title: Skeletal muscle PGC-1α modulates systemic ketone body homeostasis and ameliorates diabetic hyperketonemia in mice.
abstract: Ketone bodies (KBs) are crucial energy substrates during states of low carbohydrate availability. However, an aberrant regulation of KB homeostasis can lead to complications such as diabetic ketoacidosis. Exercise and diabetes affect systemic KB homeostasis, but the regulation of KB metabolism is still enigmatic. In our study in mice with either knockout or overexpression of the peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α in skeletal muscle, PGC-1α regulated ketolytic gene transcription in muscle. Furthermore, KB homeostasis of these mice was investigated during withholding of food, exercise, and ketogenic diet feeding, and after streptozotocin injection. In response to these ketogenic stimuli, modulation of PGC-1α levels in muscle affected systemic KB homeostasis. Moreover, the data demonstrate that skeletal muscle PGC-1α is necessary for the enhanced ketolytic capacity in response to exercise training and overexpression of PGC-1α in muscle enhances systemic ketolytic capacity and is sufficient to ameliorate diabetic hyperketonemia in mice. In cultured myotubes, the transcription factor estrogen-related receptor-α was a partner of PGC-1α in the regulation of ketolytic gene transcription. These results demonstrate a central role of skeletal muscle PGC-1α in the transcriptional regulation of systemic ketolytic capacity.-Svensson, K., Albert, V., Cardel, B., Salatino, S., Handschin, C. Skeletal muscle PGC-1α modulates systemic ketone body homeostasis and ameliorates diabetic hyperketonemia in mice.
authors: Biozentrum, University of Basel, Basel, Switzerland.
authors: Kristoffer
authors: K
authors: Svensson
authors: Biozentrum, University of Basel, Basel, Switzerland.
authors: Verena
authors: V
authors: Albert
authors: Biozentrum, University of Basel, Basel, Switzerland.
authors: Bettina
authors: B
authors: Cardel
authors: Biozentrum, University of Basel, Basel, Switzerland.
authors: Silvia
authors: S
authors: Salatino
authors: Biozentrum, University of Basel, Basel, Switzerland christoph.handschin@unibas.ch.
authors: Christoph
authors: C
authors: Handschin
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D002460:Cell Line; D055423:Diet, Ketogenic; D005508:Food Deprivation; D006706:Homeostasis / Q000502:physiology*; D007657:Ketone Bodies / Q000097:blood* / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000235:genetics / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D000097983:ERRalpha Estrogen-Related Receptor
chemical_list: D007657:Ketone Bodies; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011960:Receptors, Estrogen; D000097983:ERRalpha Estrogen-Related Receptor; C485290:Ppargc1a protein, mouse
keywords: diabetes; exercise; ketoacidosis; ketone body metabolism; transcriptional regulation