title: High-fat diet and FGF21 cooperatively promote aerobic thermogenesis in mtDNA mutator mice.
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.
authors.affiliation: Gene Expression Laboratory, Salk Institute, La Jolla, CA 92037; Biomedical Sciences Graduate Program, University of California at San Diego, La Jolla, CA 92093;
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Wall
authors.affiliation: Gene Expression Laboratory, Salk Institute, La Jolla, CA 92037;
authors.forename: Jamie
authors.initials: J
authors.lastname: Whyte
authors.affiliation: Gene Expression Laboratory, Salk Institute, La Jolla, CA 92037;
authors.forename: Jae M
authors.initials: JM
authors.lastname: Suh
authors.affiliation: Gene Expression Laboratory, Salk Institute, La Jolla, CA 92037;
authors.forename: Weiwei
authors.initials: W
authors.lastname: Fan
authors.affiliation: Gene Expression Laboratory, Salk Institute, La Jolla, CA 92037;
authors.forename: Brett
authors.initials: B
authors.lastname: Collins
authors.affiliation: The Storr Liver Unit, Westmead Millennium Institute and University of Sydney, Westmead Hospital, Westmead, NSW 2145, Australia;
authors.forename: Christopher
authors.initials: C
authors.lastname: Liddle
authors.affiliation: Gene Expression Laboratory, Salk Institute, La Jolla, CA 92037;
authors.forename: Ruth T
authors.initials: RT
authors.lastname: Yu
authors.affiliation: Gene Expression Laboratory, Salk Institute, La Jolla, CA 92037;
authors.forename: Annette R
authors.initials: AR
authors.lastname: Atkins
authors.affiliation: 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;
authors.forename: Jane C
authors.initials: JC
authors.lastname: Naviaux
authors.affiliation: 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;
authors.forename: Kefeng
authors.initials: K
authors.lastname: Li
authors.affiliation: 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;
authors.forename: Andrew Taylor
authors.initials: AT
authors.lastname: Bright
authors.affiliation: 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;
authors.forename: William A
authors.initials: WA
authors.lastname: Alaynick
authors.affiliation: Gene Expression Laboratory, Salk Institute, La Jolla, CA 92037;
authors.forename: Michael
authors.initials: M
authors.lastname: Downes
authors.affiliation: 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;
authors.forename: Robert K
authors.initials: RK
authors.lastname: Naviaux
authors.affiliation: Gene Expression Laboratory, Salk Institute, La Jolla, CA 92037; Howard Hughes Medical Institute, Salk Institute, La Jolla, CA 92037 evans@salk.edu.
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Evans
mesh_terms: D002001:Adipose Tissue, Brown / Q000378:metabolism; D000332:Aerobiosis; D000818:Animals; D059305:Diet, High-Fat; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008928:Mitochondria / Q000378:metabolism; D022722:Thermogenesis / Q000235:genetics*
chemical_list: C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors
keywords: FGF21; brown fat; mitochondria; polymerase gamma; thermogenesis