Insulin Resistance and Altered Systemic Glucose Metabolism in Mice Lacking Nur77

• Published in: Diabetes (New York, N.Y.) Vol. 58; no. 12; pp. 2788 - 2796
• Main Authors: Chao, Lily C, Wroblewski, Kevin, Zhang, Zidong, Pei, Liming, Vergnes, Laurent, Ilkayeva, Olga R, Ding, Shi Ying, Reue, Karen, Watt, Matthew J, Newgard, Christopher B, Pilch, Paul F, Hevener, Andrea L, Tontonoz, Peter
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01-12-2009
• Subjects: Animals; Biological and medical sciences; Blood Glucose - metabolism; Calorimetry, Indirect; Diabetes; Diabetes. Impaired glucose tolerance; Diet; Dietary Fats - administration & dosage; Dietary Fats - adverse effects; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Fatty Liver - etiology; Fatty Liver - metabolism; Genetic aspects; Glucose; Glucose - metabolism; Glucose Clamp Technique; Glucose Transporter Type 4 - metabolism; Glycolysis; Insulin - metabolism; Insulin Resistance; Ligands; Lipid Metabolism; Lipids; Liver; Medical sciences; Metabolism; Mice; Mice, Knockout; Muscle, Skeletal - metabolism; Muscles; Musculoskeletal system; Nuclear Receptor Subfamily 4, Group A, Member 1 - genetics; Nuclear Receptor Subfamily 4, Group A, Member 1 - metabolism; Obesity; Original; Oxygen Consumption; Phosphorylation; Physiological aspects; Receptor, Insulin - metabolism; Research Design; Signal Transduction; Skeletal muscle; United States; Endocrinopathy; Target tissue resistance; Vertebrata; Mammalia; Mouse; Animal; Diabetes mellitus; Rodentia; Metabolic diseases; Insulin resistance; Glucose; Metabolism
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db09-0763

Insulin Resistance and Altered Systemic Glucose Metabolism in Mice Lacking Nur77
Lily C. Chao 1 ,
Kevin Wroblewski 1 ,
Zidong Zhang 2 ,
Liming Pei 1 ,
Laurent Vergnes 3 ,
Olga R. Ilkayeva 4 ,
Shi Ying Ding 2 ,
Karen Reue 3 ,
Matthew J. Watt 5 ,
Christopher B. Newgard 4 ,
Paul F. Pilch 2 ,
Andrea L. Hevener 6 and
Peter Tontonoz 1
1 Howard Hughes Medical Institute, Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los
Angeles, California;
2 Department of Biochemistry, Boston University Medical Center, Boston, Massachusetts;
3 Department of Human Genetics and Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles,
California;
4 Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, North Carolina;
5 Department of Physiology, Monash University, Clayton, Victoria, Australia;
6 Division of Endocrinology, Diabetes and Hypertension, David Geffen School of Medicine, University of California Los Angeles,
Los Angeles, California.
Corresponding author: Peter Tontonoz, ptontonoz{at}mednet.ucla.edu .
Abstract
OBJECTIVE Nur77 is an orphan nuclear receptor with pleotropic functions. Previous studies have identified Nur77 as a transcriptional
regulator of glucose utilization genes in skeletal muscle and gluconeogenesis in liver. However, the net functional impact
of these pathways is unknown. To examine the consequence of Nur77 signaling for glucose metabolism in vivo, we challenged
Nur77 null mice with high-fat feeding.
RESEARCH DESIGN AND METHODS Wild-type and Nur77 null mice were fed a high-fat diet (60% calories from fat) for 3 months. We determined glucose tolerance,
tissue-specific insulin sensitivity, oxygen consumption, muscle and liver lipid content, muscle insulin signaling, and expression
of glucose and lipid metabolism genes.
RESULTS Mice with genetic deletion of Nur77 exhibited increased susceptibility to diet-induced obesity and insulin resistance. Hyperinsulinemic-euglycemic
clamp studies revealed greater high-fat diet–induced insulin resistance in both skeletal muscle and liver of Nur77 null mice
compared with controls. Loss of Nur77 expression in skeletal muscle impaired insulin signaling and markedly reduced GLUT4
protein expression. Muscles lacking Nur77 also exhibited increased triglyceride content and accumulation of multiple even-chained
acylcarnitine species. In the liver, Nur77 deletion led to hepatic steatosis and enhanced expression of lipogenic genes, likely
reflecting the lipogenic effect of hyperinsulinemia.
CONCLUSIONS Collectively, these data demonstrate that loss of Nur77 influences systemic glucose metabolism and highlight the physiological
contribution of muscle Nur77 to this regulatory pathway.
Footnotes
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received May 20, 2009.
Accepted September 1, 2009.
© 2009 American Diabetes Association