PGC-1β controls mitochondrial metabolism to modulate circadian activity, adaptive thermogenesis, and hepatic steatosis

doi:10.1073/pnas.0611623104

PGC-1β controls mitochondrial metabolism to modulate circadian activity, adaptive thermogenesis, and hepatic steatosis

Howard Hughes Medical Institute and Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037

Contributed by Ronald M. Evans, December 28, 2006 (received for review December 21, 2006)

Abstract

The transcriptional coactivator peroxisome proliferator-activated receptor-γ coactivator 1β (PGC-1β) is believed to control mitochondrial oxidative energy metabolism by activating specific target transcription factors including estrogen-related receptors and nuclear respiratory factor 1, yet its physiological role is not yet clearly understood. To define its function in vivo, we generated and characterized mice lacking the functional PGC-1β protein [PGC-1β knockout (KO) mice]. PGC-1β KO mice are viable and fertile and show no overt phenotype under normal laboratory conditions. However, the KO mice displayed an altered expression in a large number of nuclear-encoded genes governing mitochondrial and metabolic functions in multiple tissues including heart, skeletal muscle, brain, brown adipose tissue, and liver. In contrast to PGC-1α KO mice that are reportedly hyperactive, PGC-1β KO mice show greatly decreased activity during the dark cycle. When acutely exposed to cold, the KO mice developed abnormal hypothermia and morbidity. Furthermore, high-fat feeding induced hepatic steatosis and increased serum triglyceride and cholesterol levels in the KO mice. These results suggest that PGC-1β in mouse plays a nonredundant role in controlling mitochondrial oxidative energy metabolism.

Footnotes

*To whom correspondence should be addressed. E-mail: evans{at}salk.edu
Author contributions: J.S. and R.M.E. designed research; J.S. and L.-W.C. performed research; J.S. and R.R.N. contributed new reagents/analytic tools; J.S. and I.R.M. analyzed data; and J.S. and R.M.E. wrote the paper.
The authors declare no conflict of interest.
Abbreviations:

BAT,

brown adipose tissue;

ERR,

estrogen-related receptor;

FAO,

fatty acid β-oxidation;

FFA,

free fatty acid;

GTT,

glucose tolerance test;

HFD,

high-fat diet;

ITT,

insulin tolerance test;

KO,

knockout;

nDNA,

nuclear DNA;

PGC-1,

peroxisome proliferator-activated receptor-γ coactivator 1;

Q-PCR,

quantitative PCR;

SREBP,

sterol regulatory element-binding protein;

TG,

triglyceride;

UCP,

uncoupling protein;

WAT,

white adipose tissue.