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Allostatic hypermetabolic response in PGC1α/β heterozygote mouse despite mitochondrial defects.

Published version
Peer-reviewed

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Article

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Authors

Rodriguez-Cuenca, Sergio  ORCID logo  https://orcid.org/0000-0001-9635-0504
Lelliot, Christopher J 
Campbell, Mark 
Peddinti, Gopal 
Martinez-Uña, Maite 

Abstract

Aging, obesity, and insulin resistance are associated with low levels of PGC1α and PGC1β coactivators and defective mitochondrial function. We studied mice deficient for PGC1α and PGC1β [double heterozygous (DH)] to investigate their combined pathogenic contribution. Contrary to our hypothesis, DH mice were leaner, had increased energy dissipation, a pro-thermogenic profile in BAT and WAT, and improved carbohydrate metabolism compared to wild types. WAT showed upregulation of mitochondriogenesis/oxphos machinery upon allelic compensation of PGC1α4 from the remaining allele. However, DH mice had decreased mitochondrial OXPHOS and biogenesis transcriptomes in mitochondria-rich organs. Despite being metabolically healthy, mitochondrial defects in DH mice impaired muscle fiber remodeling and caused qualitative changes in the hepatic lipidome. Our data evidence first the existence of organ-specific compensatory allostatic mechanisms are robust enough to drive an unexpected phenotype. Second, optimization of adipose tissue bioenergetics is sufficient to maintain a healthy metabolic phenotype despite a broad severe mitochondrial dysfunction in other relevant metabolic organs. Third, the decrease in PGC1s in adipose tissue of obese and diabetic patients is in contrast with the robustness of the compensatory upregulation in the adipose of the DH mice.

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Keywords

PGC-1alpha, adipose tissue, hepatic lipidome, lipotoxicity, mitochondrial dysfunction, Adipose Tissue, Aging, Animals, Disease Models, Animal, Energy Metabolism, Heterozygote, Insulin Resistance, Male, Mice, Mitochondria, Nuclear Proteins, Obesity, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Thermogenesis, Transcription Factors, Transcriptome

Journal Title

FASEB J

Conference Name

Journal ISSN

0892-6638
1530-6860

Volume Title

35

Publisher

Wiley
Sponsorship
MRC (Unknown)
Wellcome Trust (208363/Z/17/Z)
Medical Research Council (MC_UU_12012/2)
MRC (MC_UU_00014/5)
Medical Research Council (MC_UU_12012/5)
British Heart Foundation (RG/18/7/33636)
Medical Research Council (G0802051)
Medical Research Council (MC_G0802535)
Medical Research Council (G0400192)
MRC (MC_UU_00014/2)
Medical Research Council (MC_PC_12012)
This work was funded by FP7-MITIN [HEALTH-F4-2008-223450] and the MRC MDU [MC_UU_12012/2]. SRC was also funded by MEIF-CT-2005-023061. The Biochemistry Assay Lab and the Histopathology Core are funded by MRC Metabolic Diseases Unit [MC_UU_00014/5]; Imaging Core is funded by Wellcome Trust Major Award [208363/Z/17/Z].