- Highlights from SfE BES 2018. [Journal Article]
- NRNat Rev Endocrinol 2018 Dec 05
- Modelling the endocrine pancreas in health and disease. [Review]
- NRNat Rev Endocrinol 2018 Nov 30
- Diabetes mellitus is a multifactorial disease affecting increasing numbers of patients worldwide. Progression to insulin-dependent diabetes mellitus is characterized by the loss or dysfunction of pan...
Diabetes mellitus is a multifactorial disease affecting increasing numbers of patients worldwide. Progression to insulin-dependent diabetes mellitus is characterized by the loss or dysfunction of pancreatic β-cells, but the pathomechanisms underlying β-cell failure in type 1 diabetes mellitus and type 2 diabetes mellitus are still poorly defined. Regeneration of β-cell mass from residual islet cells or replacement by β-like cells derived from stem cells holds great promise to stop or reverse disease progression. However, the development of new treatment options is hampered by our limited understanding of human pancreas organogenesis due to the restricted access to primary tissues. Therefore, the challenge is to translate results obtained from preclinical model systems to humans, which requires comparative modelling of β-cell biology in health and disease. Here, we discuss diverse modelling systems across different species that provide spatial and temporal resolution of cellular and molecular mechanisms to understand the evolutionary conserved genotype-phenotype relationship and translate them to humans. In addition, we summarize the latest knowledge on organoids, stem cell differentiation platforms, primary micro-islets and pseudo-islets, bioengineering and microfluidic systems for studying human pancreas development and homeostasis ex vivo. These new modelling systems and platforms have opened novel avenues for exploring the developmental trajectory, physiology, biology and pathology of the human pancreas.
- Hepatic HKDC1 expression contributes to liver metabolism. [Journal Article]
- EEndocrinology 2018 Dec 03
- Glucokinase (GCK) is the principal hexokinase (HK) in the liver, operating as a glucose sensor to regulate glucose metabolism and lipid homeostasis. Recently, we proposed Hexokinase Domain Containing...
Glucokinase (GCK) is the principal hexokinase (HK) in the liver, operating as a glucose sensor to regulate glucose metabolism and lipid homeostasis. Recently, we proposed Hexokinase Domain Containing-1 (HKDC1) to be a novel 5th HK with expression in the liver. Here, we reveal HKDC1 to have low glucose-phosphorylating ability and demonstrate its association with the mitochondria in hepatocytes. As we have shown previously that genetic deletion of HKDC1 leads to altered hepatic triglyceride levels, we also explored the influence of overexpression of HKDC1 in hepatocytes on cellular metabolism observing reduced glycolytic capacity and maximal mitochondrial respiration with concurrent reductions in glucose oxidation and mitochondrial membrane potential. Furthermore, we found that acute in vivo overexpression of HKDC1 in the liver induced significant changes in mitochondrial dynamics. Altogether, these findings suggest overexpression of HKDC1 causes mitochondrial dysfunction in hepatocytes. However, its overexpression was not enough to alter energy storage in the liver, but led to mild improvement in glucose tolerance. We next investigated the conditions necessary to induce HKDC1 expression, observing HKDC1 expression to be elevated in human patients whose livers were at more advanced stages of NAFLD and similarly found high liver expression in mice on diets causing high levels of liver inflammation and fibrosis. Overall, our data suggests HKDC1 expression in hepatocytes results in defective mitochondrial function and altered hepatocellular metabolism and speculate that its expression in liver may play a role in the development of NAFLD.
- GnRH - a key regulator of FSH. [Journal Article]
- EEndocrinology 2018 Dec 04
- The hypothalamic decapeptide, GnRH, is the gatekeeper of mammalian reproductive development and function. Activation of specific, high affinity cell surface receptors (GnRHR) on gonadotropes by GnRH ...
The hypothalamic decapeptide, GnRH, is the gatekeeper of mammalian reproductive development and function. Activation of specific, high affinity cell surface receptors (GnRHR) on gonadotropes by GnRH triggers signal transduction cascades to stimulate the coordinated synthesis and secretion of the pituitary gonadotropins, FSH and LH. These hormones direct gonadal steroidogenesis and gametogenesis, making their tightly regulated production and secretion essential for normal sexual maturation and reproductive health. FSH and LH are glycoprotein heterodimers comprised of a common α-subunit and a unique β-subunit (FSHβ and LHβ, respectively), which determines the biological specificity of the gonadotropins. The unique β-subunit is the rate limiting step for the production of the mature gonadotropins. Therefore, FSH synthesis is regulated at the transcriptional level by Fshb gene expression. The overarching goal of this review is to expand our understanding of the mechanisms and pathways underlying the carefully orchestrated control of FSH synthesis and secretion by GnRH, focusing on the transcriptional regulation of the Fshb gene. Identification of these regulatory mechanisms is not only fundamental to our understanding of normal reproductive function but will also provide a context for the elucidation of the pathophysiology of reproductive disorders and infertility to lead to potential new therapeutic approaches.
- Impact of genes and environment on obesity and cardiovascular disease. [Journal Article]
- EEndocrinology 2018 Dec 03
- Obesity and abdominal obesity have been closely related to cardiovascular outcomes, and recent evidence has indicated that environmental and genetic factors act in concert in determining the risks of...
Obesity and abdominal obesity have been closely related to cardiovascular outcomes, and recent evidence has indicated that environmental and genetic factors act in concert in determining the risks of these conditions. Improving adherence to healthy lifestyle habits and healthy dietary patterns can at least partly counteract genetic variations related risks of obesity and cardiovascular disease (CVD). Other factors, such as epigenetic alterations, may also modulate a relationship between genetic susceptibility and these disorders. In this review, we highlighted data from recent studies on gene and environmental risk factors for obesity and CVD, and described how these findings might inform understanding of the complex roles of interactions between genes and environmental factors in the development of obesity and CVD.
- Training your brain can improve food choice. [Journal Article]
- NRNat Rev Endocrinol 2018 Dec 04
- Bisphenol A alters Bmal1, Per2 and Rev-Erba mRNA and requires Bmal1 to increase neuropeptide Y expression in hypothalamic neurons. [Journal Article]
- EEndocrinology 2018 Nov 30
- Bisphenol A (BPA), a ubiquitous, environmental endocrine disruptor, is considered an obesogen. Its role in the hypothalamic control of energy balance, however, remains largely unexplored. As disrupti...
Bisphenol A (BPA), a ubiquitous, environmental endocrine disruptor, is considered an obesogen. Its role in the hypothalamic control of energy balance, however, remains largely unexplored. As disruption of the circadian clock is tightly associated with metabolic consequences, we explored how BPA affects the components of the molecular circadian clock in the feeding-related neurons of the hypothalamus. In immortalized POMC and NPY/AgRP-expressing hypothalamic cell lines and primary culture, we describe that BPA significantly alters mRNA expression of circadian clock genes Bmal1, Per2 and Rev-Erbα. Furthermore, we use newly generated Bmal1-knock-out (KO) hypothalamic cell lines to link the BPA-induced neuropeptide dysregulation to the molecular clock. Specifically, BPA increased Npy, Agrp and Pomc mRNA expression in wildtype hypothalamic cells, whereas the increase in Npy, but not Agrp or Pomc, was abolished in cell lines lacking BMAL1. In line with this, BPA led to increased BMAL1 binding to the Npy promotor, potentially increasing Npy transcription. In conclusion, we show for the first time that BPA-mediated dysregulation of the circadian molecular clock is linked to the deleterious effects of BPA on neuropeptide expression. Furthermore, we describe novel hypothalamic Bmal1-KO cell lines to study the role of BMAL1 in hypothalamic responses to metabolic, hormonal and environmental factors.
- A Role for the Wandering Uterus? [Journal Article]
- EEndocrinology 2018 Nov 28
- Genetically inherited - and high fat diet induced - obesity differentially alters spermatogenesis in adult male rats. [Journal Article]
- EEndocrinology 2018 Nov 28
- Obesity is a multifactorial disorder with predominantly genetic and/or environmental causes. Thus, our aim was to delineate effects of genetically inherited and high fat diet induced obesity on ferti...
Obesity is a multifactorial disorder with predominantly genetic and/or environmental causes. Thus, our aim was to delineate effects of genetically inherited and high fat diet induced obesity on fertility and spermatogenesis using two Wistar rat models: genetically inherited obese (GIO): WNIN/Ob and diet induced obese (DIO): High fat diet. The terminal body weights were similar in both GIO and DIO groups, but, there was a significant difference in metabolic and hormone profile between the two groups. Fertility assessment revealed significant decrease in the litter size due to increased pre- and post-implantation loss in DIO group, while GIO group were infertile due to lack of libido. Significant decrease in sperm counts were observed in GIO but not in DIO group despite body weights being comparable in both groups. To study the effect of obesity on spermatogenesis, enumeration of testicular cells based on ploidy and cell type specific expression markers demonstrated that both GIO and DIO affects mitosis process as spermatogonia and S phase population were increased. However, distinctive effects were observed on meiosis and spermiogenesis in both the groups. Our results indicate that the differential effects of GIO and DIO on fertility and spermatogenesis could be due to the significant difference in the white adipose tissue accumulation between the groups and not due to high body weights. The differential effects of obesity suggest that male obesity induced infertility observed in humans could be a combination of both genetic and environmental factors.
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- A Carboxy-Terminal Monoleucine-Based Motif Participates in the Basolateral Targeting of the Na+/I- Symporter (NIS). [Journal Article]
- EEndocrinology 2018 Nov 28
- The Na+/I- symporter (NIS), a glycoprotein expressed at the basolateral plasma membrane of thyroid follicular cells, mediates I- accumulation for thyroid hormonogenesis, and radioiodide therapy for d...
The Na+/I- symporter (NIS), a glycoprotein expressed at the basolateral plasma membrane of thyroid follicular cells, mediates I- accumulation for thyroid hormonogenesis, and radioiodide therapy for differentiated thyroid carcinoma. However, differentiated thyroid tumors often exhibit lower I- transport than normal thyroid tissue (or even undetectable I- transport). Paradoxically, the majority of differentiated thyroid cancers show intracellular NIS expression, suggesting abnormal targeting to the plasma membrane. Therefore, a thorough understanding of the mechanisms that regulate NIS plasma membrane transport would have multiple implications for radioiodide therapy. Herein, we show that the intracellularly facing carboxy-terminus of NIS is required for the transport of the protein to the plasma membrane. Moreover, the carboxy-terminus contains dominant basolateral information. Using internal deletions and site-directed mutagenesis at the carboxy-terminus, we identified a highly conserved monoleucine-based sorting motif that determines NIS basolateral expression. Furthermore, in clathrin adaptor protein (AP)-1B-deficient cells, NIS sorting to the basolateral plasma membrane is compromised, causing the protein to also be expressed at the apical plasma membrane. Computer simulations suggest that the AP-1B subunit σ1 recognizes the monoleucine-based sorting motif in NIS carboxy-terminus. Although the mechanisms by which NIS is intracellularly retained in thyroid cancer remain elusive, our findings may open up new avenues for identifying molecular targets that can be used to treat radioiodide-refractory thyroid tumors that express NIS intracellularly.