Search Results

You are looking at 1 - 2 of 2 items for

  • Author: S. W. C. CHAN x
  • Refine by access: Content accessible to me x
Clear All Modify Search
T S McQuaid Department of Biomedical Sciences, Atlantic Veterinary College, University of Prince Edward Island, 550 University Avenue, Charlottetown, Prince Edward, C1A 4P3 Canada
Departments of Medicine and Physiology, University of Toronto, 1 Kings College Circle, Toronto, Ontario, M5F 1A8 Canada

Search for other papers by T S McQuaid in
Google Scholar
PubMed
Close
,
M C Saleh Department of Biomedical Sciences, Atlantic Veterinary College, University of Prince Edward Island, 550 University Avenue, Charlottetown, Prince Edward, C1A 4P3 Canada
Departments of Medicine and Physiology, University of Toronto, 1 Kings College Circle, Toronto, Ontario, M5F 1A8 Canada

Search for other papers by M C Saleh in
Google Scholar
PubMed
Close
,
J W Joseph Department of Biomedical Sciences, Atlantic Veterinary College, University of Prince Edward Island, 550 University Avenue, Charlottetown, Prince Edward, C1A 4P3 Canada
Departments of Medicine and Physiology, University of Toronto, 1 Kings College Circle, Toronto, Ontario, M5F 1A8 Canada

Search for other papers by J W Joseph in
Google Scholar
PubMed
Close
,
A Gyulkhandanyan Department of Biomedical Sciences, Atlantic Veterinary College, University of Prince Edward Island, 550 University Avenue, Charlottetown, Prince Edward, C1A 4P3 Canada
Departments of Medicine and Physiology, University of Toronto, 1 Kings College Circle, Toronto, Ontario, M5F 1A8 Canada

Search for other papers by A Gyulkhandanyan in
Google Scholar
PubMed
Close
,
J E Manning-Fox Department of Biomedical Sciences, Atlantic Veterinary College, University of Prince Edward Island, 550 University Avenue, Charlottetown, Prince Edward, C1A 4P3 Canada
Departments of Medicine and Physiology, University of Toronto, 1 Kings College Circle, Toronto, Ontario, M5F 1A8 Canada

Search for other papers by J E Manning-Fox in
Google Scholar
PubMed
Close
,
J D MacLellan Department of Biomedical Sciences, Atlantic Veterinary College, University of Prince Edward Island, 550 University Avenue, Charlottetown, Prince Edward, C1A 4P3 Canada
Departments of Medicine and Physiology, University of Toronto, 1 Kings College Circle, Toronto, Ontario, M5F 1A8 Canada

Search for other papers by J D MacLellan in
Google Scholar
PubMed
Close
,
M B Wheeler Department of Biomedical Sciences, Atlantic Veterinary College, University of Prince Edward Island, 550 University Avenue, Charlottetown, Prince Edward, C1A 4P3 Canada
Departments of Medicine and Physiology, University of Toronto, 1 Kings College Circle, Toronto, Ontario, M5F 1A8 Canada

Search for other papers by M B Wheeler in
Google Scholar
PubMed
Close
, and
C B Chan Department of Biomedical Sciences, Atlantic Veterinary College, University of Prince Edward Island, 550 University Avenue, Charlottetown, Prince Edward, C1A 4P3 Canada
Departments of Medicine and Physiology, University of Toronto, 1 Kings College Circle, Toronto, Ontario, M5F 1A8 Canada

Search for other papers by C B Chan in
Google Scholar
PubMed
Close

We investigated whether an increase in cAMP could normalize glucose-stimulated insulin secretion (GSIS) in uncoupling protein-2 (UCP2) overexpressing (ucp2-OE) β-cells. Indices of β-cell (β-TC-6f7 cells and rodent islets) function were measured after induction of ucp2, in the presence or absence of cAMP-stimulating agents, analogs, or inhibitors. Islets of ob/ob mice had improved glucose-responsiveness in the presence of forskolin. Rat islets overexpressing ucp2 had significantly lower GSIS than controls. Acutely, the protein kinase A (PKA) and epac pathway stimulant forskolin normalized insulin secretion in ucp2-OE rat islets and β-TC-6f7 β-cells, an effect blocked by specific PKA inhibitors but not mimicked by epac agonists. However, there was no effect of ucp2-OE on cAMP concentrations or PKA activity. In ucp2-OE islets, forskolin inhibited ATP-dependent potassium (KATP) channel currents and 86Rb+ efflux, indicative of KATP block. Likewise, forskolin application increased intracellular Ca2+, which could account for its stimulatory effects on insulin secretion. Chronic exposure to forskolin increased ucp2 mRNA and exaggerated basal secretion but not GSIS. In mice deficient in UCP2, there was no augmentation of either cAMP content or cAMP-dependent insulin secretion. Thus, elevating cellular cAMP can reverse the deficiency in GSIS invoked by ucp2-OE, at least partly through PKA-mediated effects on the KATP channel.

Free access
T V Novoselova Centre for Endocrinology, Queen Mary University of London, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Charterhouse Square, London, UK

Search for other papers by T V Novoselova in
Google Scholar
PubMed
Close
,
R Larder University of Cambridge Metabolic Research Laboratories, MRC Metabolic Disease Unit, Wellcome Trust-MRC Institute of Metabolic Science and NIHR Cambridge Biomedical Research Centre, Addenbrooke’s Hospital, Cambridge, UK

Search for other papers by R Larder in
Google Scholar
PubMed
Close
,
D Rimmington University of Cambridge Metabolic Research Laboratories, MRC Metabolic Disease Unit, Wellcome Trust-MRC Institute of Metabolic Science and NIHR Cambridge Biomedical Research Centre, Addenbrooke’s Hospital, Cambridge, UK

Search for other papers by D Rimmington in
Google Scholar
PubMed
Close
,
C Lelliott Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK

Search for other papers by C Lelliott in
Google Scholar
PubMed
Close
,
E H Wynn Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK

Search for other papers by E H Wynn in
Google Scholar
PubMed
Close
,
R J Gorrigan Centre for Endocrinology, Queen Mary University of London, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Charterhouse Square, London, UK

Search for other papers by R J Gorrigan in
Google Scholar
PubMed
Close
,
P H Tate Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK

Search for other papers by P H Tate in
Google Scholar
PubMed
Close
,
L Guasti Centre for Endocrinology, Queen Mary University of London, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Charterhouse Square, London, UK

Search for other papers by L Guasti in
Google Scholar
PubMed
Close
,
The Sanger Mouse Genetics Project Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK

Search for other papers by The Sanger Mouse Genetics Project in
Google Scholar
PubMed
Close
,
S O’Rahilly University of Cambridge Metabolic Research Laboratories, MRC Metabolic Disease Unit, Wellcome Trust-MRC Institute of Metabolic Science and NIHR Cambridge Biomedical Research Centre, Addenbrooke’s Hospital, Cambridge, UK

Search for other papers by S O’Rahilly in
Google Scholar
PubMed
Close
,
A J L Clark Centre for Endocrinology, Queen Mary University of London, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Charterhouse Square, London, UK

Search for other papers by A J L Clark in
Google Scholar
PubMed
Close
,
D W Logan Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK

Search for other papers by D W Logan in
Google Scholar
PubMed
Close
,
A P Coll University of Cambridge Metabolic Research Laboratories, MRC Metabolic Disease Unit, Wellcome Trust-MRC Institute of Metabolic Science and NIHR Cambridge Biomedical Research Centre, Addenbrooke’s Hospital, Cambridge, UK

Search for other papers by A P Coll in
Google Scholar
PubMed
Close
, and
L F Chan Centre for Endocrinology, Queen Mary University of London, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Charterhouse Square, London, UK

Search for other papers by L F Chan in
Google Scholar
PubMed
Close

Melanocortin receptor accessory protein 2 (MRAP2) is a transmembrane accessory protein predominantly expressed in the brain. Both global and brain-specific deletion of Mrap2 in mice results in severe obesity. Loss-of-function MRAP2 mutations have also been associated with obesity in humans. Although MRAP2 has been shown to interact with MC4R, a G protein-coupled receptor with an established role in energy homeostasis, appetite regulation and lipid metabolism, the mechanisms through which loss of MRAP2 causes obesity remains uncertain. In this study, we used two independently derived lines of Mrap2 deficient mice (Mrap2 tm1a/tm1a ) to further study the role of Mrap2 in the regulation of energy balance and peripheral lipid metabolism. Mrap2 tm1a/tm1a mice have a significant increase in body weight, with increased fat and lean mass, but without detectable changes in food intake or energy expenditure. Transcriptomic analysis showed significantly decreased expression of Sim1, Trh, Oxt and Crh within the hypothalamic paraventricular nucleus of Mrap2 tm1a/tm1a mice. Circulating levels of both high-density lipoprotein and low-density lipoprotein were significantly increased in Mrap2 deficient mice. Taken together, these data corroborate the role of MRAP2 in metabolic regulation and indicate that, at least in part, this may be due to defective central melanocortin signalling.

Open access