Systemic PPARγ deletion in mice provokes lipoatrophy, organomegaly, severe type 2 diabetes and metabolic inflexibility

Abstract

Background: The peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-dependent transcription factor involved in many aspects of metabolism, immune response and development. Numerous studies relying on tissue-specific invalidation of the Pparg gene have shown distinct facets of its activity, whereas the effects of its systemic inactivation remain unexplored due to embryonic lethality. By maintaining PPARγ expression in the placenta, we recently generated a mouse model carrying Pparg full body deletion (Pparg^Δ/Δ), which in contrast to a previously published model is totally deprived of any form of adipose tissue. Herein, we propose an in-depth study of the metabolic alterations observed in this new model.

Methods: Young adult mice, both males and females analyzed separately, were first phenotyped for their gross anatomical alterations. Systemic metabolic parameters were analyzed in the blood, in static and in dynamic conditions. A full exploration of energy metabolism was performed in calorimetric cages as well as in metabolic cages. Our study was completed by expression analyses of a set of specific genes.

Main findings: Pparg^Δ/Δ mice show a striking complete absence of any form of adipose tissue, which triggers a complex metabolic phenotype including increased lean mass with organomegaly, hypermetabolism, urinary energy loss, hyperphagia, and increased amino acid metabolism. Pparg^Δ/Δ mice develop severe type 2 diabetes, characterized by hyperglycemia, hyperinsulinemia, polyuria and polydispsia. They show a remarkable metabolic inflexibility, as indicated by the inability to shift substrate oxidation between glucose and lipids, in both ad libitum fed state and fed/fasted/refed transitions. Moreover, upon fasting Pparg^Δ/Δ mice enter a severe hypometabolic state.

Conclusions: Our data comprehensively describe the impact of lipoatrophy on metabolic homeostasis. As such, the presented data on Pparg^Δ/Δ mice gives new clues on what and how to explore severe lipodystrophy and its subsequent metabolic complications in human.

Keywords: In-depth metabolic exploration; Lipodystrophy; Metabolic inflexibility; PPARγ; Type 2 diabetes.