scholarly journals 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 ◽  
2015 ◽  
Vol 62 (2) ◽  
pp. 163-172 ◽  
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.

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

2016 ◽  
Vol 118 (5) ◽  
pp. 810-821 ◽  
Author(s):  
Xinghui Sun ◽  
Jibin Lin ◽  
Yu Zhang ◽  
Sona Kang ◽  
Nathan Belkin ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Endothelial Function ◽  
Glucose Homeostasis ◽  
White Adipose Tissue

Participation of ERα and ERβ in glucose homeostasis in skeletal muscle and white adipose tissue

2009 ◽  
Vol 297 (1) ◽  
pp. E124-E133 ◽  
Author(s):  
Rodrigo P. A. Barros ◽  
Chiara Gabbi ◽  
Andrea Morani ◽  
Margaret Warner ◽  
Jan-Åke Gustafsson
Keyword(s):  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Glucose Homeostasis ◽  
White Adipose Tissue ◽  
Glucose Transporter ◽  
Wild Type ◽  
Glut4 Expression ◽  
Glucose Challenge ◽  
Fasting Hypoglycemia

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.

scholarly journals Glucose homeostasis and insulin sensitivity in growth hormone-transgenic mice: a cross-sectional analysis

2010 ◽  
Vol 391 (10) ◽  
Author(s):  
Ravneet K. Boparai ◽  
Oge Arum ◽  
Romesh Khardori ◽  
Andrzej Bartke
Keyword(s):  
Growth Hormone ◽  
Insulin Sensitivity ◽  
Transgenic Mice ◽  
Glucose Homeostasis ◽  
Endocrine Control ◽  
Cross Sectional ◽  
Systematic Assessment ◽  
Beneficial Effects ◽  
Glucose Stimulated Insulin Secretion ◽  
The Impact

Abstract In contrast to its stimulatory effects on musculature, bone, and organ development, and its lipolytic effects, growth hormone (GH) opposes insulin effects on glucose metabolism. Chronic GH overexposure is thought to result in insulin insensitivity and decreased blood glucose homeostatic control. Yet, despite the importance of this concept for basic biology, as well as human conditions of GH excess or deficiency, no systematic assessment of the impact of GH over- expression on glucose homeostasis and insulin sensitivity has been conducted. We report that male and female adult GH transgenic mice have enhanced glucose tolerance compared to littermate controls and this effect is not dependent on age or on the particular heterologous GH transgene used. Furthermore, increased glucose-stimulated insulin secretion, augmented insulin sensitivity, and muted gluconeogenesis were also observed in bovine GH overexpressing mice. These results show that markedly increased systemic GH concentration in GH-transgenic mice exerts unexpected beneficial effects on glucose homeostasis, presumably via a compensatory increase in insulin release. The counterintuitive nature of these results challenges previously held presumptions of the physiology of these mice and other states of GH overexpression or suppression. In addition, they pose intriguing queries about the relationships between GH, endocrine control of metabolism, and aging.

scholarly journals Markedly Reduced White Adipose Tissue and Increased Insulin Sensitivity in Adcyap1-Deficient Mice

2008 ◽  
Vol 107 (1) ◽  
pp. 41-48 ◽  
Author(s):  
Shuhei Tomimoto ◽  
Tatsuya Ojika ◽  
Norihito Shintani ◽  
Hitoshi Hashimoto ◽  
Ken-ichi Hamagami ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
White Adipose Tissue ◽  
Deficient Mice

INSULIN SENSITIVITY AND CARBOHYDRATE METABOLISM OF RATS WITH HYPOTHALAMIC OBESITY

1965 ◽  
Vol 33 (3) ◽  
pp. 437-446 ◽  
Author(s):  
JANET TUCKER ◽  
J. TRETHEWEY ◽  
G. A. STEWART ◽  
R. W. J. NEVILLE ◽  
T. HANLEY
Keyword(s):  
Body Weight ◽  
Adipose Tissue ◽  
Blood Glucose ◽  
Insulin Sensitivity ◽  
Fasting Blood Glucose ◽  
Diaphragm Muscle ◽  
Fixed Dose ◽  
Insulin Dosage ◽  
Control Group ◽  
Hypothalamic Obesity

SUMMARY A fixed dose of glucose, irrespective of body weight, used for i.v. glucose tolerance tests in rats with hypothalamic obesity and in non-obese control rats caused almost identical blood glucose increments in both kinds of rats, and the K values (coefficients of glucose assimilation) were not significantly different. Glucose doses proportional to body weight caused much larger increments of blood glucose in the obese animals but the K value was not significantly different from that for the controls. On the other hand, the insulin sensitivity of obese rats was found to be less than that of control rats when a fixed dose of the hormone was given. When the insulin dosage was proportional to body weight, the fall of fasting blood glucose produced in the obese animals was not significantly different from that in the control group. In vitro, the diaphragm muscle of the obese animals was insensitive to the action of insulin as compared with controls. There was no evidence of insulin insensitivity of the obese animals' adipose tissue; the very low metabolic activity of the adipose tissue of both the control and obese animals may have been responsible. The interpretation of these findings is discussed in the light of similar work in human obesity.

scholarly journals Association of Elevated Plasma FGF21 and Activated FGF21 Signaling in Visceral White Adipose Tissue and Improved Insulin Sensitivity in Gestational Diabetes Mellitus Subtype: A Case-Control Study

2021 ◽  
Vol 12 ◽  
Author(s):  
Ning Wang ◽  
Bo Sun ◽  
Haonan Guo ◽  
Yingyu Jing ◽  
Qi Ruan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Diabetes Mellitus ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Gestational Diabetes ◽  
Gestational Diabetes Mellitus ◽  
White Adipose Tissue ◽  
Fasting Blood Glucose ◽  
Normal Glucose Tolerance ◽  
Fgf Receptor

ObjectiveTo study the discrepancy of the insulin sensitivity alteration pattern, circulating fibroblast growth factor (FGF21) levels and FGF21 signaling in visceral white adipose tissue (vWAT) of gestational diabetes mellitus (GDM) subtypes.Methods26 GDM women with either a predominant of insulin-secretion defect (GDM-dysfunction, n = 9) or insulin-sensitivity defect (GDM-resistance, n = 17) and 13 normal glucose tolerance (NGT) women scheduled for caesarean-section at term were studied. Blood and vWAT samples were collected at delivery.ResultsThe insulin sensitivity was improved from the 2nd trimester to delivery in the GDM-resistance group. Elevated circulating FGF21 concentration at delivery, increased FGF receptor 1c and decreased klotho beta gene expression, enhanced ERK1/2 phosphorylation, and increased GLUT1, IR-B, PPAR-γ gene expression in vWAT were found in the GDM-resistance group as compared with the NGT group. The circulating FGF21 concentration was negatively correlated with fasting blood glucose (r = -0.574, P &lt; 0.001), and associated with the GDM-resistance group (r = 0.574, P &lt; 0.001) in pregnant women at delivery. However, we observed no insulin sensitivity alteration in GDM-dysfunction and NGT groups during pregnancy. No differences of plasma FGF21 level and FGF21 signaling in vWAT at delivery were found between women in the GDM-dysfunction and the NGT group.ConclusionsWomen with GDM heterogeneity exhibited different insulin sensitivity alteration patterns. The improvement of insulin sensitivity may relate to the elevated circulating FGF21 concentration and activated FGF21 signaling in vWAT at delivery in the GDM-resistance group.

Impact of human visceral and glutealfemoral adipose tissue transplant on glycemic control in a mouse model of diet-induced obesity

2020 ◽  
Vol 319 (3) ◽  
pp. E519-E528
Author(s):  
Thomas Tsiloulis ◽  
Arthe Raajendiran ◽  
Stacey N. Keenan ◽  
Geraldine Ooi ◽  
Renea A. Taylor ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Glycemic Control ◽  
Glucose Homeostasis ◽  
High Fat Diet ◽  
Fasting Blood Glucose ◽  
Whole Body ◽  
High Fat ◽  
Positive Effects ◽  
Tissue Transplant

Regional distribution of adipose tissue is an important factor in conferring cardiometabolic risk and obesity-related morbidity. We tested the hypothesis that human visceral adipose tissue (VAT) impairs glucose homeostasis, whereas subcutaneous glutealfemoral adipose tissue (GFAT) protects against the development of impaired glucose homeostasis in mice. VAT and GFAT were collected from patients undergoing bariatric surgery and grafted onto the epididymal adipose tissue of weight- and age-matched severe, combined immunodeficient mice. SHAM mice underwent surgery without transplant of tissue. Mice were fed a high-fat diet after xenograft. Energy homeostasis, glucose metabolism, and insulin sensitivity were assessed 6 wk later. Xenograft of human adipose tissues was successful, as determined by histology, immunohistochemical evaluation of collagen deposition and angiogenesis, and maintenance of lipolytic function. Adipose tissue transplant did not affect energy expenditure, food intake, whole body substrate partitioning, or plasma free fatty acid, triglyceride, and insulin levels. Fasting blood glucose was significantly reduced in GFAT and VAT compared with SHAM, whereas glucose tolerance was improved only in mice transplanted with VAT compared with SHAM mice. This improvement was not associated with differences in whole body insulin sensitivity or plasma insulin between groups. Together, these data suggest that VAT improves glycemic control and GFAT does not protect against the development of high-fat diet-induced glucose intolerance. Hence, the intrinsic properties of VAT and GFAT do not necessarily explain the postulated negative and positive effects of these adipose tissue depots on metabolic health.

scholarly journals Estrogen sulfotransferase regulates body fat and glucose homeostasis in female mice

2010 ◽  
Vol 299 (4) ◽  
pp. E657-E664 ◽  
Author(s):  
Victor K. Khor ◽  
Ravindra Dhir ◽  
Xiaoyan Yin ◽  
Rexford S. Ahima ◽  
Wen-Chao Song
Keyword(s):  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Transgenic Mice ◽  
Glucose Homeostasis ◽  
Fatty Acid Synthase ◽  
Hormone Sensitive Lipase ◽  
Estrogen Sulfotransferase ◽  
Female Mice ◽  
Brown Adipose ◽  
Adipose Mass

Estrogen regulates fat mass and distribution and glucose metabolism. We have previously found that estrogen sulfotransferase (EST), which inactivates estrogen through sulfoconjugation, was highly expressed in adipose tissue of male mice and induced by testosterone in female mice. To determine whether inhibition of estrogen in female adipose tissue affects adipose mass and metabolism, we generated transgenic mice expressing EST via the aP2 promoter. As expected, EST expression was increased in adipose tissue as well as macrophages. Parametrial and subcutaneous inguinal adipose mass and adipocyte size were significantly reduced in EST transgenic mice, but there was no change in retroperitoneal or brown adipose tissue. EST overexpression decreased the differentiation of primary adipocytes, and this was associated with reductions in the expression of peroxisome proliferator-activated receptor-γ, fatty acid synthase, hormone-sensitive lipase, lipoprotein lipase, and leptin. Serum leptin levels were significantly lower in EST transgenic mice, whereas total and high-molecular-weight adiponectin levels were not different in transgenic and wild-type mice. Glucose uptake was blunted in parametrial adipose tissue during hyperinsulinemic-euglycemic clamp in EST transgenic mice. In contrast, hepatic insulin sensitivity was improved but muscle insulin sensitivity did not change in EST transgenic mice. These results reveal novel effects of EST on adipose tissue and glucose homeostasis in female mice.

scholarly journals Adipocyte JAK2 Mediates Growth Hormone-Induced Hepatic Insulin Resistance

2016 ◽  
Author(s):  
Kevin C. Corbit ◽  
João Paulo G. Camporez ◽  
Jennifer L. Tran ◽  
Camella G. Wilson ◽  
Dylan Lowe ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Growth Hormone ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Glucose Homeostasis ◽  
Metabolic Stress ◽  
Hepatic Insulin Resistance ◽  
Whole Body ◽  
Insulin Signal Transduction ◽  
Conditional Deletion

ABSTRACTFor nearly 100 years, Growth Hormone (GH) has been known to impact insulin sensitivity and risk of diabetes. However, the tissue governing the effects of GH signaling on insulin and glucose homeostasis remains unknown. Excess GH reduces fat mass and insulin sensitivity. Conversely, GH insensitivity (GHI) is associated with increased adiposity, augmented insulin sensitivity, and protection from diabetes. Here we induce adipocyte-specific GHI through conditional deletion of Jak2 (JAK2A), an obligate transducer of GH signaling. Similar to whole-body GHI, JAK2A mice had increased adiposity and extreme insulin sensitivity. Loss of adipocyte Jak2 augmented hepatic insulin sensitivity and conferred resistance to diet-induced metabolic stress without overt changes in circulating fatty acids. While GH injections induced hepatic insulin resistance in control mice, the diabetogenic action was absent in JAK2A mice. Adipocyte GH signaling directly impinged on both adipose and hepatic insulin signal transduction. Collectively, our results show that adipose tissue governs the effects of GH on insulin and glucose homeostasis. Further, we show that JAK2 mediates liver insulin sensitivity via an extra-hepatic, adipose tissue-dependent mechanism.

Effect of Dapagliflozin on Intestinal Flora in MafA-deficient Mice

2018 ◽  
Vol 24 (27) ◽  
pp. 3223-3231 ◽  
Author(s):  
Luyao Li ◽  
Shiyao Xu ◽  
Tingting Guo ◽  
Shouliang Gong ◽  
Chuan Zhang
Keyword(s):  
Blood Glucose ◽  
High Throughput Sequencing ◽  
Fatty Acid Content ◽  
Fasting Blood Glucose ◽  
Intestinal Flora ◽  
Short Chain Fatty Acids ◽  
The Body ◽  
Short Chain ◽  
Control Group ◽  
Deficient Mice

Objective: To investigate the effect of dapagliflozin on intestinal microflora in MafA-deficient mice using an animal model of diabetes. Methods: Male MafA-deficient mice were administered dapagliflozin (1.0 mg/kg/d) intragastrically for 6 weeks. Mouse body weights and fasting blood glucose levels were measured, and intestinal short-chain fatty acids were measured by gas chromatography. A series of methods was used to analyse the number of primary harmful bacteria in the faeces, and high-throughput sequencing was used to sequence the changes in intestinal flora. Results: The weight of the mice decreased after dapagliflozin gavage, and fasting blood glucose was significantly lower than that in the control group (P < 0.001). Acetic acid and butyric acid contents in the intestinal tracts of the mice increased, and the growth of harmful microorganisms, such as Clostridium perfringens, enterococci, Enterobacteriaceae, and intestinal enterococci, was inhibited. Blautia is a species found in the experimental group and was significantly different from the control and blank groups as determined by the LDA score from highthroughput sequencing. Conclusion: Dapagliflozin can reduce fasting blood glucose, decrease body weight, increase short-chain fatty acid content, regulate the intestinal microecological balance of the body and promote blood glucose and energy homeostasis.

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