Nuclear receptors and AMPK: can exercise mimetics cure diabetes?
Endurance exercise can lead to systemic improvements in insulin sensitivity and metabolic homeostasis, and is an effective approach to combat metabolic diseases. Pharmacological compounds that recapitulate the beneficial effects of exercise, also known as 'exercise mimetics', have the potential to improve disease symptoms of metabolic syndrome. These drugs, which can increase energy expenditure, suppress hepatic gluconeogenesis, and induce insulin sensitization, have accordingly been highly scrutinized for their utility in treating metabolic diseases including diabetes. Nevertheless, the identity of an efficacious exercise mimetic still remains elusive. In this review, we highlight several nuclear receptors and cofactors that are putative molecular targets for exercise mimetics, and review recent studies that provide advancements in our mechanistic understanding of how exercise mimetics exert their beneficial effects. We also discuss evidence from clinical trials using these compounds in human subjects to evaluate their efficacy in treating diabetes.
Gene Expression LaboratorySalk Institute, La Jolla, California, USA Biomedical Sciences Graduate ProgramUC San Diego, La Jolla, California, USA.
Christopher E
CE
Wall
Gene Expression LaboratorySalk Institute, La Jolla, California, USA.
Ruth T
RT
Yu
Gene Expression LaboratorySalk Institute, La Jolla, California, USA.
Anne R
AR
Atkins
Gene Expression LaboratorySalk Institute, La Jolla, California, USA.
Michael
M
Downes
Gene Expression LaboratorySalk Institute, La Jolla, California, USA Howard Hughes Medical InstituteSalk Institute, La Jolla, California, USA evans@salk.edu.
Ronald M
RM
Evans
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D003920:Diabetes Mellitus / Q000378:metabolism* / Q000628:therapy; D004734:Energy Metabolism / Q000187:drug effects; D015444:Exercise; D005081:Exercise Therapy; D005346:Fibroblast Growth Factors / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D007333:Insulin Resistance; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000378:metabolism; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D037761:Sirtuins / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology
C425931:GW 501516; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D047492:Peroxisome Proliferator-Activated Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D055372:AMP-Activated Protein Kinases; D037761:Sirtuins
AMPK; PGC1α; PPARs; diabetes; exercise mimetics; nuclear receptors; sirtuins