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Title: Allostatic hypermetabolic response in PGC1α/β heterozygote mouse despite mitochondrial defects
Author: Rodriguez-Cuenca, Sergio
Lelliot, Christopher J
Campbell, Mark
Peddinti, Gopal
Martinez-Uña, Maite
Ingvorsen, Camilla
Rita Dias, Ana
Relat Pardo, Joana
Mora Fayos, Sílvia
Hyötyläinen, Tuulia
Zorzano Olarte, Antonio
Oresic, Matej
Bjursell, Mikael
Bohlooly-Y, Mohammad
Lindén, Daniel
Vidal-Puig, Antonio
Keywords: Teixit adipós
Adipose tissues
Issue Date: Sep-2021
Publisher: The Federation of American Society of Experimental Biology
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.
Note: Versió preprint del document publicat a:
It is part of: The FASEB Journal , 2021, vol. 35, num. 9, p. e21752
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ISSN: 0892-6638
Appears in Collections:Publicacions de projectes de recerca finançats per la UE
Articles publicats en revistes (Bioquímica i Biomedicina Molecular)

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