A5081451972- Metabolism, Diabetes, and Cancer
- Pancreatic function and diabetes
- Cannabis and Cannabinoid Research
- Adipose Tissue and Metabolism
- Protein Kinase Regulation and GTPase Signaling
- Diet, Metabolism, and Disease
- Caveolin-1 and cellular processes
- PI3K/AKT/mTOR signaling in cancer
- Sphingolipid Metabolism and Signaling
- Mitochondrial Function and Pathology
- Sleep and Wakefulness Research
- Genetics and Neurodevelopmental Disorders
- Neuroscience of respiration and sleep
- Muscle metabolism and nutrition
- Lipid Membrane Structure and Behavior
- Sirtuins and Resveratrol in Medicine
- Epigenetics and DNA Methylation
- Glycosylation and Glycoproteins Research
- Receptor Mechanisms and Signaling
- Adipokines, Inflammation, and Metabolic Diseases
- Calcium signaling and nucleotide metabolism
- Liver Disease Diagnosis and Treatment
- Wnt/β-catenin signaling in development and cancer
- Ovarian function and disorders
- Plant Gene Expression Analysis
University of Dundee
2012-2024
Google (United States)
2016
Christ University
2016
Ninewells Hospital
2003-2008
PDK1 activates a group of kinases, including protein kinase B (PKB)/Akt, p70 ribosomal S6 (S6K), and serum glucocorticoid-induced (SGK), that mediate many the effects insulin as well other agonists. interacts with phosphoinositides through pleckstrin homology (PH) domain. To study role this interaction, we generated knock-in mice expressing mutant incapable binding phosphoinositides. The are significantly small, resistant, hyperinsulinemic. Activation PKB is markedly reduced in result lower...
Elevated ceramide concentrations in adipocytes and skeletal muscle impair PKB (protein kinase B; also known as Akt)-directed insulin signalling to key hormonal end points. An important feature of this inhibition involves the ceramide-induced activation atypical PKCzeta C-zeta), which associates with negatively regulates PKB. In present study, we demonstrate that is critically dependent on targeting subsequent retention PKCzeta-PKB within CEM (caveolin-enriched microdomains), facilitated by...
ABSTRACT Emerging evidence indicates that G‐protein coupled receptor 55 (GPR55), a nonclassic of the endocannabinoid system is activated by L‐α‐lysophosphatidylinositol and various cannabinoid ligands, may regulate endocrine function energy metabolism. We examined how GPR55 deficiency modulation affects insulin signaling in skeletal muscle, adipose tissue, liver alongside expression analysis proteins implicated action show GPR55‐null mice display decreased sensitivity these tissues, as...
The liver plays an important role in insulin-regulated glucose homoeostasis. To study the function of PDK1 (3-phosphoinositide-dependent protein kinase-1) signalling pathway mediating insulin's actions liver, we employed CRE recombinase/loxP technology to generate L(liver)-PDK1−/− mice, which lack expression hepatocytes and insulin failed induce activation PKB liver. L-PDK1−/− mice were not insulin-intolerant, possessed normal levels blood under feeding conditions, but markedly...
Myostatin deficiency leads to both an increased rate of protein synthesis and skeletal muscle hypertrophy. However, the mechanisms involved in mediating these effects are not yet fully understood. Here, we demonstrate that genetic loss myostatin enhanced expression kinase B mammalian target rapamycin/S6K signalling components, consistent with their elevated activity. This is associated a reduction PGC1α COX IV, proteins which play important roles maintaining mitochondrial function....
OBJECTIVE The endogenous cannabinoid (or endocannabinoid) system (ECS) is part of a central neuromodulatory thought to play key role in the regulation feeding behavior and energy balance. However, increasing evidence suggests that modulation ECS may also act regulate peripheral mechanisms involved these processes, including lipogenesis adipose tissue liver, insulin release from pancreatic β-cells, glucose uptake into skeletal muscle. It was recently shown receptor type 1 (CB1) 2 (CB2), both...
Ceramides are known to promote insulin resistance in a number of metabolically important tissues including skeletal muscle, the predominant site insulin-stimulated glucose disposal. Depending on cell type, these lipid intermediates have been shown inhibit protein kinase B (PKB/Akt), key mediator metabolic actions insulin, via two distinct pathways: one involving action atypical C (aPKC) isoforms, and second dependent phosphatase-2A (PP2A). The main aim this study was explore mechanisms by...
Iron is an indispensable micronutrient that regulates many aspects of cell function, including growth and proliferation. These processes are critically dependent upon signalling via the mammalian or mechanistic target rapamycin complex 1 (mTORC1). Herein, we test whether iron depletion induced by incubation with chelator, deferoxamine (DFO), mediates its effects on through mTORC1-directed protein synthesis. We have used Caco-2 cells, a well-established in vitro model human intestinal...
The phospholipid l-α-lysophosphatidylinositol (LPI), an endogenous ligand for GPR55, is elevated in patients with acute coronary syndrome, and a GPR55 antagonist cannabidiol (CBD) reduces experimental ischemia/reperfusion (I/R) injury. While LPI activates multiple signaling pathways, little known about which ones are important cardiomyocytes. In this study we explored whether activation of the Rho kinase/ROCK/p38 MAPK pathway responsible LPI-induced extension I/R Using high-throughput...
Chronic exposure of skeletal muscle to saturated fatty acids, such as palmitate (C16:0), enhances proinflammatory IKK-NFκB signaling by a mechanism involving the MAP kinase (Raf-MEK-ERK) pathway. Raf activation can be induced its dissociation from Raf-kinase inhibitor protein (RKIP) diacylglycerol (DAG)-sensitive C (PKC). However, whether these molecules mediate action palmitate, an important precursor for DAG synthesis, is currently unknown. Here, involvement DAG-sensitive PKCs, RKIP, and...
Summary The endocannabinoid system can modulate energy homeostasis by regulating feeding behaviour as well peripheral storage and utilization. Importantly, many of its metabolic actions are mediated through the cannabinoid type 1 receptor ( CB 1R), whose hyperactivation is associated with obesity impaired function. Herein, we explored effects administering rimonabant, a selective 1R inverse agonist, upon key parameters in young (4 month old) aged (17 adult male C57 BL /6 mice. Daily...
Insulin resistance is a recognized feature of PCOS (polycystic ovary syndrome). However, the molecular reason(s) underlying this reduced cellular insulin sensitivity not clear. The present study compares major signalling pathways in skeletal muscle isolated from and controls. We measured whole-body biopsies taken before after acute exposure to hyperinsulinaemia nine women diagnosed with seven examined expression, basal activity response vivo stimulation three molecules within these human...
Aims/Hypothesis Reduced skeletal muscle insulin sensitivity is a feature associated with sustained exposure to excess saturated fatty acids (SFA), whereas mono and polyunsaturated (MUFA PUFA) not only improve but blunt SFA-induced resistance. The mechanisms by which MUFAs PUFAs institute these favourable changes remain unclear, may involve stimulating signalling counter-modulation/repression of protein phosphatase 2A (PP2A). This study investigated the effects oleic acid (OA; MUFA), linoleic...
Amino acids are essential for cellular metabolism, and it is important to understand how nutrient supply coordinated with changing energy requirements during embryogenesis. Here, we show that the amino acid transporter Slc7a5/Lat1 highly expressed in tissues undergoing morphogenesis Slc7a5-null mouse embryos have profound neural limb bud outgrowth defects. tissue exhibited aberrant mTORC1 activity cell proliferation; transcriptomics, protein phosphorylation apoptosis analyses further...
Insulin resistance (IR), an impaired cellular, tissue and whole body response to insulin, is a major pathophysiological defect of type 2 diabetes mellitus. Although IR closely associated with obesity, the identity molecular defect(s) underlying obesity-induced in skeletal muscle remains controversial; reduced post-receptor signalling insulin receptor substrate 1 (IRS1) adaptor protein downstream effectors such as kinase B (PKB) have previously been implicated. We examined expression and/or...
Reduced insulin-mediated glucose transport in skeletal muscle is a hallmark of the pathophysiology T2DM (Type II diabetes mellitus). Impaired intracellular insulin signalling implicated as key underlying mechanism. Attention has focused on early events such defective tyrosine phosphorylation IRS1 (insulin receptor substrate-1), major target for kinase. This required normal induction pathways to many metabolic actions insulin. Conversely, increased serine/threonine following prolonged...
The relationship between glucose and lipid metabolism has been of significant interest in understanding the pathogenesis obesity-induced insulin resistance. To gain insight into this metabolic paradigm, we explored potential interplay cellular flux lipid-induced dysfunction within skeletal muscle. Here, show that palmitate (PA)-induced resistance proinflammation muscle cells, which is associated with reduced mitochondrial integrity oxidative capacity, can be attenuated under conditions...