Impairments in the intrinsic contractility of mesenteric collecting lymphatics in a rat model of metabolic syndrome

Numerous studies on metabolic syndrome (MetSyn), a cluster of metabolic abnormalities, have demonstrated its profound impact on cardiovascular and blood microvascular health; however, the effects of MetSyn on lymphatic function are not well understood. We hypothesized that MetSyn would modulate lymphatic muscle activity and alter muscularized lymphatic function similar to the impairment of blood vessel function associated with MetSyn, particularly given the direct proximity of the lymphatics to the chronically inflamed adipose depots. To test this hypothesis, rats were placed on a high-fructose diet (60%) for 7 wk, and their progression to MetSyn was assessed through serum insulin and triglyceride levels in addition to the expression of metabolic and inflammatory genes in the liver. Mesenteric lymphatic vessels were isolated and subjected to different transmural pressures while lymphatic pumping and contractile parameters were evaluated. Lymphatics from MetSyn rats had significant negative chronotropic effects at all pressures that effectively reduced the intrinsic flow-generating capacity of these vessels by ∼50%. Furthermore, lymphatics were remodeled to a significantly smaller diameter in the animals with MetSyn. Wire myograph experiments demonstrated that permeabilized lymphatics from the MetSyn group exhibited a significant decrease in force generation and were less sensitive to Ca2+, although there were no significant changes in lymphatic muscle cell coverage or morphology. Thus, our data provide the first evidence that MetSyn induces a remodeling of collecting lymphatics, thereby effectively reducing their potential load capabilities and impairing the intrinsic contractility required for proper lymph flow.

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Roles of sarcoplasmic reticulum Ca2+ ATPase pump in the impairments of lymphatic contractile activity in a metabolic syndrome rat model

10.1101/2020.01.14.906503 ◽

2020 ◽

Author(s):

Yang Lee ◽

Sanjukta Chakraborty ◽

Mariappan Muthuchamy

Keyword(s):

Metabolic Syndrome ◽

Sarcoplasmic Reticulum ◽

Molecular Mechanisms ◽

Contractile Activity ◽

Lymphatic Vessels ◽

Insulin Resistant ◽

High Fructose ◽

Serca Pump ◽

Lymphatic Pumping ◽

Pumping Activity

AbstractThe intrinsic lymphatic contractile activity is necessary for proper lymph transport. Mesenteric lymphatic vessels from high-fructose diet-induced metabolic syndrome (MetSyn) rats exhibited impairments in its intrinsic phasic contractile activity; however, the molecular mechanisms responsible for the weaker lymphatic pumping activity in MetSyn conditions are unknown. Several metabolic disease models have shown that dysregulation of sarcoplasmic reticulum Ca2+ ATPase (SERCA) pump is one of the key determinants of the phenotypes seen in various muscle tissues. Hence, we hypothesized that a decrease in SERCA pump expression and/or activity in lymphatic muscle influences the diminished lymphatic vessel contractions in MetSyn animals. Results demonstrated that SERCA inhibitor, thapsigargin, significantly reduced lymphatic phasic contractile frequency and amplitude in control vessels, whereas, the reduced MetSyn lymphatic contractile activity was not further diminished by thapsigargin. While SERCA2a expression was significantly decreased in MetSyn lymphatic vessels, myosin light chain 20, MLC20 phosphorylation was increased in these vessels. Additionally, insulin resistant lymphatic muscle cells exhibited elevated intracellular calcium and decreased SERCA2a expression and activity. The SERCA activator, CDN 1163 increased phasic contractile frequency in the vessels from MetSyn, thereby, partially restored lymph flow. Thus, our data provide the first evidence that SERCA2a modulates the lymphatic pumping activity by regulating phasic contractile amplitude and frequency, but not the lymphatic tone. Diminished lymphatic contractile activity in the vessels from the MetSyn animal is associated with the decreased SERCA2a expression and impaired SERCA2 activity in lymphatic muscle.

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Modulation of lymphatic muscle contractility by the neuropeptide substance P

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01029.2007 ◽

2008 ◽

Vol 295 (2) ◽

pp. H587-H597 ◽

Cited By ~ 55

Author(s):

Michael J. Davis ◽

Megan M. Lane ◽

Ann M. Davis ◽

David Durtschi ◽

David C. Zawieja ◽

...

Keyword(s):

Substance P ◽

Capillary Permeability ◽

Lymphatic Vessels ◽

Sensory Innervation ◽

Pump Efficiency ◽

Lymphatic Function ◽

Low Concentrations ◽

Chronotropic Effects ◽

Spontaneous Contractions ◽

Lymphatic Pumping

Substance P (SP) is a neuropeptide associated with sensory innervation of lymphoid tissue and a suspected modulator of lymphatic function in inflammation. Only a few studies have examined the effects of SP on lymphatic contraction, and it is not clear to what extent SP acts directly on the lymphatic muscle and/or endothelium or indirectly through changes in intraluminal filling pressure secondary to increases in capillary permeability/filtration. We tested the effects of SP on the spontaneous contractions of rat isolated mesenteric lymphatic vessels under isometric and isobaric conditions, hypothesizing that low concentrations would stimulate lymphatic pumping by enhancing lymphatic muscle contraction in a manner complementary to the effect of increased preload. Under isometric conditions, SP (10 nM) dramatically enhanced lymphatic chronotropy and inotropy. Unlike guinea pig lymphatics, SP actions were not blocked by cyclooxygenase or PLA2inhibition. In the absence of SP, ramp increases in isometric preload resulted in ×∼1.6 increases in contraction amplitude (Amp) and ×∼1.7 increases in frequency (Freq). SP increased Freq by ×∼2.4, Amp by ×∼1.9, and the Amp-Freq product (AFP) by ×∼3.5. Under isobaric conditions, the pressure elevation from 0.5 to 10 cmH2O in the absence of SP decreased Amp by ×∼0.6 and increased Freq by ×∼1.8. SP caused a modest increase in Amp, a robust increase in Freq at all pressures, and shifted the AFP-pressure relationship upward and leftward. Therefore, SP has substantial positive inotropic and chronotropic effects on rat lymphatic muscle, improving pump efficiency independent of the effects of preload and broadening of the working range of the lymphatic pump.

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Amelioration of High Fructose Diet-Induced Insulin Resistance, Hyperuricemia, and Liver Oxidative Stress by Combined Use of Selective Agonists of PPAR-α and PPAR-γ in Rats

Dubai Medical Journal ◽

10.1159/000506899 ◽

2020 ◽

Vol 3 (2) ◽

pp. 76-86

Author(s):

Mahmoud M. Farag ◽

Ehab H. Ashour ◽

Wessam F. El-Hadidy

Keyword(s):

Oxidative Stress ◽

Metabolic Syndrome ◽

Serum Insulin ◽

Combined Treatment ◽

Vehicle Group ◽

Control Group ◽

Peroxisome Proliferator ◽

Ppar Γ ◽

The Metabolic Syndrome ◽

High Fructose

Background: The use of high-fructose (Fr) corn sweeteners and sucrose in manufactured food has markedly increased recently. This excessive Fr intake has been proposed in the etiology of the metabolic syndrome, which shows an increasing prevalence throughout the world. Objective: In this study, we questioned whether fenofibrate (FF), a peroxisome proliferator-activated receptor (PPAR)-α agonist, and pioglitazone (PG), a PPAR-γ agonist, might be effective in ameliorating the metabolic syndrome in a rat model. Materials and Methods: The metabolic syndrome was induced by feeding rats a high-Fr (60%) diet for 10 weeks. The rats were divided into 5 groups: control group, fed a normal rat chow; Fr + vehicle group; Fr + FF group; Fr + PG group; and Fr + (FF + PG) group (treated with both drugs). Drug or vehicle treatment was given daily for 6 weeks (from weeks 5 to 10). Thereafter, blood and liver samples were obtained for biochemical studies. Results: Rats fed a high-Fr diet developed hyperglycemia, hyperinsulinemia, hyperuricemia, hypertriglyceridemia, and hypercholesterolemia, and had increased serum alanine aminotransferase, hepatic tumor necrosis factor-α, and malondialdehyde levels but decreases in both glutathione content and superoxide dismutase activity. Rat treatment with FF and/or PG attenuated these alterations. The improvement was greater with the combined treatment than with either drug alone, and normalization of insulin sensitivity was observed only in rats treated with the combination therapy. Conclusion: Acting on the 2 main PPAR subfamilies, the combination of FF and PG provides a more efficacious therapy for modulating the changes in serum insulin, uric acid, and lipids, as well as the accompanying hepatic inflammation and oxidative stress that characterize the Fr-induced metabolic syndrome.

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Recent Developments in Rodent Models of High-Fructose Diet-Induced Metabolic Syndrome: A Systematic Review

Nutrients ◽

10.3390/nu13082497 ◽

2021 ◽

Vol 13 (8) ◽

pp. 2497

Author(s):

Alvin Man Lung Chan ◽

Angela Min Hwei Ng ◽

Mohd Heikal Mohd Yunus ◽

Ruszymah Bt Hj Idrus ◽

Jia Xian Law ◽

...

Keyword(s):

Metabolic Syndrome ◽

Animal Studies ◽

18Th Century ◽

Disease Model ◽

Hepatic Function ◽

Chronic Illnesses ◽

Paradigm Shifts ◽

Response Factors ◽

High Fructose ◽

Recent Developments

Metabolic syndrome (MetS) is the physiological clustering of hypertension, hyperglycemia, hyperinsulinemia, dyslipidemia, and insulin resistance. The MetS-related chronic illnesses encompass obesity, the cardiovascular system, renal operation, hepatic function, oncology, and mortality. To perform pre-clinical research, it is imperative that these symptoms be successfully induced and optimized in lower taxonomy. Therefore, novel and future applications for a disease model, if proven valid, can be extrapolated to humans. MetS model establishment is evaluated based on the significance of selected test parameters, paradigm shifts from new discoveries, and the accessibility of the latest technology or advanced methodologies. Ultimately, the outcome of animal studies should be advantageous for human clinical trials and solidify their position in advanced medicine for clinicians to treat and adapt to serious or specific medical situations. Rodents (Rattus norvegicus and Mus musculus) have been ideal models for mammalian studies since the 18th century and have been mapped extensively. This review compiles and compares studies published in the past five years between the multitude of rodent comparative models. The response factors, niche parameters, and replicability of diet protocols are also compiled and analyzed to offer insight into MetS-related disease-specific modelling.

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Raised TSH is associated with endothelial dysfunction in Metabolic Syndrome: A case control study

Romanian Journal of Internal Medicine ◽

10.1515/rjim-2017-0023 ◽

2017 ◽

Vol 55 (4) ◽

pp. 212-221 ◽

Cited By ~ 2

Author(s):

Ashok Kumar Ahirwar ◽

Archana Singh ◽

Anju Jain ◽

Surajeet Kumar Patra ◽

Binita Goswami ◽

...

Keyword(s):

Metabolic Syndrome ◽

Endothelial Dysfunction ◽

Subclinical Hypothyroidism ◽

Serum Insulin ◽

Binary Logistic Regression ◽

Binary Logistic Regression Analysis ◽

Healthy Controls ◽

Healthy Control ◽

Study Population ◽

Serum Tsh

AbstractIntroduction. Endothelial dysfunction has been considered as one of the important factors in pathogenesis of Metabolic Syndrome (Met S). Subclinical hypothyroidism (SCH) has also been reported to be associated with Met S. The aim of our study is to evaluate the association of raised TSH with mediators of endothelial dysfunction in Met S with Subclinical hypothyroidism as compared to healthy controls.Methods. Study population consisted of 100 subjects, out of which 50 were cases of Met S and 50 were healthy controls. Met S group were further divided into two, based on the presence & absence of SCH. Serum insulin, T3, T4, TSH were measured by chemiluminescence based immunoassay (CLIA). Serum nitric oxide (NO) levels were measured by Modified Griess’s method and serum endothelin-1 (ET-1) levels were measured by ELISA.Results. Out of 50 cases of Met S, SCH was diagnosed in 22. The mean serum TSH levels were significantly higher in Met S cases as compared to healthy controls (5.7 ± 1.2 μIU/mL vs. 2.3 ± 1.6 μIU/mL, P <0.0001). Mean serum NO levels were significantly lower in Met S cases as compared to healthy control (15.4 ± 10 μM vs. 21 ± 10 μM, p = 0.009). Mean serum ET-1 levels were significantly higher in Met S cases as compared to healthy controls (2.68 ± 1.7 fmol/mL vs. 2.1 ± 0.84 fmol/mL, p = 0.011). On Pearson’s correlation analysis, TSH showed positive correlation with ET-1 (r = 0.341, p = 0.001) and negative correlation with NO (r = −0.331, p = 0.001). Binary logistic regression analysis showed that TSH, NO and ET-1 has significant odd’s ratio for predicting Met S.Conclusion. Met S cases were screened for thyroid abnormalities and found to have 44% of SCH along with co-existing endothelial dysfunction. Raised TSH in SCH could cause endothelial dysfunction which may lead to Met S and associated co-morbidities. Present study gives new insight in linking endothelial dysfunction and raised TSH in Met S. Therefore, Met S cases should be screened for SCH and treated appropriately to attenuate endothelial dysfunction and associated comorbidities in Met S.

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Relationship Between High-Fructose Corn Syrup, Uric Acid, and Metabolic Syndrome

Journal of Pediatric Surgical Nursing ◽

10.1097/jps.0000000000000115 ◽

2016 ◽

Vol 5 (4) ◽

pp. 88

Author(s):

Monica J. McChesney

Keyword(s):

Metabolic Syndrome ◽

Uric Acid ◽

High Fructose Corn Syrup ◽

Corn Syrup ◽

High Fructose

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Glucose Transporter 8 (GLUT8) Regulates Enterocyte Fructose Transport and Global Mammalian Fructose Utilization

Endocrinology ◽

10.1210/en.2012-1541 ◽

2012 ◽

Vol 153 (9) ◽

pp. 4181-4191 ◽

Cited By ~ 42

Author(s):

Brian J. DeBosch ◽

Maggie Chi ◽

Kelle H. Moley

Keyword(s):

Glucose Transporter ◽

Serum Insulin ◽

Density Lipoprotein ◽

Wild Type ◽

In Vivo Models ◽

The Metabolic Syndrome ◽

High Fructose

Enterocyte fructose absorption is a tightly regulated process that precedes the deleterious effects of excess dietary fructose in mammals. Glucose transporter (GLUT)8 is a glucose/fructose transporter previously shown to be expressed in murine intestine. The in vivo function of GLUT8, however, remains unclear. Here, we demonstrate enhanced fructose-induced fructose transport in both in vitro and in vivo models of enterocyte GLUT8 deficiency. Fructose exposure stimulated [14C]-fructose uptake and decreased GLUT8 protein abundance in Caco2 colonocytes, whereas direct short hairpin RNA-mediated GLUT8 knockdown also stimulated fructose uptake. To assess GLUT8 function in vivo, we generated GLUT8-deficient (GLUT8KO) mice. GLUT8KO mice exhibited significantly greater jejunal fructose uptake at baseline and after high-fructose diet (HFrD) feeding vs. wild-type mice. Strikingly, long-term HFrD feeding in GLUT8KO mice exacerbated fructose-induced increases in blood pressure, serum insulin, low-density lipoprotein and total cholesterol vs. wild-type controls. Enhanced fructose uptake paralleled with increased abundance of the fructose and glucose transporter, GLUT12, in HFrD-fed GLUT8KO mouse enterocytes and in Caco2 cultures exposed to high-fructose medium. We conclude that GLUT8 regulates enterocyte fructose transport by regulating GLUT12, and that disrupted GLUT8 function has deleterious long-term metabolic sequelae. GLUT8 may thus represent a modifiable target in the prevention and treatment of malnutrition or the metabolic syndrome.

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Abstract P088: Obesity, Hypertension and Insulin Resistance in a Primary Pediatric Setting in Southern Italy

Circulation ◽

10.1161/circ.129.suppl_1.p088 ◽

2014 ◽

Vol 129 (suppl_1) ◽

Author(s):

Giampaolo De Filippo ◽

Domenico Rendina ◽

Domenico Viggiano ◽

Antonio Fasolino ◽

Paola Sabatini ◽

...

Keyword(s):

Insulin Resistance ◽

Metabolic Syndrome ◽

Body Weight ◽

Children And Adolescents ◽

Diagnostic Criteria ◽

Southern Italy ◽

Serum Insulin ◽

High Density Lipoproteins ◽

Obese Children ◽

Campania Region

Background: Obesity is the main risk factor for essential hypertension (EH) in childhood. The O.Si.Me. study (Obesity and Metabolic Syndrome in children and adolescents) evaluated the prevalence of metabolic syndrome (MetS) and its constitutive traits in a sample of obese children and adolescents living in Campania, southern Italy. Patients and methods: Four hundred and fifteen children and adolescents consecutively referred to the National Health Service participating Outpatient Clinics for minor health problems and found to have a Body Mass Index (BMI) Z-score > 2.0 were enrolled in the study. The entire sample was screened for MetS, which was defined as the presence of at least 2 of the following alterations in addition to obesity: fasting hyperglycemia, low levels of high-density lipoproteins cholesterol, hypertriglyceridemia, and EH. The present analysis evaluated the clinical characteristics of the O.Si.Me subgroup of EH participants (systolic and/or diastolic BP ≥ 95 th percentile for age, gender and height) as compared with normotensive participants. Results: The prevalence of EH in the O.Si.Me population was 23.6 % (98/415, 48M and 50F.) and two-thirds of the EH participants met the MetS diagnostic criteria. The EH participants featured serum insulin and HOMA-IR levels significantly higher compared with normotensive ones (11.6±0.6 vs. 9.5±0.4 μIU/ml, p = 0.014; 2.6±0.1 vs. 2.2±0.1, p = 0.028 for insulin and HOMA-IR, respectively). These differences were common to boys and girls and remained significant after correction for age, pubertal stage, body weight, length, BMI, gestational age at birth, duration of breastfeeding and anthropometric parental parameters. Accordingly, children and adolescents with EH had a a relative risk of being insulin resistant (defined as a HOMA-IR ≥2.5) significantly greater compared to those without. Moreover, they exhibited higher serum creatinine levels (53.8±7.1 vs. 35.4±6.8 μmol/l, p=0.025) accounting for gender and body weight. Conclusions: More than a quarter of obese children and adolescents meet the diagnostic criteria for EH in the Campania region in southern Italy. These obese boys and girls have an increased prevalence of insulin resistance and apparently an initial reduction in renal function compared with obese children and adolescents with normal BP.

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The analysis of surface saccharide profiles through fluorescein-labelled lectins in a rat pancreatic tissue with established metabolic syndrome model

Turkish Journal of Biochemistry ◽

10.1515/tjb-2017-0194 ◽

2018 ◽

Vol 44 (1) ◽

pp. 98-104

Author(s):

Yosun Mater ◽

Sule Beyhan-Ozdas

Keyword(s):

Metabolic Syndrome ◽

Metabolic Diseases ◽

Pancreatic Tissue ◽

Control Group ◽

High Fructose Diet ◽

Tissue Sections ◽

Membrane Surfaces ◽

High Fructose ◽

A Cell ◽

And Control

Abstract“Glycans”, which are generally referred as oligosaccharides and polysaccharides, are structures that are present on all cellular surfaces with proteins and lipids being attached to their basic chain structures. Many studies in the field of glycobiology have identified the various and complicated biological roles of these glycans which make them perfect molecules to use in labelling and selecting body cells specifically. This study aims at analyzing the modifications in saccharide units of glycans on a cell membrane surfaces of the pancreatic tissue of rats to which normal and metabolic syndrome (MetS) are established. To this end, a MetS model was created through a high fructose diet in Spraque Dawley breed of rats and the pancreatic tissue sections of the group with MetS and control group animals were evaluated comparatively. The targeted saccharide units were examined with Fluorescent Microscope by using two different Fluorescein (FITC) labelled lectins, namely Maackia amurensis-1 lectin [FITC-(MAL-I)] and the Wheat Germ Agglutinin (FITC-WGA). It was observed that FITC-MAL-1-labelled Galβ4GlcNAc units did not change much due to high- fructose diet. On the other hand, more GlcNAc, Neu5Ac and β-GlcNAc units which are labelled with FITC-WGA lectin increase in numbers in pancreatic sections of high fructose diet, compared to control group. Thus, a rapid and specific labelling method, which can identify surface saccharide sequences specifically, was developed. The method can be used in early diagnosis and/or treatment for metabolic diseases.

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