| 1. |
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| 2. |
- Ahmed, Fozia, et al.
(författare)
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Increased OCT3 Expression in Adipose Tissue With Aging : Implications for Catecholamine and Lipid Turnover and Insulin Resistance in Women
- 2023
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Ingår i: Endocrinology. - : Oxford University Press. - 0013-7227 .- 1945-7170. ; 165:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Catecholamine-stimulated lipolysis is reduced with aging, which may promote adiposity and insulin resistance. Organic cation transporter 3 (OCT3), which is inhibited by estradiol (E2), mediates catecholamine transport into adipocytes for degradation, thus decreasing lipolysis. In this study, we investigated the association of OCT3 mRNA levels in subcutaneous adipose tissue (SAT) with aging and markers of insulin resistance in women.Methods SAT biopsies were obtained from 66 women with (19) or without (47) type 2 diabetes (age 22-76 years, 20.0-40.1 kg/m2). OCT3 mRNA and protein levels were measured for group comparisons and correlation analysis. SAT was incubated with E2 and OCT3 mRNA levels were measured. Associations between OCT3 single nucleotide polymorphisms (SNPs) and diabetes-associated traits were assessed.Results OCT3 mRNA and protein levels in SAT increased with aging. SAT from postmenopausal women had higher levels of OCT3 than premenopausal women, and there was a dose-dependent reduction in OCT3 mRNA levels in SAT treated with E2. OCT3 mRNA levels were negatively associated with markers of insulin resistance, and ex vivo lipolysis. OCT3 SNPs were associated with BMI, waist to hip ratio, and circulating lipids (eg, triglycerides).Conclusion OCT3 mRNA and protein levels in SAT increased with aging, and mRNA levels were negatively associated with markers of insulin resistance. E2 incubation downregulated OCT3 mRNA levels, which may explain lower OCT3 mRNA in premenopausal vs postmenopausal women. High OCT3 protein levels in adipose tissue may result in increased catecholamine degradation, and this can contribute to the reduction in lipolysis observed in women with aging.
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| 3. |
- Ahrén, Bo, et al.
(författare)
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Inhibition of dipeptidyl peptidase-4 augments insulin secretion in response to exogenously administered glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide, pituitary adenylate cyclase-activating polypeptide, and gastrin-releasing peptide in mice
- 2005
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Ingår i: Endocrinology. - : The Endocrine Society. - 0013-7227 .- 1945-7170. ; 146:4, s. 2055-2059
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Tidskriftsartikel (refereegranskat)abstract
- Inhibition of dipeptidyl peptidase- 4 ( DPP- 4) is currently being explored as a new approach to the treatment of type 2 diabetes. This concept has emerged from the powerful and rapid action of the enzyme to inactivate glucagon- like peptide-1 ( GLP- 1). However, other bioactive peptides with potential influence of islet function are also substrates of DPP- 4. Whether this inactivation may add to the beneficial effects of DPP- 4 inhibition is not known. In this study, we explored whether DPP- 4 inhibition by valine- pyrrolidide ( val- pyr; 100 mu mol/ kg administered through gastric gavage at t = -30 min) affects the insulin and glucose responses to iv glucose ( 1 g/ kg) together with GLP- 1 ( 10 nmol/ kg), glucose- dependent insulinotropic polypeptide ( GIP; 10 nmol/ kg), pituitary adenylate cyclase- activating polypeptide 38 ( PACAP38; 1.3 nmol/ kg), or gastrin- releasing peptide ( GRP; 20 nmol/ kg) given at t = 0 in anesthetized C57BL/ 6J mice. It was found that the acute ( 1 - 5 min) insulin response to GLP- 1 was augmented by val- pyr by 80% ( 4.2 +/- 0.4 vs. 7.6 +/- 0.8 nmol/ liter), that to GIP by 40% ( 2.7 +/- 0.3 vs. 3.8 +/- 0.4 nmol/ liter), that to PACAP38 by 75% ( 4.6 +/- 0.5 vs. 8.1 +/- 0.6 nmol/ liter), and that to GRP by 25% ( 1.8 +/- 0.2 vs. 2.3 +/- 0.3 nmol/ liter; all P < 0.05 or less). This was associated with enhanced glucose elimination rate after GLP- 1 [ glucose elimination constant ( K-G) 2.1 +/- 0.2 vs. 3.1 +/- 0.3%/ min] and PACAP38 ( 2.1 +/- 0.3 vs. 3.2 +/- 0.3%/ min; both P < 0.01), but not after GIP or GRP. The augmented insulin response to GRP by val- pyr was prevented by the GLP- 1 receptor antagonist, exendin(3) ( 9- 39), raising the possibility that GRP effects may occur secondary to stimulation of GLP- 1 secretion. We conclude that DPP- 4 inhibition augments the insulin response not only to GLP- 1 but also to GIP, PACAP38, and GRP.
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| 4. |
- Ahrén, Bo, et al.
(författare)
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Loss-of-Function Mutation of the Galanin Gene is Associated with Perturbed Islet Function in Mice.
- 2004
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Ingår i: Endocrinology. - : The Endocrine Society. - 0013-7227 .- 1945-7170. ; 145:7, s. 3190-3196
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Tidskriftsartikel (refereegranskat)abstract
- The neuropeptide galanin is expressed in sympathetic nerve terminals that surround islet cells and inhibits insulin secretion. To explore its role for islet function, we studied mice with a loss-of-function mutation in the galanin gene [galanin knockout (KO) mice]. Intravenous 2-deoxy-glucose, which activates both the sympathetic and parasympathetic branches of the autonomic nervous system, caused an initial (1–5 min) inhibition of insulin secretion that was impaired in galanin KO mice (P = 0.027), followed by a subsequent stimulation of insulin secretion that was augmented in galanin KO mice (P < 0.01). Similar effects were seen after chemical sympathectomy by 6-hydroxydopamine. In contrast, galanin KO mice had a reduced insulin response to glucose, both in vivo (P < 0.001) and in isolated islets (P < 0.001), and to arginine, both in vivo (P = 0.012) and in vitro (P = 0.018). During an iv glucose tolerance test, galanin KO mice had impaired glucose disposal (P = 0.005) due to a reduced insulin response (P < 0.001) and a reduced insulin-independent glucose elimination (glucose effectiveness; P = 0.040). Insulin sensitivity, as judged by a euglycemic, hyperinsulinemic clamp technique, was slightly increased in galanin KO mice (P = 0.032). We conclude that 1) galanin may contribute to sympathetic influences inhibiting insulin secretion in mice, and 2) galanin KO mice have a reduced glucose-induced insulin secretion.
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| 5. |
- Al-Alem, Linah, et al.
(författare)
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Chemokine Ligand 20: A Signal for Leukocyte Recruitment During Human Ovulation?
- 2015
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Ingår i: Endocrinology. - : The Endocrine Society. - 1945-7170 .- 0013-7227. ; 156:9, s. 3358-69
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Tidskriftsartikel (refereegranskat)abstract
- Ovulation is one of the cornerstones of female fertility. Disruption of the ovulatory process results in infertility, which affects approximately 10% of couples. Using a unique model in which the dominant follicle is collected across the periovulatory period in women, we have identified a leukocyte chemoattractant, chemokine ligand 20 (CCL20), in the human ovary. CCL20 mRNA is massively induced after an in vivo human chorionic gonadotropin (hCG) stimulus in granulosa (>10 000-fold) and theca (>4000-fold) cells collected during the early ovulatory (12-18 h) and late ovulatory (18-34 h) periods after hCG administration. Because the LH surge sets in motion an inflammatory reaction characterized by an influx of leukocytes and CCL20 is known to recruit leukocytes in other systems, the composition of ovarian leukocytes (CD45+) containing the CCL20 receptor CCR6 was determined immediately prior to ovulation. CD45+/CCR6+ cells were primarily natural killer cells (41%) along with B cells (12%), T cells (11%), neutrophils (10%), and monocytes (9%). Importantly, exogenous CCL20 stimulated ovarian leukocyte migration 59% within 90 minutes. Due to the difficulties in obtaining human follicles, an in vitro model was developed using granulosa-lutein cells to explore CCL20 regulation. CCL20 expression increased 40-fold within 6 hours after hCG, was regulated partially by the epithelial growth factor pathway, and was positively correlated with progesterone production. These results demonstrate that hCG dramatically increases CCL20 expression in the human ovary, that ovarian leukocytes contain the CCL20 receptor, and that CCL20 stimulates leukocyte migration. Our findings raise the prospect that CCL20 may aid in the final ovulatory events and contribute to fertility in women.
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| 6. |
- Alexanderson, Camilla, 1978, et al.
(författare)
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Postnatal testosterone exposure results in insulin resistance, enlarged mesenteric adipocytes, and an atherogenic lipid profile in adult female rats: comparisons with estradiol and dihydrotestosterone.
- 2007
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Ingår i: Endocrinology. - : The Endocrine Society. - 0013-7227 .- 1945-7170. ; 148:11, s. 5369-76
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Tidskriftsartikel (refereegranskat)abstract
- Postnatal events contribute to features of the metabolic syndrome in adulthood. In this study, postnatally administered testosterone reduced insulin sensitivity and increased the mesenteric fat depot, the size of mesenteric adipocytes, serum levels of total cholesterol, low-density lipoprotein cholesterol, and triglycerides, and the atherogenic index in adult female rats. To assess the involvement of estrogen and androgen receptors in these programming effects, we compared testosterone-exposed rats to rats exposed to estradiol or dihydrotestosterone (DHT). Estradiol-treated rats had lower insulin sensitivity than testosterone-treated rats and, like those rats, had enlarged mesenteric adipocytes and increased triglyceride levels. DHT also reduced insulin sensitivity but did not mimic the other metabolic effects of testosterone. All treated rats were probably anovulatory, but only those treated with testosterone had reduced testosterone levels. This study confirms our previous finding that postnatal administration of testosterone reduces insulin sensitivity in adult female rats and shows that this effect is accompanied by unfavorable changes in mesenteric fat tissue and in serum lipid levels. The findings in the estradiol and DHT groups suggest that estrogen receptors exert stronger metabolic programming effects than androgen receptors. Thus, insults such as sex hormone exposure in early life may have long-lasting effects, thereby creating a predisposition to disturbances in insulin sensitivity, adipose tissue, and lipid profile in adulthood.
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| 7. |
- Allander, SV, et al.
(författare)
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Hepatic nuclear factor 3 and high mobility group I/Y proteins bind the insulin response element of the insulin-like growth factor-binding protein-1 promoter
- 1997
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Ingår i: Endocrinology. - : The Endocrine Society. - 0013-7227 .- 1945-7170. ; 138:10, s. 4291-4300
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Tidskriftsartikel (refereegranskat)abstract
- The insulin response element (IRE) of the human insulin-like growth factor-binding protein-1 (IGFBP-1) promoter contains a palindrome of the T(A/G)TTT sequence crucial to hormonal regulation of many genes. In initial studies of how this IRE participates in hormonal regulation, the electromobility shift assay was used under a variety of conditions to identify IRE-binding proteins. An exhaustive search identified five proteins that specifically bind this IRE; purified proteins were used to show that all five are related to either the high mobility group I/Y (HMGI/Y) or hepatic nuclear factor 3 (HNF3) protein families. Further studies used purified HNF3 and HMGI proteins to show: 1) each protects the IGFBP-1 IRE from deoxyribonuclease I (DNaseI) digestion; and 2) HNF3 but not HMGI/Y binds to the related phosphoenolpyruvate carboxykinase and Apo CIII IREs. A series of IRE mutants with variable responsiveness to insulin were used to show that the presence of a TGTTT sequence in the mutants did parallel, but HMGI/Y and HNF3 binding to the mutants did not parallel, the ability of the mutants to confer the inhibitory effect of insulin. In contrast, HNF3 binding to these IRE mutants roughly correlates with response of the mutants to glucocorticoids. The way by which HNF3 and/or other as yet unidentified IRE-binding proteins confer insulin inhibition to IGFBP-1 transcription and the role of HMGI/Y in IRE function have yet to be established.
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| 8. |
- Andersson, Annica, 1983, et al.
(författare)
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Suppression of Experimental Arthritis and Associated Bone Loss by a Tissue-Selective Estrogen Complex.
- 2016
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Ingår i: Endocrinology. - : The Endocrine Society. - 1945-7170 .- 0013-7227. ; 157:3, s. 1013-20
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Tidskriftsartikel (refereegranskat)abstract
- In addition to the systemic inflammation present in rheumatoid arthritis (RA), decreased estradiol levels in postmenopausal RA patients further accelerate bone loss in these patients. The tissue-selective estrogen complex (TSEC), an estrogen combined with a selective estrogen receptor modulator, is a new hormone replacement therapy option. The first approved TSEC, containing conjugated estrogens and bazedoxifene (BZA), reduces menopausal symptoms and prevents osteoporosis with an improved safety profile compared with conventional hormone replacement therapy. Previous studies have shown that estrogens strongly inhibit experimental arthritis whereas BZA is mildly suppressive. In this study the antiarthritic potential of combined BZA and estradiol is explored for the first time. Female ovariectomized DBA/1 mice were subjected to collagen-induced arthritis, an experimental postmenopausal RA model, and treated with BZA, 17β-estradiol (E2), combined BZA and E2 (BZA/E2), or vehicle. BZA/E2 suppressed arthritis severity and frequency, synovitis, and joint destruction, equally efficient as E2 alone. Unwanted estrogenic proliferative effects on the endometrium were blocked by the addition of BZA, determined by collecting uterine weights. Bone mineral density was measured by peripheral quantitative computed tomography, and all treatments protected collagen-induced arthritis mice from both trabecular and cortical bone loss. Moreover, BZA/E2, but not E2 alone, inhibited preosteoclast formation and reduced serum anticollagen type II antibodies. In conclusion, a TSEC, herein combined BZA/E2, suppresses experimental arthritis and prevents associated bone loss as efficiently as E2 alone but with minimal uterine effects, highlighting the need for clinical trials that evaluate the addition of a TSEC to conventional postmenopausal RA treatment.
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| 9. |
- Andersson, Louise, 1979, et al.
(författare)
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Role of EphA4 receptor signaling in thyroid development: regulation of folliculogenesis and propagation of the C-cell lineage.
- 2011
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Ingår i: Endocrinology. - : The Endocrine Society. - 1945-7170 .- 0013-7227. ; 152:3, s. 1154-64
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Tidskriftsartikel (refereegranskat)abstract
- Transcriptome analysis revealed that the tyrosine kinase receptor EphA4 is enriched in the thyroid bud in mouse embryos. We used heterozygous EphA4-EGFP knock-in mice in which enhanced green fluorescent protein (EGFP) replaced the intracellular receptor domain (EphA4(+/EGFP)) to localize EphA4 protein in thyroid primordial tissues. This showed that thyroid progenitors originating in the pharyngeal floor express EphA4 at all embryonic stages and when follicles are formed in late development. Also, the ultimobranchial bodies developed from the pharyngeal pouch endoderm express EphA4, but the ultimobranchial epithelium loses the EGFP signal before it merges with the median thyroid primordium. Embryonic C cells invading the thyroid are exclusively EphA4-negative. EphA4 expression continues in the adult thyroid. EphA4 knock-out mice and EphA4-EGFP homozygous mutants are euthyroid and have a normal thyroid anatomy but display subtle histological alterations regarding number, size, and shape of follicles. Of particular interest, the pattern of follicular abnormality differs between EphA4(-/-) and EphA4(EGFP/EGFP) thyroids. In addition, the number of C cells is reduced by >50% exclusively in animals lacking EphA4 forward signaling (EphA4(EGFP/EGFP)). Heterozygous EphA4 mutants have no apparent thyroid phenotype. We conclude that EphA4 is a novel regulator of thyroid morphogenesis that impacts on postnatal development of the two endocrine cell lineages of the differentiating gland. In this process both EphA4 forward signaling (in the follicular epithelium) and reverse signaling mediated by its cognate ligand(s) (A- and/or B-ephrins expressed in follicular cells and C cells, respectively) are probably functionally important.
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| 10. |
- Arregi, Igor, et al.
(författare)
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Retinol dehydrogenase-10 regulates pancreas organogenesis and endocrine cell differentiation via paracrine retinoic acid signaling
- 2016
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Ingår i: Endocrinology. - : The Endocrine Society. - 0013-7227 .- 1945-7170. ; 157:12, s. 4615-4631
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Tidskriftsartikel (refereegranskat)abstract
- Vitamin A-derived retinoic acid (RA) signals are critical for the development of several organs, including the pancreas. However, the tissue-specific control of RA synthesis in organ and cell lineage development has only poorly been addressed in vivo. Here, we show that retinol dehydrogenase-10 (Rdh10), a key enzyme in embryonic RA production, has important functions in pancreas organogenesis and endocrine cell differentiation. Rdh10 was expressed in the developing pancreas epithelium and surrounding mesenchyme. Rdh10 null mutant mouse embryos exhibited dorsal pancreas agenesis and a hypoplastic ventral pancreas with retarded tubulogenesis and branching. Conditional disruption of Rdh10 from the endoderm caused increased mortality, reduced body weight, and lowered blood glucose levels after birth. Endodermal Rdh10 deficiency led to a smaller dorsal pancreas with a reduced density of early glucagonβ and insulinβ cells. During the secondary transition, the reduction of Neurogenin3β endocrine progenitors in the mutant dorsal pancreas accounted for fewer β-and α-cells. Changes in the expression of β-and α-cellspecific transcription factors indicated that Rdh10 might also participate in the terminal differentiation of endocrine cells. Together, our results highlight the importance of both mesenchymal andepithelialRdh10forpancreogenesisandthefirstwaveofendocrinecell differentiation.Wefurther propose a model in which the Rdh10-expressing exocrine tissue acts as an essential source ofRAsignals in the second wave of endocrine cell differentiation.
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