A1 Refereed original research article in a scientific journal
Allostatic hypermetabolic response in PGC1 alpha/beta heterozygote mouse despite mitochondrial defects
Authors: Rodriguez-Cuenca Sergio, Lelliot Christopher J, Campbell Mark, Peddinti Gopal, Martinez-Uña Maite, Ingvorsen Camilla, Dias Ana Rita, Relat Joana, Mora Silvia, Hyötyläinen Tuulia, Zorzano Antonio, Orešič Matej, Bjursell Mikael, Bohlooly-Y Mohammad, Lindén Daniel, Vidal-Puig Antonio
Publisher: WILEY
Publication year: 2021
Journal: FASEB Journal
Journal name in source: FASEB JOURNAL
Journal acronym: FASEB J
Article number: e21752
Volume: 35
Issue: 9
Number of pages: 15
ISSN: 0892-6638
eISSN: 1530-6860
DOI: https://doi.org/10.1096/fj.202100262RR
Web address : https://faseb.onlinelibrary.wiley.com/doi/10.1096/fj.202100262RR
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/67259176
Aging, obesity, and insulin resistance are associated with low levels of PGC1 alpha and PGC1 beta coactivators and defective mitochondrial function. We studied mice deficient for PGC1 alpha and PGC1 beta [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 PGC1 alpha 4 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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