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

Sergio Rodriguez-Cuenca (Corresponding Author), Christopher J. Lelliot, Mark Campbell, Gopal Peddinti, Maite Martinez-Uña, Camilla Ingvorsen, Ana Rita Dias, Joana Relat, Silvia Mora, Tuulia Hyötyläinen, Antonio Zorzano, Matej Orešič, Mikael Bjursell, Mohammad Bohlooly-Y, Daniel Lindén (Corresponding Author), Antonio Vidal-Puig

Research output: Contribution to journalArticleScientificpeer-review

2 Citations (Scopus)


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.

Original languageEnglish
Article numbere21752
Number of pages15
JournalFASEB Journal
Issue number9
Early online date9 Aug 2021
Publication statusPublished - Sept 2021
MoE publication typeA1 Journal article-refereed


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].


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


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