MicroRNA-181b Improves Glucose Homeostasis and Insulin Sensitivity by Regulating Endothelial Function in White Adipose Tissue

Glucose uptake and homeostasis are regulated mainly by skeletal muscle (SM), white adipose tissue (WAT), pancreas, and the liver. Participation of estradiol in this regulation is still under intense investigation. We have demonstrated that, in SM of male mice, expression of the insulin-regulated glucose transporter (GLUT)4 is reduced by estrogen receptor (ER)β agonists. In the present study, to investigate the relative contributions of ERα and ERβ in glucose homeostasis, we examined the effects of tamoxifen (Tam) on GLUT4 expression in SM and WAT in wild-type (WT) and ER−/− mice. ERβ−/− mice were characterized by fasting hypoglycemia, increased levels of SM GLUT4, pancreatic islet hypertrophy, and a belated rise in plasma insulin in response to a glucose challenge. ERα−/− mice, on the contrary, were hyperglycemic and glucose intolerant, and expression of SM GLUT4 was markedly lower than in WT mice. Tam had no effect on glucose tolerance or insulin sensitivity in WT mice. In ERα−/− mice, Tam increased GLUT4 and improved insulin sensitivity. i.e., it behaved as an ERβ antagonist in SM but had no effect on WAT. In ERβ−/− mice, Tam did not affect GLUT4 in SM but acted as an ERα antagonist in WAT, decreasing GLUT4. Thus, in the interplay between ERα and ERβ, ERβ-mediated repression of GLUT4 predominates in SM but ERα-mediated induction of GLUT4 predominates in WAT. This tissue-specific difference in dominance of one ER over the other is reflected in the ratio of the expression of the two receptors. ERα predominates in WAT and ERβ in SM.

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Growth Hormone Receptor Antagonist Transgenic Mice Have Increased Subcutaneous Adipose Tissue Mass, Altered Glucose Homeostasis and No Change in White Adipose Tissue Cellular Senescence

Gerontology ◽

10.1159/000439050 ◽

2015 ◽

Vol 62 (2) ◽

pp. 163-172 ◽

Cited By ~ 9

Author(s):

Ross Comisford ◽

Ellen R. Lubbers ◽

Lara A. Householder ◽

Ozan Suer ◽

Tamara Tchkonia ◽

...

Keyword(s):

Growth Hormone ◽

Adipose Tissue ◽

Blood Glucose ◽

Insulin Sensitivity ◽

Transgenic Mice ◽

Glucose Homeostasis ◽

Cellular Senescence ◽

White Adipose Tissue ◽

Fasting Blood Glucose ◽

Deficient Mice

Background: Growth hormone (GH)-resistant/deficient mice experience improved glucose homeostasis and substantially increased lifespan. Recent evidence suggests that long-lived GH-resistant/deficient mice are protected from white adipose tissue (WAT) dysfunction, including WAT cellular senescence, impaired adipogenesis and loss of subcutaneous WAT in old age. This preservation of WAT function has been suggested to be a potential mechanism for the extended lifespan of these mice. Objective: The objective of this study was to examine WAT senescence, WAT distribution and glucose homeostasis in dwarf GH receptor antagonist (GHA) transgenic mice, a unique mouse strain having decreased GH action but normal longevity. Methods: 18-month-old female GHA mice and wild-type (WT) littermate controls were used. Prior to dissection, body composition, fasting blood glucose as well as glucose and insulin tolerance tests were performed. WAT distribution was determined by weighing four distinct WAT depots at the time of dissection. Cellular senescence in four WAT depots was assessed using senescence-associated β-galactosidase staining to quantify the senescent cell burden, and real-time qPCR to quantify gene expression of senescence markers p16 and IL-6. Results: GHA mice had a 22% reduction in total body weight, a 33% reduction in lean mass and a 10% increase in body fat percentage compared to WT controls. GHA mice had normal fasting blood glucose and improved insulin sensitivity; however, they exhibited impaired glucose tolerance. Moreover, GHA mice displayed enhanced lipid storage in the inguinal subcutaneous WAT depot (p < 0.05) and a 1.7-fold increase in extra-/intraperitoneal WAT ratio compared to controls (p < 0.05). Measurements of WAT cellular senescence showed no difference between GHA mice and WT controls. Conclusions: Similar to other mice with decreased GH action, female GHA mice display reduced age-related lipid redistribution and improved insulin sensitivity, but no change in cellular senescence. The similar abundance of WAT senescent cells in GHA and control mice suggests that any protection against generation of senescent cells afforded by decreased GH action, low insulin-like growth factor 1 and/or improved insulin sensitivity in the GHA mice may be offset by their severe adiposity, since obesity is known to increase senescence.

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Central Leptin Regulates Total Ceramide Content and Sterol Regulatory Element Binding Protein-1C Proteolytic Maturation in Rat White Adipose Tissue

Endocrinology ◽

10.1210/en.2008-0505 ◽

2008 ◽

Vol 150 (1) ◽

pp. 169-178 ◽

Cited By ~ 36

Author(s):

Elena Bonzón-Kulichenko ◽

Dominik Schwudke ◽

Nilda Gallardo ◽

Eduardo Moltó ◽

Teresa Fernández-Agulló ◽

...

Keyword(s):

Nervous System ◽

Adipose Tissue ◽

Insulin Sensitivity ◽

White Adipose Tissue ◽

Binding Protein ◽

Regulatory Element ◽

Mrna Levels ◽

Element Binding Protein ◽

Ceramide Content ◽

Sterol Regulatory Element

Obesity and type 2 diabetes are associated with insulin and leptin resistance, and increased ceramide contents in target tissues. Because the adipose tissue has become a central focus in these diseases, and leptin-induced increases in insulin sensitivity may be related to effects of leptin on lipid metabolism, we investigated herein whether central leptin was able to regulate total ceramide levels and the expression of enzymes involved in ceramide metabolism in rat white adipose tissue (WAT). After 7 d central leptin treatment, the total content of ceramides was analyzed by quantitative shotgun lipidomics mass spectrometry. The effects of leptin on the expression of several enzymes of the sphingolipid metabolism, sterol regulatory element binding protein (SREBP)-1c, and insulin-induced gene 1 (INSIG-1) in this tissue were studied. Total ceramide levels were also determined after surgical WAT denervation. Central leptin infusion significantly decreased both total ceramide content and the long-chain fatty acid ceramide species in WAT. Concomitant with these results, leptin decreased the mRNA levels of enzymes involved in de novo ceramide synthesis (SPT-1, LASS2, LASS4) and ceramide production from sphingomyelin (SMPD-1/2). The mRNA levels of enzymes of ceramide degradation (Asah1/2) and utilization (sphingomyelin synthase, ceramide kinase, glycosyl-ceramide synthase, GM3 synthase) were also down-regulated. Ceramide-lowering effects of central leptin were prevented by local autonomic nervous system denervation of WAT. Finally, central leptin treatment markedly increased INSIG-1 mRNA expression and impaired SREBP-1c activation in epididymal WAT. These observations indicate that in vivo central leptin, acting through the autonomic nervous system, regulates total ceramide levels and SREBP-1c proteolytic maturation in WAT, probably contributing to improve the overall insulin sensitivity. Central leptin decreases total ceramide levels and prevents sterol regulatory element binding protein (SREBP-1C) proteolytic maturation in white adipose tissue, and probably, in this way, contributes to improve the overall insulin sensitivity.

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Resistin expression and plasma concentration peak at different times during pregnancy in rats

Journal of Endocrinology ◽

10.1677/joe.1.05932 ◽

2005 ◽

Vol 185 (3) ◽

pp. 551-559 ◽

Cited By ~ 13

Author(s):

Sergio Caja ◽

Izaskun Martínez ◽

María Abelenda ◽

Marisa Puerta

Keyword(s):

Adipose Tissue ◽

Insulin Sensitivity ◽

Plasma Concentration ◽

White Adipose Tissue ◽

Post Partum ◽

Time Lag ◽

Simultaneous Increase ◽

Tissue Mass ◽

Pregnant Rats ◽

Adipose Tissue Mass

Resistin has been proposed as both an anti-adipogenic factor and an inducer of insulin resistance. During late pregnancy, white adipose tissue mass increases and insulin sensitivity decreases. To check for the involvement of resistin in these processes, we measured plasma resistin in pregnant and non-pregnant rats and in lactating dams. Plasma resistin increased by day 15 of pregnancy and remained high 5 days post partum. The simultaneous increase in plasma resistin concentration and the decrease in insulin sensitivity is compatible with resistin depressing maternal insulin sensitivity. Resistin expression increased 5–15 times in visceral white adipose tissue depots by day 8 of pregnancy but was similar to pre-pregnancy values by day 19. Resistin expression in the placenta and mammary gland was similar to that in the parametrial adipose depot by day 8 but was almost null by day 19. There was therefore a time-lag between the peaks in expression and in plasma concentration. White adipose tissue mass increased without changes in adipocyte size once peaks in resistin expression had passed, which is compatible with an anti-adipogenic role for enhanced resistin expression. A bolus injection of chorionic gonadotrophin – which peaks in early pregnancy – to non-pregnant rats increased resistin expression in white adipose tissue, indicating that this hormone is involved in controlling resistin expression. Resistin was not detected in cerebrospinal fluid. Our results have suggested a role for resistin in pregnancy.

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