title: β-Cell deletion of Nr4a1 and Nr4a3 nuclear receptors impedes mitochondrial respiration and insulin secretion.
abstract: β-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. Previously, we have 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 16 mM 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.
authors.affiliation: Nutrition, Dietetics, and Food Science Department, College of Life Sciences, Brigham Young University, Provo, Utah; and.
authors.forename: Merrick S
authors.initials: MS
authors.lastname: Reynolds
authors.affiliation: Nutrition, Dietetics, and Food Science Department, College of Life Sciences, Brigham Young University, Provo, Utah; and.
authors.forename: Chad R
authors.initials: CR
authors.lastname: Hancock
authors.affiliation: Nutrition, Dietetics, and Food Science Department, College of Life Sciences, Brigham Young University, Provo, Utah; and.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Ray
authors.affiliation: Nutrition, Dietetics, and Food Science Department, College of Life Sciences, Brigham Young University, Provo, Utah; and.
authors.forename: Kyle B
authors.initials: KB
authors.lastname: Kener
authors.affiliation: Nutrition, Dietetics, and Food Science Department, College of Life Sciences, Brigham Young University, Provo, Utah; and.
authors.forename: Carrie
authors.initials: C
authors.lastname: Draney
authors.affiliation: Nutrition, Dietetics, and Food Science Department, College of Life Sciences, Brigham Young University, Provo, Utah; and.
authors.forename: Kevin
authors.initials: K
authors.lastname: Garland
authors.affiliation: Nutrition, Dietetics, and Food Science Department, College of Life Sciences, Brigham Young University, Provo, Utah; and.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Hardman
authors.affiliation: Physiology and Developmental Biology Department, College of Life Sciences, Brigham Young University, Provo, Utah.
authors.forename: Benjamin T
authors.initials: BT
authors.lastname: Bikman
authors.affiliation: Nutrition, Dietetics, and Food Science Department, College of Life Sciences, Brigham Young University, Provo, Utah; and jeffery_tessem@byu.edu.
authors.forename: Jeffery S
authors.identifier: 0000-0003-3081-3187
authors.initials: JS
authors.lastname: Tessem
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D019069:Cell Respiration / Q000235:genetics*; D002470:Cell Survival; D004268:DNA-Binding Proteins / Q000235:genetics*; D055785:Gene Knockdown Techniques; D005947:Glucose / Q000378:metabolism; D015151:Immunoblotting; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007521:Isocitrate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D013385:Succinate Dehydrogenase / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D007328:Insulin; D009419:Nerve Tissue Proteins; C539820:Nr4a1 protein, rat; C091333:Nr4a3 protein, rat; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D012333:RNA, Messenger; D000255:Adenosine Triphosphate; D007521:Isocitrate Dehydrogenase; D013385:Succinate Dehydrogenase; D005947:Glucose
keywords: Nr4a1; Nr4a3; insulin secretion; mitochondria; pancreatic β-cell; proliferation; respiration