Format

Send to

Choose Destination
Proc Natl Acad Sci U S A. 2015 Jul 14;112(28):8714-9. doi: 10.1073/pnas.1509930112. Epub 2015 Jun 29.

High-fat diet and FGF21 cooperatively promote aerobic thermogenesis in mtDNA mutator mice.

Author information

1
Gene Expression Laboratory, Salk Institute, La Jolla, CA 92037; Biomedical Sciences Graduate Program, University of California at San Diego, La Jolla, CA 92093;
2
Gene Expression Laboratory, Salk Institute, La Jolla, CA 92037;
3
The Storr Liver Unit, Westmead Millennium Institute and University of Sydney, Westmead Hospital, Westmead, NSW 2145, Australia;
4
The Mitochondrial and Metabolic Disease Center, Departments of Medicine, Pediatrics, Pathology, and Neurosciences, University of California at San Diego School of Medicine, San Diego, CA 92103;
5
The Mitochondrial and Metabolic Disease Center, Departments of Medicine, Pediatrics, Pathology, and Neurosciences, University of California at San Diego School of Medicine, San Diego, CA 92103; Veterans Affairs Center for Excellence in Stress and Mental Health, La Jolla, CA 92161;
6
Gene Expression Laboratory, Salk Institute, La Jolla, CA 92037; Howard Hughes Medical Institute, Salk Institute, La Jolla, CA 92037 evans@salk.edu.

Abstract

Mitochondria are highly adaptable organelles that can facilitate communication between tissues to meet the energetic demands of the organism. However, the mechanisms by which mitochondria can nonautonomously relay stress signals remain poorly understood. Here we report that mitochondrial mutations in the young, preprogeroid polymerase gamma mutator (POLG) mouse produce a metabolic state of starvation. As a result, these mice exhibit signs of metabolic imbalance including thermogenic defects in brown adipose tissue (BAT). An unexpected benefit of this adaptive response is the complete resistance to diet-induced obesity when POLG mice are placed on a high-fat diet (HFD). Paradoxically, HFD further increases oxygen consumption in part by inducing thermogenesis and mitochondrial biogenesis in BAT along with enhanced expression of fibroblast growth factor 21 (FGF21). Collectively, these findings identify a mechanistic link between FGF21, a long-known marker of mitochondrial disease, and systemic metabolic adaptation in response to mitochondrial stress.

KEYWORDS:

FGF21; brown fat; mitochondria; polymerase gamma; thermogenesis

PMID:
26124126
PMCID:
PMC4507233
DOI:
10.1073/pnas.1509930112
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center