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

Area of Science:

• Mitochondrial biology
• Metabolic regulation
• Molecular endocrinology

Background:

• Aging, obesity, and insulin resistance are linked to reduced PGC1α/PGC1β coactivators and impaired mitochondrial function.
• PGC1 coactivators are critical regulators of mitochondrial biogenesis and function.
• Understanding the combined role of PGC1α and PGC1β is essential for metabolic health research.

Purpose of the Study:

• To investigate the pathogenic contribution of combined PGC1α and PGC1β deficiency using double heterozygous (DH) mice.
• To explore compensatory mechanisms in response to PGC1 coactivator loss.
• To assess the impact of PGC1 deficiency on energy metabolism, mitochondrial function, and organ-specific phenotypes.

Main Methods:

• Generation and characterization of PGC1α/PGC1β double heterozygous (DH) mice.
• Assessment of energy expenditure, thermogenesis in brown adipose tissue (BAT) and white adipose tissue (WAT).
• Analysis of carbohydrate metabolism, mitochondrial gene expression (OXPHOS, biogenesis), muscle fiber remodeling, and hepatic lipidome.

Main Results:

• DH mice exhibited leanness, increased energy dissipation, and a pro-thermogenic profile in adipose tissues.
• Improved carbohydrate metabolism was observed in DH mice compared to wild-type controls.
• Despite compensatory upregulation in WAT, DH mice showed decreased mitochondrial OXPHOS and biogenesis in other organs, leading to muscle and liver alterations.

Conclusions:

• Organ-specific compensatory allostatic mechanisms can drive unexpected metabolic phenotypes.
• Adipose tissue bioenergetic optimization can maintain metabolic health despite widespread mitochondrial dysfunction.
• The compensatory upregulation of PGC1s in adipose tissue of DH mice contrasts with findings in obese/diabetic patients, suggesting complex regulatory roles.