Reynolds 2016 Am J Physiol Endocrinol Metab

Reynolds MS, Hancock CR, Ray JD, Kener KB, Draney C, Garland K, Hardman J, Bikman BT, Tessem JS (2016) β-cell deletion of Nr4a1 and Nr4a3 nuclear receptors impedes mitochondrial respiration and insulin secretion. Am J Physiol Endocrinol Metab 311:E186-201.

» PMID: 27221116

Reynolds MS, Hancock CR, Ray JD, Kener KB, Draney C, Garland K, Hardman J, Bikman BT, Tessem JS (2016) Am J Physiol Endocrinol Metab

Abstract: Iβ-cell insulin secretion is dependent on proper mitochondrial function. Various studies have clearly shown that the Nr4a family of orphan nuclear receptors is essential for fuel utilization and mitochondrial function in liver, muscle and adipose. We have previously demonstrated that overexpression of Nr4a1 or Nr4a3 is sufficient to induce proliferation of pancreatic β-cells. In this study we examined whether Nr4a expression impacts pancreatic β-cell mitochondrial function. Here we show that β-cell mitochondrial respiration is dependent on the nuclear receptors Nr4a1 and Nr4a3. Mitochondrial respiration in permeabilized cells was significantly decreased in β-cells lacking Nr4a1 or Nr4a3. Furthermore, respiration rates of intact cells deficient for Nr4a1 or Nr4a3 in the presence of 16mM glucose resulted in decreased glucose mediated oxygen consumption. Consistent with this reduction in respiration, a significant decrease in glucose stimulated insulin secretion rates is observed with deletion of Nr4a1 or Nr4a3. Interestingly, the changes in respiration and insulin secretion occur without a reduction in mitochondrial content, suggesting decreased mitochondrial function. We establish that knockdown of Nr4a1 and Nr4a3 results in decreased expression of the mitochondrial dehydrogenase subunits Idh3g and Sdhb. We demonstrate that loss of Nr4a1 and Nr4a3 impedes production of ATP, and ultimately inhibits glucose stimulated insulin secretion. These data demonstrate for the first time that the orphan nuclear receptors Nr4a1 and Nr4a3 are critical for β-cell mitochondrial function and insulin secretion.

Copyright © 2016, American Journal of Physiology - Endocrinology and Metabolism. • Keywords: Beta cell, Nr4a1, Nr4a3, Insulin secretion, Mitochondrial respiration

• O2k-Network Lab: US UT Provo Hancock CR, SG Singapore Hausenloy DJ, US UT Provo Bikman BT

Labels: MiParea: Respiration, Genetic knockout;overexpression 

Organism: Rat  Tissue;cell: Islet cell;pancreas;thymus  Preparation: Intact cells, Permeabilized cells 

Coupling state: LEAK, ROUTINE, OXPHOS, ETS"ETS" is not in the list (LEAK, ROUTINE, OXPHOS, ET) of allowed values for the "Coupling states" property.  Pathway: N, S, ROX  HRR: Oxygraph-2k 

2016-06