| 11. |
- Pereira, Maria J, 1981-, et al.
(författare)
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Direct effects of glucagon on glucose uptake and lipolysis in human adipocytes
- 2020
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Ingår i: Molecular and Cellular Endocrinology. - : ELSEVIER IRELAND LTD. - 0303-7207 .- 1872-8057. ; 503
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Tidskriftsartikel (refereegranskat)abstract
- We aim to investigate the expression of the glucagon receptor (GCGR) in human adipose tissue, and the impact of glucagon in glucose uptake and lipolysis in human adipocytes. GCGR gene expression in human subcutaneous and visceral adipose tissue was demonstrated, albeit at low levels and with an inter-individual variation. Furthermore, GCGR expression was not significantly different between subjects with T2D and matched controls, and we found no significant association with BMI. Glucagon only at a supra-physiological concentration (10-100 nM) significantly increased basal and insulin-stimulated glucose uptake by up to 1.5-fold. Also, glucagon (0.01 and 1 nM) dose-dependently increased basal and isoproterenol-stimulated lipolysis up to 3.7- and 1.7-fold, respectively, compared to control. In addition, glucagon did not change insulin sensitivity to stimulate glucose uptake or inhibit lipolysis. In conclusion, we show that the GCGR gene is expressed at low levels in human adipose tissue, and glucagon at high concentrations can increase both glucose uptake and lipolysis in human adipocytes. Taken together, our data suggest that glucagon at physiological levels has minor direct effects on the regulation of adipocyte metabolism, but does not antagonize the insulin effect to stimulate glucose uptake and inhibit lipolysis in human adipocytes.
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| 12. |
- Schumacher, Rocio, et al.
(författare)
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Temporary effects of neonatal overfeeding on homeostatic control of food intake involve alterations in POMC promoter methylation in male rats
- 2021
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Ingår i: Molecular and Cellular Endocrinology. - : ELSEVIER IRELAND LTD. - 0303-7207 .- 1872-8057. ; 522
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Tidskriftsartikel (refereegranskat)abstract
- A small litter (SL) model was used to determine how neonatal overfeeding affects the homeostatic control of food intake in male rats at weaning and postnatal day (PND) 90. At PND4, litters were reduced to small (4 pups/dam) or normal (10 pups/dam) litters. At weaning, SL rats showed higher body weight and characteristic features of the metabolic syndrome. Gene expression of pro-opiomelanocortin (POMC), cocaine and amphetamine regulated transcript, neuropeptide Y (NPY) and leptin and ghrelin (GHSR) receptors were increased and POMC promoter was hypomethylated in arcuate nucleus, indicating that the early development of obesity may involve the GHSR/NPY system and changes in POMC methylation state. At PND90, body weight, metabolic parameters and gene expression were restored; however, POMC methylation state remained altered. This work provides insight into the effects of neonatal overfeeding, showing the importance of developmental plasticity in restoring early changes in central pathways involved in metabolic programming.
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| 13. |
- Vinnars, Marie-Therese, et al.
(författare)
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Pregnancy-related maternal physiological adaptations and fetal chemical exposure
- 2023
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Ingår i: Molecular and Cellular Endocrinology. - : Elsevier. - 0303-7207 .- 1872-8057. ; 578
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Tidskriftsartikel (refereegranskat)abstract
- Prenatal life represents a susceptible window of development during which chemical exposures can permanently alter fetal development, leading to an increased likelihood of disease later in life. Therefore, it is essential to assess exposure in the fetus. However, direct assessment in human fetuses is challenging, so most research measures maternal exposure. Pregnancy induces a range of significant physiological changes in women that may affect chemical metabolism and responses. Moreover, placental function, fetal sex, and pregnancy complications may further modify these exposures. The purpose of this narrative review is to give an overview of major pregnancy-related physiological changes, including placental function and impacts of pregnancy complications, to summarize existing studies assessing chemical exposure in human fetal organs, and to discuss possible interactions between physiological changes and exposures. Our review reveals major knowledge gaps in factors affecting fetal chemical exposure, highlighting the need to develop more sophisticated tools for chemical health risk assessment in fetuses.
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| 14. |
- Vranic, Milica, et al.
(författare)
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Effects of the second-generation antipsychotic drugs aripiprazole and olanzapine on human adipocyte differentiation
- 2023
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Ingår i: Molecular and Cellular Endocrinology. - : Elsevier. - 0303-7207 .- 1872-8057. ; 561
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Tidskriftsartikel (refereegranskat)abstract
- Second-generation antipsychotics (SGAs), used as the cornerstone treatment for schizophrenia and other mental disorders, can cause adverse metabolic effects (e.g. obesity and type 2 diabetes). We investigated the effects of SGAs on adipocyte differentiation and metabolism. The presence of therapeutic concentrations of aripiprazole (ARI) or its active metabolite dehydroaripiprazole (DARI) during human adipocyte differentiation impaired adipocyte glucose uptake while the expression of gene markers of fatty acid oxidation were increased. Additionally, the use of a supra-therapeutic concentration of ARI inhibited adipocyte differentiation. Furthermore, olanzapine (OLA), a highly obesogenic SGA, directly increased leptin gene expression but did not affect adipocyte differentiation and metabolism. These molecular insights are novel, and suggest that ARI, but not OLA, may directly act via alterations in adipocyte differentiation and potentially by causing a switch from glucose to lipid utilization in human adipocytes. Additionally, SGAs may effect crosstalk with other organs, such as the brain, to exert their adverse metabolic effects.
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| 15. |
- Fontaine, C., et al.
(författare)
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The tissue-specific effects of different 17 beta-estradiol doses reveal the key sensitizing role of AF1 domain in ER alpha activity
- 2020
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Ingår i: Molecular and Cellular Endocrinology. - : Elsevier BV. - 0303-7207. ; 505
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Tidskriftsartikel (refereegranskat)abstract
- 17 beta-Estradiol (E2) action can be mediated by the full-length estrogen receptor alpha (ER alpha 66), and also by the AF1 domain-deficient ER alpha (ER alpha 46) isoform, but their respective sensitivity to E2 is essentially unknown. We first performed a dose response study using subcutaneous home-made pellets mimicking either metestrus, proestrus or a pharmacological doses of E2, which resulted in plasma concentrations around 3, 30 and 600 pM, respectively. Analysis of the uterus, vagina and bone after chronic exposure to E2 demonstrated dose-dependent effects, with a maximal response reached at the proestrus-dose in wild type mice expressing mainly ER alpha 66. In contrast, in transgenic mice harbouring only an ER alpha deleted in AF1, these effects of E2 were either strongly shifted rightward (10-100-fold) and/or attenuated, depending on the tissue studied. Finally, experiments in different cell lines transfected with ER alpha 66 or ER alpha 46 also delineated varying profiles of ER alpha AF1 sensitivity to E2. Altogether, this work emphasizes the importance of dose in the tissue-specific actions of E2 and demonstrates the key sensitizing role of AF1 in ER alpha activity.
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| 16. |
- Niss, Kristoffer, et al.
(författare)
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Effects of active farnesoid X receptor on GLUTag enteroendocrine L cells
- 2020
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Ingår i: Molecular and Cellular Endocrinology. - : Elsevier BV. - 0303-7207. ; 517
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Tidskriftsartikel (refereegranskat)abstract
- Activated transcription factor (TF) farnesoid X receptor (FXR) represses glucagon-like peptide-1 (GLP-1) secretion in enteroendocrine L cells. This, in turn, reduces insulin secretion, which is triggered when β cells bind GLP-1. Preventing FXR activation could boost GLP-1 production and insulin secretion. Yet, FXR's broader role in L cell biology still lacks understanding. Here, we show that FXR is a multifaceted TF in L cells using proteomics and gene expression data generated on GLUTag L cells. Most striking, 252 proteins regulated upon glucose stimulation have their abundances neutralized upon FXR activation. Mitochondrial repression or glucose import block are likely mechanisms of this. Further, FXR physically targets bile acid metabolism proteins, growth factors and other TFs, regulates ChREBP, while extensive text-mining found 30 FXR-regulated proteins to be well-known in L cell biology. Taken together, this outlines FXR as a powerful TF, where GLP-1 secretion block is just one of many downstream effects.
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| 17. |
- Panzitt, K., et al.
(författare)
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Recent advances on FXR-targeting therapeutics
- 2022
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Ingår i: Molecular and Cellular Endocrinology. - : Elsevier BV. - 0303-7207. ; 552
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Tidskriftsartikel (refereegranskat)abstract
- The bile acid receptor FXR has emerged as a bona fide drug target for chronic cholestatic and metabolic liver diseases, ahead of all non-alcoholic fatty liver disease (NAFLD). FXR is highly expressed in the liver and intestine and activation at both sites differentially contributes to its desired metabolic effects. Unrestricted FXR activation, however, also comes along with undesired effects such as a pro-atherogenic lipid profile, pruritus and hepatocellular toxicity under certain conditions. Several pre-clinical studies have confirmed the potency of FXR activation for cholestatic and metabolic liver diseases, but overall it remains still open whether selective activation of intestinal FXR is advantageous over pan-FXR activation and whether restricted or modulated FXR activation can limit some of the side effects. Even more, FXR antagonist also bear the potential as intestinal-selective drugs in NAFLD models. In this review we will discuss the molecular prerequisites for FXR activation, pan-FXR activation and intestinal FXR in/activation from a therapeutic point of view, different steroidal and non-steroidal FXR agonists, ways to restrict FXR activation and finally what we have learned from pre-clinical models and clinical trials with different FXR therapeutics.
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| 18. |
- Rulli, Susana B, et al.
(författare)
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Elevated chorionic gonadotropic hormone in transgenic mice induces parthenogenetic activation and ovarian teratomas.
- 2024
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Ingår i: Molecular and cellular endocrinology. - 1872-8057. ; 587
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Tidskriftsartikel (refereegranskat)abstract
- Both male and female reproductive functions are impacted by altered gonadotrophin secretion and action, which may also influence the development of endocrine tumours. To ascertain if chronic hypersecretion of human chorionic gonadotropin (hCG) contributes to the development of gonadal tumours, double transgenic (TG) mice that overexpress hCGα- and β-subunits were analysed. By the age of two months, ovarian tumours with characteristics of teratomas developed with 100% penetrance. Teratomas were also seen in wild-type ovaries orthotopically transplanted into TG mice, demonstrating an endocrine/paracrine mechanism for the hCG-induced ovarian tumorigenesis. Both in vitro and in vivo experiments showed oocyte parthenogenetic activation in TG females. In addition, ovaries showed reduced ovulatory gene expression, inhibited ERK1/2 phosphorylation, and impaired cumulus cell expansion. Hence, persistently high endocrine hCG activity causes parthenogenetic activation and development of ovarian teratomas, along with altered follicle development and impaired ERK1/2 signalling, offering a novel mechanism associated with the molecular pathogenesis of ovarian teratomas.
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| 19. |
- Ruuskanen, Suvi, et al.
(författare)
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Endocrinology of thermoregulation in birds in a changing climate
- 2020
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Ingår i: Molecular and Cellular Endocrinology. - : Elsevier BV. - 0303-7207.
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Tidskriftsartikel (refereegranskat)abstract
- The ability to maintain a (relatively) stable body temperature in a wide range of thermal environments by use of endogenous heat production is a unique feature of endotherms such as birds. Endothermy is acquired and regulated via various endocrine and molecular pathways, and ultimately allows wide aerial, aquatic, and terrestrial distribution in variable environments. However, due to our changing climate, birds are faced with potential new challenges for thermoregulation, such as more frequent extreme weather events, lower predictability of climate, and increasing mean temperature. We provide an overview on thermoregulation in birds and its endocrine and molecular mechanisms, pinpointing gaps in current knowledge and recent developments, focusing especially on non-model species to understand the generality of, and variation in, mechanisms. We highlight plasticity of thermoregulation and underlying endocrine regulation, because thorough understanding of plasticity is key to predicting responses to changing environmental conditions. To this end, we discuss how changing climate is likely to affect avian thermoregulation and associated endocrine traits, and how the interplay between these physiological processes may play a role in facilitating or constraining adaptation to a changing climate. We conclude that while the general patterns of endocrine regulation of thermogenesis are quite well understood, at least in poultry, the molecular and endocrine mechanisms that regulate, e.g. mitochondrial function and plasticity of thermoregulation over different time scales (from transgenerational to daily variation), need to be unveiled. Plasticity may ameliorate climate change effects on thermoregulation to some extent, but the increased frequency of extreme weather events, and associated changes in resource availability, may be beyond the scope and/or speed for plastic responses. This could lead to selection for more tolerant phenotypes, if the underlying physiological traits harbour genetic and individual variation for selection to act on – a key question for future research.
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| 20. |
- Saliha, Musovic, 1990, et al.
(författare)
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Noradrenaline and ATP regulate adiponectin exocytosis in white adipocytes: Disturbed adrenergic and purinergic signalling in obese and insulin-resistant mice
- 2022
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Ingår i: Molecular and Cellular Endocrinology. - : Elsevier BV. - 0303-7207. ; 549
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Tidskriftsartikel (refereegranskat)abstract
- White adipocyte adiponectin exocytosis is triggered by cAMP and a concomitant increase of cytosolic Ca2+ potentiates its release. White adipose tissue is richly innervated by sympathetic nerves co-releasing noradrenaline (NA) and ATP, which may act on receptors in the adipocyte plasma membrane to increase cAMP via adrenergic receptors and Ca2+ via purinergic receptors. Here we determine the importance of NA and ATP for the regulation of white adipocyte adiponectin exocytosis, at the cellular and molecular level, and we specifically detail the ATP signalling pathway. We demonstrate that tyrosine hydroxylase (enzyme involved in catecholamine synthesis) is dramatically reduced in inguinal white adipose tissue (IWAT) isolated from mice with diet induced obesity; this is associated with diminished levels of NA in IWAT and with a reduced ratio of high molecular-weight (HMW) to total adiponectin in serum. Adiponectin exocytosis (measured as an increase in plasma membrane capacitance and as secreted product) is triggered by NA or ATP alone in cultured and primary mouse IWAT adipocytes, and enhanced by a combination of the two secretagogues. The ATP-induced adiponectin exocytosis is largely Ca2+-dependent and activated via purinergic P2Y2 receptors (P2Y2Rs) and the Gq11/PLC pathway. Adiponectin release induced by the nucleotide is abrogated in adipocytes isolated from obese and insulin-resistant mice, and this is associated with ~70% reduced abundance of P2Y2Rs. The NA-triggered adiponectin exocytosis is likewise abolished in "obese adipocytes ", concomitant with a 50% lower gene expression of beta 3 adrenergic receptors (beta 3ARs). An increase in intracellular Ca2+ is not required for the NA-stimulated adiponectin secretion. Collectively, our data suggest that sympathetic innervation is a principal regulator of adiponectin exocytosis and that disruptions of this control are associated with the obesity-associated reduction of circulating levels of HMW/total adiponectin.
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