Table 1.
Mediator Subunits and Interacting Nuclear Receptors that Regulate Metabolism
| Mediator Subunit or NR | Target Tissue (Organism, Driver) | Phenotype | Reference |
|---|---|---|---|
| MED1 | skeletal muscle deletion (mouse, MCK-Cre) | enhanced insulin sensitivity, improved glucose tolerance on high-fat diet | Chen et al., 2010 |
| MED1 | liver deletion (mouse, Albumin-Cre) | reduced hepatic steatosis on high-fat diet | Jia et al., 2004 |
| MED12 | heart/muscle deletion (Drosophila, Mef2-Gal4) | increased susceptibility to obesity | Lee et al., 2014 |
| MED13 | heart/muscle deletion (Drosophila, Mef2-Gal4) | increased susceptibility to obesity | Lee et al., 2014 |
| MED13 | heart deletion (mouse, αMHC-Cre) | increased susceptibility to obesity | Grueter et al., 2012 |
| MED13 | heart transgenic (mouse, αMHC) | enhanced lipid metabolism and insulin sensitivity, leanness, decreased susceptibility to obesity | Grueter et al., 2012; Baskin et al., 2014b |
| MED15 | global knockdown (C. elegans, RNAi) | decreased fat storage | Yang et al., 2006 |
| MED23 | liver deletion (mouse, Albumin-Cre) | increased glucose and lipid metabolism and insulin responsiveness | Chu et al., 2014 |
| MED30 | global missense mutation (mouse) | mitochondrial dysfunction in heart and heart failure | Krebs et al., 2011 |
| CDK8 | liver knockdown (mouse, tail vein injection of adenovirus expressing shRNA against CDK8) | hepatic steatosis | Zhao et al., 2012 |
| PPARα | global deletion (mouse) | etoxomir-induced cardiac lipotoxicity, hypoglycemia, lethality | Djouadi et al., 1998 |
| PPARα | heart transgenic (mouse, αMHC) | cardiac insulin resistance, diabetic cardiomyopathy | Finck et al., 2002 |
| PPARα | skeletal muscle transgenic (mouse, MCK) | skeletal muscle insulin resistance | Finck et al., 2005 |
| PPARβ/δ | heart deletion (mouse, αMHC-Cre) | lipotoxic cardiomyopathy | Cheng et al., 2004 |
| PPARβ/δ | heart transgenic (mouse, αMHC) | increased cardiac glucose metabolism, hearts protected from ischemia-reperfusion injury | Burkart et al., 2007 |
| PPARβ/δ | skeletal muscle deletion (mouse, HSA-Cre) | increased number of fast muscle fibers with reduced oxidative capacity, insulin resistance, adiposity | Schuler et al., 2006 |
| PPARβ/δ | skeletal muscle transgenic (mouse, HSA) | increased number of slow muscle fibers, leanness, decreased susceptibility to obesity, increased exercise endurance | Wang et al., 2004 |
| PPARγ | heart transgenic (mouse, αMHC) | dilated cardiomyopathy, increased cardiac lipid and glycogen storage | Son et al., 2007 |
| PPARγ | skeletal muscle deletion (mouse, MCK-Cre) | glucose intolerant, insulin resistant, increased adiposity | Hevener et al., 2003; Norris et al., 2003; |
| PPARγ | muscle constitutively active transgenic (mouse, HSA) | decreased intramuscular lipid accumulation, decreased susceptibility to obesity and insulin resistance, increased number of slow muscle fibers | Amin et al., 2010 |
| TRα | global deletion of α1 (mouse) | decreased muscle weight, increased proportion of slow-twitch fibers | Yu et al., 2000 |
| TRα/β | global deletion of α1/β (mouse) | decreased body and muscle weight, increased proportion of slow-twitch fibers | Yu et al., 2000 |
| TRα | global knock-in mutation (mouse) | decreased body weight, heart size, blood pressure, cardiac glucose utilization | Esaki et al., 2004 |
| TRβ | global knock-in mutation (mouse) | increased cardiac glucose utilization | Esaki et al., 2004 |
| TRβ | heart dominant-negative β1 (mouse, αMHC) | cardiac dysfunction, reduced substrate flux through multiple pathways in the heart | Pazos-Moura et al., 2000; Hyyti et al., 2008; |
| ERRα | global deletion (mouse) | impaired cardiac metabolism, cardiac maladaptation to hemodynamic stress and ischemia | Huss et al., 2007 |
| ERRα | skeletal muscle deletion (mouse, MCK-Cre) | impaired muscle regeneration and recovery of mitochondrial function in muscle after injury | LaBarge et al., 2014 |
| ERRβ/γ | skeletal muscle deletion (mouse, HSA-Cre) | decreased exercise endurance | Gan et al., 2013 |
| ERRγ | global deletion (mouse) | lethal, decreased embryonic cardiac function, disruption of perinatal cardiometabolic switching | Alaynick et al., 2007 |
| ERRγ | skeletal muscle transgenic (mouse, HSA) | increased exercise endurance, resistance to diet-induced obesity | Narkar et al., 2011 |
| Nur77 | global deletion (mouse) | high-fat-diet-induced skeletal muscle insulin resistance, increased susceptibility to obesity | Chao et al., 2009 |
| Nur77 | skeletal muscle transgenic (mouse, MCK) | increased mitochondrial number and function in skeletal muscle, improved muscle performance | Chao et al., 2012 |
Summary of genetic models of Mediator subunits that display a metabolic phenotype, and genetic mouse models of nuclear receptors that affect striated muscle, some of which interact with Mediator subunits, as discussed in the text. MCK, muscle creatine kinase; αMHC, alpha myosin heavy chain; HSA, human skeletal muscle actin.