PAS kinase is required for normal cellular energy balance

doi:10.1073/pnas.0705407104

PAS kinase is required for normal cellular energy balance

*Department of Biochemistry and
^†Division of Endocrinology, Diabetes and Metabolism, University of Utah School of Medicine, Salt Lake City, UT 84112

Edited by Steven L. McKnight, University of Texas Southwestern Medical Center, Dallas, TX, and approved August 8, 2007 (received for review June 11, 2007)

Abstract

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 β-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.

Footnotes

^‡To whom correspondence should be addressed. E-mail: rutter{at}biochem.utah.edu
Author contributions: E.D.A., D.A.M., and J.R. designed research; H.-X.H., C.M.C., W.S., R.C.C., T.L.S., J.W., and S.B. performed research; H.-X.H., W.S., R.C.C., S.B., E.D.A., D.A.M., and J.R. analyzed data; and H.-X.H. and J.R. wrote the paper.
Conflict of interest statement: J.R. is a consultant to BioEnergenix, LLC.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0705407104/DC1.
Abbreviations:

AMPK,

AMP-activated protein kinase;

mTOR,

mammalian target of rapamycin;

PASK,

PAS kinase;

PGC-1,

peroxisome proliferator-activated receptor γ coactivator 1;

GSIS,

glucose-stimulated insulin secretion;

GTT,

glucose tolerance test;

ITT,

insulin tolerance test;

HFD,

high-fat diet;

NCD,

normal chow diet;

PPARγ,

peroxisome proliferator-activated receptor γ;

SCD1,

stearoyl-CoA desaturase 1;

PXR,

pregnane X receptor;

shRNA,

short hairpin RNA.