Diacylglycerol kinase-δ regulates AMPK signaling, lipid metabolism, and skeletal muscle energetics
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Diacylglycerol kinase-δ regulates AMPK signaling, lipid metabolism, and skeletal muscle energetics. / Jiang, Lake Q; de Castro Barbosa, Thais; Massart, Julie; Deshmukh, Atul S; Löfgren, Lars; Duque-Guimaraes, Daniella E; Ozilgen, Arda; Osler, Megan E; Chibalin, Alexander V; Zierath, Juleen R.
In: American Journal of Physiology: Endocrinology and Metabolism, Vol. 310, No. 1, 01.01.2016, p. E51-60.Research output: Contribution to journal › Journal article › peer-review
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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 - 2016/1/1
Y1 - 2016/1/1
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
VL - 310
SP - E51-60
JO - American Journal of Physiology - Endocrinology and Metabolism
JF - American Journal of Physiology - Endocrinology and Metabolism
SN - 0193-1849
IS - 1
ER -
ID: 170597210