PAS kinase is required for normal cellular energy balance.
The metabolic syndrome, a complex set of phenotypes typically associated with obesity and diabetes, is an increasing threat to global public health. Fundamentally, the metabolic syndrome is caused by a failure to properly sense and respond to cellular metabolic cues. We studied the role of the cellular metabolic sensor PAS kinase (PASK) in the pathogenesis of metabolic disease by using PASK(-/-) mice. We identified tissue-specific metabolic phenotypes caused by PASK deletion consistent with its role as a metabolic sensor. Specifically, PASK(-/-) mice exhibited impaired glucose-stimulated insulin secretion in pancreatic beta-cells, altered triglyceride storage in liver, and increased metabolic rate in skeletal muscle. Further, PASK deletion caused nearly complete protection from the deleterious effects of a high-fat diet including obesity and insulin resistance. We also demonstrate that these cellular effects, increased rate of oxidative metabolism and ATP production, occur in cultured cells. We therefore hypothesize that PASK acts in a cell-autonomous manner to maintain cellular energy homeostasis and is a potential therapeutic target for metabolic disease.
Hao
Huai-Xiang
HX
Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
Cardon
Caleb M
CM
Swiatek
Wojtek
W
Cooksey
Robert C
RC
Smith
Tammy L
TL
Wilde
James
J
Boudina
Sihem
S
Abel
E Dale
ED
McClain
Donald A
DA
Rutter
Jared
J
D000818:Animals; D002460:Cell Line; D017353:Gene Deletion; D005947:Glucose / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000502:physiology*; D051381:Rats; D014280:Triglycerides / Q000378:metabolism
D007328:Insulin; D014280:Triglycerides; C116037:PAS domain kinases; D017346:Protein Serine-Threonine Kinases; D005947:Glucose; D010100:Oxygen