on reproduction in males

2019

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Leptin, an adipocyte-derived hormone, serves numerous physiological functions in the body, particularly during puberty and reproduction. The exact mechanism by which leptin activates the gonadotropin-releasing hormone (GnRH) neurons to trigger puberty and reproduction remains unclear. Given the widespread distribution of leptin receptors in the body, both central and peripheral mechanisms involving the hypothalamic-pituitary-gonadal axis have been hypothesized. Leptin is necessary for normal reproductive function, but when present in excess, it can have detrimental effects on the male reproductive system. Human and animal studies point to leptin as a link between infertility and obesity, a suggestion that is corroborated by findings of low sperm count, increased sperm abnormalities, oxidative stress, and increased leptin levels in obese men. In addition, daily leptin administration to normal-weight rats has been shown to result in similar abnormalities in sperm parameters. The major pathways causing these abnormalities remain unidentified; however, these adverse effects have been attributed to leptin-induced increased oxidative stress because they are prevented by concurrently administering melatonin. Studies on leptin and its impact on sperm function are highly relevant in understanding and managing male infertility, particularly in overweight and obese men.

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ACE2 activation by xanthenone prevents leptin-induced increases in blood pressure and proteinuria during pregnancy in Sprague-Dawley rats

Cited by 28 publications

References 63 publications

Leptin induces the expression of tumorigenic genes in the gastric mucosa of male Sprague-Dawley rats

Leptin induces the expression of tumorigenic genes in the gastric mucosa of male Sprague-Dawley rats

Leptin levels in SARS-CoV-2 infection related respiratory failure: A cross-sectional study and a pathophysiological framework on the role of fat tissue

Leptin and its actions on reproduction in males

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