A muscle-specific knockout implicates nuclear receptor coactivator MED1 in the regulation of glucose and energy metabolism.
As conventional transcriptional factors that are activated in diverse signaling pathways, nuclear receptors play important roles in many physiological processes that include energy homeostasis. The MED1 subunit of the Mediator coactivator complex plays a broad role in nuclear receptor-mediated transcription by anchoring the Mediator complex to diverse promoter-bound nuclear receptors. Given the significant role of skeletal muscle, in part through the action of nuclear receptors, in glucose and fatty acid metabolism, we generated skeletal muscle-specific Med1 knockout mice. Importantly, these mice show enhanced insulin sensitivity and improved glucose tolerance as well as resistance to high-fat diet-induced obesity. Furthermore, the white muscle of these mice exhibits increased mitochondrial density and expression of genes specific to type I and type IIA fibers, indicating a fast-to-slow fiber switch, as well as markedly increased expression of the brown adipose tissue-specific UCP-1 and Cidea genes that are involved in respiratory uncoupling. These dramatic results implicate MED1 as a powerful suppressor in skeletal muscle of genetic programs implicated in energy expenditure and raise the significant possibility of therapeutical approaches for metabolic syndromes and muscle diseases through modulation of MED1-nuclear receptor interactions.
Chen
Wei
W
Laboratories of Biochemistry and Molecular Biology and Molecular Genetics, The Rockefeller University, New York, NY 10065, USA.
Zhang
Xiaoting
X
Birsoy
Kivanc
K
Roeder
Robert G
RG
D000818:Animals; D004041:Dietary Fats / Q000008:administration & dosage; D004734:Energy Metabolism / Q000235:genetics; D005947:Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D007333:Insulin Resistance; D007473:Ion Channels / Q000235:genetics; D008297:Male; D056913:Mediator Complex Subunit 1 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008931:Mitochondria, Muscle / Q000648:ultrastructure; D024101:Mitochondrial Proteins / Q000235:genetics; D018656:Muscle Fibers, Fast-Twitch / Q000378:metabolism; D018657:Muscle Fibers, Slow-Twitch / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000648:ultrastructure; D018995:Myosin Heavy Chains / Q000235:genetics; D009765:Obesity / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D020411:Oligonucleotide Array Sequence Analysis; D000071256:Uncoupling Protein 1
D004041:Dietary Fats; D007473:Ion Channels; C538856:Med1 protein, mouse; D056913:Mediator Complex Subunit 1; D024101:Mitochondrial Proteins; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; D018995:Myosin Heavy Chains; D005947:Glucose