Diacylglycerol kinase-δ regulates AMPK signaling, lipid metabolism, and skeletal muscle energetics

TY - JOUR

T1 - Diacylglycerol kinase-δ regulates AMPK signaling, lipid metabolism, and skeletal muscle energetics

AU - Jiang, Lake Q

AU - de Castro Barbosa, Thais

AU - Massart, Julie

AU - Deshmukh, Atul S

AU - Löfgren, Lars

AU - Duque-Guimaraes, Daniella E

AU - Ozilgen, Arda

AU - Osler, Megan E

AU - Chibalin, Alexander V

AU - Zierath, Juleen R

N1 - Copyright © 2016 the American Physiological Society.

PY - 2015

Y1 - 2015

N2 - Decrease of AMPK-related signal transduction and insufficient lipid oxidation contributes to the pathogenesis of obesity and type 2 diabetes. Previously, we identified that diacylglycerol kinase-δ (DGKδ), an enzyme involved in triglyceride biosynthesis, is reduced in skeletal muscle from type 2 diabetic patients. Here, we tested the hypothesis that DGKδ plays a role in maintaining appropriate AMPK action in skeletal muscle and energetic aspects of contraction. Voluntary running activity was reduced in DGKδ(+/-) mice, but glycogen content and mitochondrial markers were unaltered, suggesting that DGKδ deficiency affects skeletal muscle energetics but not mitochondrial protein abundance. We next determined the role of DGKδ in AMPK-related signal transduction and lipid metabolism in isolated skeletal muscle. AMPK activation and signaling were reduced in DGKδ(+/-) mice, concomitant with impaired lipid oxidation and elevated incorporation of free fatty acids into triglycerides. Strikingly, DGKδ deficiency impaired work performance, as evident by altered force production and relaxation dynamics in response to repeated contractions. In conclusion, DGKδ deficiency impairs AMPK signaling and lipid metabolism, thereby highlighting the deleterious role of excessive lipid metabolites in the development of peripheral insulin resistance and type 2 diabetes pathogenesis. DGKδ deficiency also influences skeletal muscle energetics, which may lead to low physical activity levels in type 2 diabetes.

AB - Decrease of AMPK-related signal transduction and insufficient lipid oxidation contributes to the pathogenesis of obesity and type 2 diabetes. Previously, we identified that diacylglycerol kinase-δ (DGKδ), an enzyme involved in triglyceride biosynthesis, is reduced in skeletal muscle from type 2 diabetic patients. Here, we tested the hypothesis that DGKδ plays a role in maintaining appropriate AMPK action in skeletal muscle and energetic aspects of contraction. Voluntary running activity was reduced in DGKδ(+/-) mice, but glycogen content and mitochondrial markers were unaltered, suggesting that DGKδ deficiency affects skeletal muscle energetics but not mitochondrial protein abundance. We next determined the role of DGKδ in AMPK-related signal transduction and lipid metabolism in isolated skeletal muscle. AMPK activation and signaling were reduced in DGKδ(+/-) mice, concomitant with impaired lipid oxidation and elevated incorporation of free fatty acids into triglycerides. Strikingly, DGKδ deficiency impaired work performance, as evident by altered force production and relaxation dynamics in response to repeated contractions. In conclusion, DGKδ deficiency impairs AMPK signaling and lipid metabolism, thereby highlighting the deleterious role of excessive lipid metabolites in the development of peripheral insulin resistance and type 2 diabetes pathogenesis. DGKδ deficiency also influences skeletal muscle energetics, which may lead to low physical activity levels in type 2 diabetes.

KW - Adenylate Kinase

KW - Animals

KW - Diabetes Mellitus, Experimental

KW - Diabetes Mellitus, Type 2

KW - Diacylglycerol Kinase

KW - Energy Metabolism

KW - Lipid Metabolism

KW - Male

KW - Mice

KW - Mice, Transgenic

KW - Motor Activity

KW - Muscle, Skeletal

KW - Physical Conditioning, Animal

KW - Signal Transduction

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1152/ajpendo.00209.2015

DO - 10.1152/ajpendo.00209.2015

M3 - Journal article

C2 - 26530149

SN - 0193-1849

VL - 310

SP - E51-60

JO - American Journal of Physiology: Endocrinology and Metabolism

JF - American Journal of Physiology: Endocrinology and Metabolism

IS - 1

ER -