Uncoupling protein 3 expression levels influence insulin sensitivity, fatty acid oxidation, and related signaling pathways.
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.
Dipartimento di Scienze della Vita, Seconda Università degli Studi di Napoli, Via Vivaldi 43, Caserta, Italy.
Rosalba
R
Senese
Vivien
V
Valli
Maria
M
Moreno
Assunta
A
Lombardi
Rosa Anna
RA
Busiello
Federica
F
Cioffi
Elena
E
Silvestri
Fernando
F
Goglia
Antonia
A
Lanni
Pieter
P
de Lange
D055372:AMP-Activated Protein Kinases; D000818:Animals; D004041:Dietary Fats / Q000494:pharmacology; D005227:Fatty Acids / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D007473:Ion Channels / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D051379:Mice; D008931:Mitochondria, Muscle / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000096:biosynthesis* / Q000235:genetics; D018482:Muscle, Skeletal / Q000378:metabolism; D010084:Oxidation-Reduction; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D000071247:Uncoupling Protein 3
D004041:Dietary Fats; D005227:Fatty Acids; D051275:Glucose Transporter Type 4; D007473:Ion Channels; D024101:Mitochondrial Proteins; C000604393:Ucp3 protein, mouse; D000071247:Uncoupling Protein 3; D051057:Proto-Oncogene Proteins c-akt; D055372:AMP-Activated Protein Kinases