Insulin Resistance in SHR/NDmc-cp Rats Correlates with Enlarged Perivascular Adipocytes and Endothelial Cell Dysfunction in Skeletal Muscle

Hariya, Natsuyo; Mochizuki, Kazuki; Inoue, Seiya; Morioka, Kousuke; Shimada, Morimi; Okuda, Tohru; Goda, Toshinao

doi:10.3177/jnsv.60.52

Cited by 5 publications

(5 citation statements)

References 40 publications

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“…1 to clarify this point. Mesenteric PVAT is a common PVAT depot that is studied for its relevance to alterations in vascular response and blood pressure (5,23,43,49,71,72), whereas PVAT around skeletal muscle arteries is more associated with mechanisms of insulin resistance (7,27,47,48,74). Therefore, mesenteric PVAT was the most relevant PVAT for us to study.…”

Section: Discussionmentioning

confidence: 99%

Organic cation transporter 3 contributes to norepinephrine uptake into perivascular adipose tissue

Ayala‐Lopez

Jackson

Burnett

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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Watts SW. Organic cation transporter 3 contributes to norepinephrine uptake into perivascular adipose tissue. Am J Physiol Heart Circ Physiol 309: H1904 -H1914, 2015. First published October 2, 2015; doi:10.1152/ajpheart.00308.2015.-Perivascular adipose tissue (PVAT) reduces vasoconstriction to norepinephrine (NE). A mechanism by which PVAT could function to reduce vascular contraction is by decreasing the amount of NE to which the vessel is exposed. PVATs from male Sprague-Dawley rats were used to test the hypothesis that PVAT has a NE uptake mechanism. NE was detected by HPLC in mesenteric PVAT and isolated adipocytes. Uptake of NE (10 M) in mesenteric PVAT was reduced by the NE transporter (NET) inhibitor nisoxetine (1 M, 73.68 Ϯ 7.62%, all values reported as percentages of vehicle), the 5-hydroxytryptamine transporter (SERT) inhibitor citalopram (100 nM) with the organic cation transporter 3 (OCT3) inhibitor corticosterone (100 M, 56.18 Ϯ 5.21%), and the NET inhibitor desipramine (10 M) with corticosterone (100 M, 61.18 Ϯ 6.82%). Aortic PVAT NE uptake was reduced by corticosterone (100 M, 53.01 Ϯ 10.96%). Confocal imaging of mesenteric PVAT stained with 4-[4-(dimethylamino)-styrl]-N-methylpyridinium iodide (ASP ϩ ), a fluorescent substrate of cationic transporters, detected ASP ϩ uptake into adipocytes. ASP ϩ (2 M) uptake was reduced by citalopram (100 nM, 66.68 Ϯ 6.43%), corticosterone (100 M, 43.49 Ϯ 10.17%), nisoxetine (100 nM, 84.12 Ϯ 4.24%), citalopram with corticosterone (100 nM and 100 M, respectively, 35.75 Ϯ 4.21%), and desipramine with corticosterone (10 and 100 M, respectively, 50.47 Ϯ 5.78%). NET protein was not detected in mesenteric PVAT adipocytes. Expression of Slc22a3 (OCT3 gene) mRNA and protein in PVAT adipocytes was detected by RT-PCR and immunocytochemistry, respectively. These end points support the presence of a transporter-mediated NE uptake system within PVAT with a potential mediator being OCT3. PERIVASCULAR ADIPOSE TISSUE (PVAT) closely envelops many blood vessels of the body (65). This relationship between PVAT and the blood vessel has earned PVAT its place as the fourth layer of the blood vessel, the "tunica adiposa" (14). Beyond providing structural support, PVAT has many roles in modulating blood vessel function (68). The release of vasoactive molecules from PVAT influences vascular function by altering the proliferation, migration, inflammation, and contraction of vascular smooth muscle (9, 20 -22, 24, 46, 68, 72). Interestingly, a releasable pool of catecholamines is present in PVAT (5, 67). Although both contractile and anticontractile substances can be released from PVAT (9,22,24,25,72), the presence of PVAT on blood vessels generally reduces vessel contraction in response to various agonists, including norepinephrine (NE) (64). Knowledge on how these mechanisms interact to influence the anticontractile properties of PVAT in NE-induced contraction is not complete (36).The anticontractile effect of PVAT is lost in obesity and hypertension, implicating PVAT as an integral lin...

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Section: Discussionmentioning

confidence: 99%

Organic cation transporter 3 contributes to norepinephrine uptake into perivascular adipose tissue

Ayala‐Lopez

Jackson

Burnett

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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“…Moreover, mouse muscle cell line C2C12 cells expressed Pparg1, but not Pparg2 (29). PPARG2 is mainly expressed in adipose tissues, and adipocytes are located in the perivascular space of the skeletal muscle, but not in the interstitium among muscle bundles, in SHR/NDmc-cp rats (13). Thus, PPARG1 expression in the skeletal muscle of SHR/ NDmc-cp rats may be associated with the expression of fatty acid oxidation-related genes and/or PPAR target genes.…”

Section: Discussionmentioning

confidence: 99%

“…We previously reported the body weight and concentrations of blood glucose, insulin and triacylglycerol in SHR/NDmc-cp rats, WKY rats and streptozotocintreated rats (13). In this study, we now reanalyze the results from SHR/NDmc-cp rats and WKY rats using Student's t-test (Table 2).…”

Section: Body Weight and Blood Biochemical Parameters In Wky And Shr/mentioning

confidence: 99%

“…Nonfasting plasma samples at 18 wk of age were collected from the tail vein using a capillary tube containing heparin-lithium (Terumo, Co., Ltd., Tokyo, Japan) between 9:30 am and 10:00 am. Rats were then killed by decapitation between 10:00 am and 12:00 pm, and gastrocnemius muscles were collected (13). The experimental procedures used in the study conformed to the guidelines of the Animal Usage Committee of the University of Shizuoka.…”

Section: Animalsmentioning

confidence: 99%

“…Total protein was extracted from the gastrocnemius muscle using RIPA buffer and the soluble supernatants were then separated by 10% sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Western blot analysis was performed as previously reported (13 Searching for putative PPREs in the upstream region of the upregulated genes. Putative PPREs in the Ϫ5000 bp to Ϫ1 bp promoter/enhancer region of upregulated genes were searched for with the web program PPRESearch (http://www.classicrus.com/PPRE/) (16,17).…”

Section: Animalsmentioning

confidence: 99%

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Putative PPAR Target Genes Express Highly in Skeletal Muscle of Insulin-Resistant MetS Model SHR/NDmc-cp Rats

Hariya

Miyake

Kubota

et al. 2015

Journal of Nutritional Science and Vitaminology, J Nutr Sci Vit

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Skeletal muscle is responsible for approximately 75% of insulin-dependent glucose incorporation. A reduction in skeletal muscle glucose incorporation leads to the development of insulin resistance and subsequent development of metabolic diseases such as type 2 diabetes (1). In particular, insulin resistance with obesity in humans is frequently associated with hypertension and hyperlipidemia, as well as with hyperglycemia. Abnormal values of more than two of the following parameters-fasting blood glucose, lipids and blood pressure-in combination with obesity is generally called metabolic syndrome (MetS). It is known that subjects with MetS have subsequent higher incidences of cardiovascular diseases (CVD) and associated death (2). Therefore, maintaining insulin sensitivity in skeletal muscle by controlling dietary habits is important for preventing the onset and progression of MetS and related diseases.The main mechanism of glucose uptake in skeletal muscle is via glucose transporter (GLUT) 4, which is translocated from intracellular storage vesicles to the plasma membrane in an insulin-dependent manner (3). Insulin-induced translocation of GLUT4 is signaled by the insulin receptor substrate-phosphoinositide 3-kinase pathway and by the AMP activated protein kinase pathway (4). Skeletal muscle glucose is stored as glycogen by dephosphorylated glycogen synthase via the insulin signal. These fi ndings indicate that the insulin signal in skeletal muscle enhances glucose incorporation independently of expression changes in metabolic genes such as glycogen synthesis-and fatty acid synthesisrelated genes. Yamanashi, 4-4-37 Takeda, Kofu, Yamanashi 400-8510, Japan (Received April 25, 2014) Summary It is known that insulin resistance in skeletal muscle induces subsequent metabolic diseases such as metabolic syndrome (MetS). However, which genes are altered in the skeletal muscle by development of insulin resistance in animal models has not been examined. In this study, we performed microarray and subsequent real-time RT-PCR analyses using total RNA extracted from the gastrocnemius muscle of the MetS model, spontaneously hypertensive corpulent congenic (SHR/NDmc-cp) rats, and control Wistar Kyoto (WKY) rats. SHR/NDmc-cp rats displayed overt insulin resistance relative to WKY rats. The expression of many genes related to fatty acid oxidation was higher in SHR/NDmc-cp rats than in WKY rats. Among 18 upregulated genes, putative peroxisome proliferator responsive elements were found in the upstream region of 15 genes. The protein expression of ACOX2, an upregulated gene, and peroxisome proliferator-activated receptor (PPAR) G1, but not of PPARG2, PPARA or PPARD, was higher in the gastrocnemius muscle of SHR/NDmc-cp rats than that in WKY rats. These results suggest that insulin resistance in the MetS model, SHR/ NDmc-cp rats, is positively associated with the expression of fatty acid oxidation-related genes, which are presumably PPARs' targets, in skeletal muscle. Putative PPAR Target Genes Express Highly in

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Role of Perivascular Adipose Tissue in Health and Disease

Fernández-Alfonso

Somoza

Tsvetkov

et al. 2017

Comprehensive Physiology

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Perivascular adipose tissue (PVAT) is cushion of fat tissue surrounding blood vessels, which is phenotypically different from other adipose tissue depots. PVAT is composed of adipocytes and stromal vascular fraction, constituted by different populations of immune cells, endothelial cells, and adipose-derived stromal cells. It expresses and releases an important number of vasoactive factors with paracrine effects on vascular structure and function. In healthy individuals, these factors elicit a net anticontractile and anti-inflammatory paracrine effect aimed at meeting hemodynamic and metabolic demands of specific organs and regions of the body. Pathophysiological situations, such as obesity, diabetes or hypertension, induce changes in its amount and in the expression pattern of vasoactive factors leading to a PVAT dysfunction in which the beneficial paracrine influence of PVAT is shifted to a pro-oxidant, proinflammatory, contractile, and trophic environment leading to functional and structural cardiovascular alterations and cardiovascular disease. Many different PVATs surrounding a variety of blood vessels have been described and exhibit regional differences. Both protective and deleterious influence of PVAT differs regionally depending on the specific vascular bed contributing to variations in the susceptibility of arteries and veins to vascular disease. PVAT therefore, might represent a novel target for pharmacological intervention in cardiovascular disease. © 2018 American Physiological Society. Compr Physiol 8:23-59, 2018.

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Insulin Resistance in SHR/NDmc-cp Rats Correlates with Enlarged Perivascular Adipocytes and Endothelial Cell Dysfunction in Skeletal Muscle

Cited by 5 publications

References 40 publications

Organic cation transporter 3 contributes to norepinephrine uptake into perivascular adipose tissue

Organic cation transporter 3 contributes to norepinephrine uptake into perivascular adipose tissue

Putative PPAR Target Genes Express Highly in Skeletal Muscle of Insulin-Resistant MetS Model SHR/NDmc-cp Rats

Role of Perivascular Adipose Tissue in Health and Disease

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