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Michael E Symonds, Mark Pope, Ian Bloor, James Law, Reham Alagal, and Helen Budge

Adipose tissue is usually laid down in small amounts in the foetus and is characterised as possessing small amounts of the brown adipose tissue-specific mitochondrial uncoupling protein (UCP)1. In adults, a primary factor determining the abundance and function of UCP1 is ambient temperature. Cold exposure causes activation and the rapid generation of heat through the free flow of protons across the mitochondria with no requirement to convert ADP to ATP. In rodents, housing at an ambient temperature below thermoneutrality promotes the appearance of beige like adipocytes. These arise as discrete regions of UCP1 containing cells in white fat depots. There is increasing evidence to show that to gain credible translational results on brown and beige fat function in rodent models that they should be housed at thermoneutrality. This not only reflects the type of environment in which humans spend a majority of their time, but is in accord with the rise of global temperature caused by industrialisation and the uncontrolled burning of fossil fuels. There is now good evidence in adult humans, that stimulating brown fat can improve glucose homeostasis which can be achieved either by nutritional or pharmacological interventions. The challenge, therefore, is to establish credible developmental models in animals maintained at thermoneutrality which will elucidate the true impact of nutrition. The primary focus should fall specifically on the components of breast milk and how these modulate long term effects on brown or beige fat development and function.

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Jennifer Chen and Jenny E Gunton

Islet transplantation, a therapeutic option to treat type 1 diabetes, is not yet as successful as whole-pancreas transplantation as a treatment for diabetes. Mouse models are commonly used for islet research. However, it is clear disparities exist between islet transplantation outcomes in mice and humans. Given the shortage of transplant-grade islets, it is crucial that we further our understanding of factors that determine long-term islet survival and function post-transplantation. In turn, that may lead to new therapeutic targets and strategies that to improve transplant outcomes. Here, we summarise the current landscape in clinical transplantation, highlight underlying similarities and differences between mouse and human islets, and review interventions that are being considered to create a new pool of β-cells for clinical application.

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Katrine Dahl Bjørnholm, Gro Klitgaard Povlsen, Maria Elm Ougaard, Charles Pyke, Günaj Rakipovski, Pernille Tveden-Nyborg, Jens Lykksefeldt, and Gry Freja Skovsted

The glucagon-like peptide-1 receptor (GLP-1R) is expressed in the renal vasculature and known to be decreased under hypertensive conditions in rats and humans. However, little is known about the regulation in other types of renal pathology involving vascular changes. This study investigates the expression of the GLP-1R in renal vasculature after glomerular injury in the nephrotoxic nephritis mouse model, high cholesterol, and atherosclerosis in the Ldlr-/- mouse on western diet, and ex vivo injury in an organ culture model. The immunohistochemical signal of the GLP-1R was significantly decreased in arteries from mice with nephrotoxic nephritis after 42 days compared to 7 days and saline control (p<0.05). Histological evaluation of kidneys from Ldlr-/- mice on western diet showed a decreased GLP-1R specific immunohistochemical signal (p<0.05). The dilatory response to liraglutide was decreased in western diet fed Ldlr-/- mice compared to C57Bl/6J controls (p<0.05). Organ culture significantly decreased the immunohistochemical signal of the GLP-1R (p<0.05) and the expression of Glp-1r mRNA (p<0.005) compared to fresh. Organ cultured vessels showed vascular smooth muscle cell remodelling as Acta2 expression was decreased (p<0.005) and Ednrb was increased (p<0.05).

In conclusion, nephrotoxic nephritis and hypercholesterolemia led to decreased GLP-1R specific immunohistochemical signal. Ex vivo vascular injury in the organ culture model lead to a decrease in expression of GLP-R expression and contractile VSMC specific markers and increase in expression of dedifferentiation markers suggestive of an inverse relationship between phenotypic swich of the VSMC and the expression of the GLP-1R however, the causal relationship remains elusive.

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Prashant Regmi, Rajesh Chaudhary, Amanda J Page, Amy T Hutchison, Andrew D Vincent, Bo Liu, and Leonie Heilbronn

Time-restricted feeding (TRF) initiated early during the dark phase prevents the metabolic consequences of a high-fat diet in rodent models. However, the metabolic consequences of delaying the initiation of TRF, akin to breakfast skipping in humans, is unclear. We assigned 8-week-old male C57BL/6J mice (n = 192) to chow or high-fat diet ad libitum (AL) for 4 weeks, before randomization to continue AL or 10 h of TRF, initiated at lights off (TRFe) or 4-h after lights off (TRFd) for a further 8 weeks. Oral glucose tolerance tests (1 g/kg), metabolic monitoring and body composition by echoMRI were performed, and tissues were collected at six time points. TRF reduced weight and fat mass vs AL, with a greater reduction in TRFe vs TRFd. TRF improved glucose tolerance and protected mice from high-fat diet-induced hepatosteatosis vs AL, with no difference between TRFe and TRFd. TRF increased the amplitude of Bmal1, Cry1, Per2, Nampt, and Nocturnin mRNA levels in liver. A phase delay in Bmal1, Cry1, Per2, Reverbα, Nampt, NAD, Sirt1, and Nocturnin was observed in TRFd. Thus, delaying TRF limited the weight benefit and induced a phase delay in the hepatic clock, but improved metabolic health. Allowing more flexibility in when TRF is initiated may increase the translational potential of this dietary approach in humans.

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Lauriane Bonnet, Esma Karkeni, Charlène Couturier, Julien Astier, Catherine Defoort, Ljubica Svilar, Franck Tourniaire, Lourdes Mounien, and Jean-François Landrier

Obesity is classically associated with low serum total and free 25(OH)D. Hypotheses have been advanced to explain this observation but mechanisms remain poorly understood, and notably priming events that could explain such association. We investigated the impact of short-term high fat (HF) diet to investigate early events occurring in vitamin D metabolism. Male C57BL/6J mice were fed with a control diet (control group) and HF diet for 4 days. HF fed mice displayed similar body weight to control mice but significantly increased adiposity, together with a decrease of free 25(OH)D concentrations, which could be explained at least in part by a decrease of Cyp2r1 and Cyp3a11 expression in the liver. An increase of 1,25(OH)2D concentration was also observed and could be explained by a decrease of Cyp24a1 expression observed in the kidney. In white adipose tissue (WAT), no modification of vitamin D metabolites quantity detected by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Nevertheless, an increase of Cyp2r1 and Cyp27a1 mRNA expression and a decrease of Cyp27b1 mRNA expression could suggest a possible storage of 25(OH)D in WAT at long-term. Our data are supportive of an active role of HF diet in mediating a priming effect leading the well-established perturbation of the vitamin D metabolism associated with obesity, including a decrease of free 25(OH)D and modulation of expression of genes involved in vitamin D metabolism.

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Andre Sarmento-Cabral, Mercedes del Rio-Moreno, Mari C Vazquez-Borrego, Mariyah Mahmood, Elena Gutierrez-Casado, Natalie Pelke, Grace Guzman, Papasani V Subbaiah, Jose Cordoba-Chacon, Shoshana Yakar, and Rhonda D Kineman

A reduction in hepatocyte growth hormone (GH)-signaling promotes non-alcoholic fatty liver disease (NAFLD). However, debate remains as to the relative contribution of the direct effects of GH on hepatocyte function vs indirect effects, via alterations in insulin-like growth factor 1 (IGF1). To isolate the role of hepatocyte GH receptor (GHR) signaling, independent of changes in IGF1, mice with adult-onset, hepatocyte-specific GHR knockdown (aHepGHRkd) were treated with a vector expressing rat IGF1 targeted specifically to hepatocytes. Compared to GHR-intact mice, aHepGHRkd reduced circulating IGF1 and elevated GH. In male aHepGHRkd, the shift in IGF1/GH did not alter plasma glucose or non-esterified fatty acids (NEFA), but was associated with increased insulin, enhanced systemic lipid oxidation and reduced white adipose tissue (WAT) mass. Livers of male aHepGHRkd exhibited steatosis associated with increased de novo lipogenesis, hepatocyte ballooning and inflammation. In female aHepGHRkd, hepatic GHR protein levels were not detectable, but moderate levels of IGF1 were maintained, with minimal alterations in systemic metabolism and no evidence of steatosis. Reconstitution of hepatocyte IGF1 in male aHepGHRkd lowered GH and normalized insulin, whole body lipid utilization and WAT mass. However, IGF1 reconstitution did not reduce steatosis or eliminate liver injury. RNAseq analysis showed IGF1 reconstitution did not impact aHepGHRkd-induced changes in liver gene expression, despite changes in systemic metabolism. These results demonstrate the impact of aHepGHRkd is sexually dimorphic and the steatosis and liver injury observed in male aHepGHRkd mice is autonomous of IGF1, suggesting GH acts directly on the adult hepatocyte to control NAFLD progression.

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Leila Arbabi, Qun Li, Belinda A Henry, and Iain J Clarke

The role of glucagon-like peptide-1 (GLP-1) on gonadotropin releasing hormone (GnRH) secretion was investigated in ovariectomised (OVX) ewes, in which GnRH and luteinising hormone (LH) secretion had been restrained by treatment with estrogen and progesterone. Guide tubes for microinjection were placed above the ME and the animals allowed to recover for 1 month. Jugular venous blood samples were taken via cannulae at 10 min intervals. Vehicle (50nl) was injected into the ME at 2h, followed by injection of GLP-1 ((7-36)-amide - 0.5 or 1 nmole) or its receptor agonist, exendin 4 (0.5 nmole) at 4h (n=5). Plasma LH levels were quantified as a surrogate measure of GnRH secretion. GLP-1 microinjection into the ME elicited a large amplitude LH pulse in jugular plasma, the effect was greater at the higher dose. Exendin-4 microinjection caused a large, sustained increase in plasma LH levels. To determine how GLP-1 might exert an effect on GnRH secretion, we employed double labelled in situ hybridisation, with RNAScope, for co-localisation of the GLP-1 receptor (GLP-1R) in GnRH, Kisspeptin and NPY cells in the hypothalami of 3 ewes in the luteal phase of the estrous cycle. GLP-1R expression was clearly visible but the receptor was not expressed in GNRH1 or NPY expressing neurons and was visualised in <5% of KISS1 expressing neurons. We conclude that GLP-1 may act at the level of the secretory terminals of GnRH neurons in the ME to stimulate GnRH secretion, the pathway through which such effect is manifest remains unknown.

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Dominik Simon Botermann, Nadine Brandes, Anke Frommhold, Ina Heß, Alexander Wolff, Arne Zibat, Heidi Hahn, Rolf Buslei, and Anja Uhmann

Ubiquitous overactivation of Hedgehog signaling in adult pituitaries results in increased expression of proopiomelanocortin (Pomc), growth hormone (Gh) and prolactin (Prl), elevated adrenocorticotropic hormone (Acth) production and proliferation of Sox2+ cells. Moreover, ACTH, GH and PRL-expressing human pituitary adenomas strongly express the Hedgehog target GLI1. Accordingly, Hedgehog signaling seems to play an important role in pathology and probably also in homeostasis of the adult hypophysis. However, the specific Hedgehog-responsive pituitary cell type has not yet been identified. We here investigated the Hedgehog pathway activation status and the effects of deregulated Hedgehog signaling cell-specifically in endocrine and non-endocrine pituitary cells. We demonstrate that Hedgehog signaling is unimportant for the homeostasis of corticotrophs, whereas it is active in subpopulations of somatotrophs and follicullo-stellate cells in vivo. Reinforcement of Hedgehog signaling activity in folliculo-stellate cells stimulates growth hormone production/release from somatotrophs in a paracrine manner, which most likely is mediated by the neuropeptide vasoactive intestinal peptide. Overall, our data show that Hedgehog signaling affects the homeostasis of pituitary hormone production via folliculo-stellate cell-mediated regulation of growth hormone production/secretion.

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Tianxue Zhao, Qian Li, Qianyun Mao, Kaida Mu, and Chen Wang

Neuronal nitric oxide synthase (nNOS) interacts with its adaptor protein NOS1AP through its PZD domain in the neurons. Previously, we had reported that NOS1AP enhanced hepatic insulin sensitivity through its PZD-binding domain, which suggested that nNOS might mediate the effect of NOS1AP. This study aimed to examine the role and underlying mechanisms of nNOS in regulating hepatic insulin sensitivity. nNOS co-localized with NOS1AP in mouse liver. The overexpression of NOS1AP in mouse liver decreased the level of phosphorylated nNOS (p-nNOS (Ser1417)), the active form of nNOS. Conversely, the liver-specific deletion of NOS1AP increased the level of p-nNOS (Ser1417). The overexpression of nNOS in the liver of high-fat diet-induced obese mice exacerbated glucose intolerance, enhanced intrahepatic lipid accumulation, decreased glycogen storage, and blunted insulin-induced phosphorylation of IRβ and Akt in the liver. Similarly, nNOS overexpression increased triglyceride production, decreased glucose utilization, and downregulated insulin-induced expression of p-IRβ, p-Akt, and p-GSK3β in the HepG2 cells. In contrast, treatment with Nω-propyl-L-arginine (L-NPA), a selective nNOS inhibitor, improved glucose tolerance and upregulated insulin-induced phosphorylation of IRβ and Akt in the liver of ob/ob mice. Furthermore, overexpression of nNOS increased p38MAPK phosphorylation in the HepG2 cells. In contrast, inhibition of p38MAPK with SB203580 significantly reversed the nNOS-induced inhibition of insulin signaling activity (all P < 0.05). This indicated that hepatic nNOS inhibited the insulin-signaling pathway through the activation of p38MAPK. These findings suggest that nNOS is involved in the development of hepatic insulin resistance and that nNOS might be a potential therapeutic target for diabetes.