Regulation of beta-cell viability and gene expression by distinct agonist fragments of adiponectin.
Obesity is an established risk factor for type 2 diabetes. Activation of the adiponectin receptors has a clear role in improving insulin resistance although conflicting evidence exists for its effects on pancreatic beta-cells. Previous reports have identified both adiponectin receptors (ADR-1 and ADR-2) in the beta-cell. Recent evidence has suggested that two distinct regions of the adiponectin molecule, the globular domain and a small N-terminal region, have agonist properties. This study investigates the effects of two agonist regions of adiponectin on insulin secretion, gene expression, cell viability and cell signalling in the rat beta-cell line BRIN-BD11, as well as investigating the expression levels of adiponectin receptors (ADRs) in these cells. Cells were treated with globular adiponectin and adiponectin (15-36) +/-leptin to investigate cell viability, expression of key beta-cell genes and ERK1/2 activation. Both globular adiponectin and adiponectin (15-36) caused significant ERK1/2 dependent increases in cell viability. Leptin co-incubation attenuated adiponectin (15-36) but not globular adiponectin induced cell viability. Globular adiponectin, but not adiponectin (15-36), caused a significant 450% increase in PDX-1 expression and a 45% decrease in LPL expression. ADR-1 was expressed at a higher level than ADR-2, and ADR mRNA levels were differentially regulated by non-esterified fatty acids and peroxisome-proliferator-activated receptor agonists. These data provide evidence of roles for two distinct adiponectin agonist domains in the beta-cell and confirm the potentially important role of adiponectin receptor agonism in maintaining beta-cell mass.
Brown
James E P
JE
Aston Research Centre for Healthy Ageing, School of Life and Health Sciences, Aston University, Birmingham, B4 7ET, UK.
Conner
Alex C
AC
Digby
Janet E
JE
Ward
Kenya L
KL
Ramanjaneya
Manjunath
M
Randeva
Harpal S
HS
Dunmore
Simon J
SJ
D052242:Adiponectin / Q000819:agonists* / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects*; D004797:Enzyme-Linked Immunosorbent Assay; D005230:Fatty Acids, Nonesterified / Q000494:pharmacology; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects; D020738:Leptin / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists; D051381:Rats; D054419:Receptors, Adiponectin / Q000378:metabolism*
D052242:Adiponectin; D005230:Fatty Acids, Nonesterified; D020738:Leptin; D047492:Peroxisome Proliferator-Activated Receptors; D054419:Receptors, Adiponectin; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3