Uncoupling protein 3 expression levels influence insulin sensitivity, fatty acid oxidation, and related signaling pathways.

Abstract

Controversy exists on whether uncoupling protein 3 (UCP3) positively or negatively influences insulin sensitivity in vivo, and the underlying signaling pathways have been scarcely studied. We studied how a progressive reduction in UCP3 expression (using UCP3 +/+, UCP3 +/-, and UCP3 -/- mice) modulates insulin sensitivity and related metabolic parameters. In order to further validate our observations, we also studied animals in which insulin resistance was induced by administration of a high-fat diet (HFD). In UCP3 +/- and UCP3 -/- mice, gastrocnemius muscle Akt/protein kinase B (Akt/PKB) (serine 473) and AMP-activated protein kinase (AMPK) (threonine 171) phosphorylation, and glucose transporter 4 (GLUT4) membrane levels were reduced compared to UCP3 +/+ mice. The HOMA-IR index (insulin resistance parameter) was increased both in the UCP3 +/- and UCP3 -/- mice. In these mice, insulin administration normalized Akt/PKB phosphorylation between genotypes while AMPK phosphorylation was further reduced, and sarcolemmal GLUT4 levels were induced but did not reach control levels. Furthermore, non-insulin-stimulated muscle fatty acid oxidation and the expression of several involved genes both in muscle and in liver were reduced. HFD administration induced insulin resistance in UCP3 +/+ mice and the aforementioned parameters resulted similar to those of chow-fed UCP3 +/- and UCP3 -/- mice. In conclusion, high-fat-diet-induced insulin resistance in wild-type mice mimics that of chow-fed UCP3 +/- and UCP3 -/- mice showing that progressive reduction of UCP3 levels results in insulin resistance. This is accompanied by decreased fatty acid oxidation and a less intense Akt/PKB and AMPK signaling.

• Authors: Rosalba Senese, Vivien Valli, Maria Moreno, Assunta Lombardi, Rosa Anna Busiello, Federica Cioffi, Elena Silvestri, Fernando Goglia, Antonia Lanni, Pieter de Lange
• Journal: Pflugers Archiv : European journal of physiology (Pflugers Arch) Vol. 461 Issue 1 Pg. 153-64 (Jan 2011) ISSN: 1432-2013 [Electronic] Germany
• PMID: 21058020 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Dietary Fats
• Fatty Acids
• Glucose Transporter Type 4
• Ion Channels
• Mitochondrial Proteins
• Ucp3 protein, mouse
• Uncoupling Protein 3
• Proto-Oncogene Proteins c-akt
• AMP-Activated Protein Kinases

Topics

• AMP-Activated Protein Kinases
• Animals
• Dietary Fats (pharmacology)
• Fatty Acids (metabolism)
• Glucose Transporter Type 4 (metabolism)
• Insulin Resistance (physiology)
• Ion Channels (biosynthesis, genetics)
• Male
• Mice
• Mitochondria, Muscle (metabolism)
• Mitochondrial Proteins (biosynthesis, genetics)
• Muscle, Skeletal (metabolism)
• Oxidation-Reduction
• Phosphorylation
• Proto-Oncogene Proteins c-akt
• Signal Transduction (drug effects, physiology)
• Uncoupling Protein 3