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 indepth 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.

Ubc9 deletion in adipocytes causes lipoatrophy in mice

“…This observation suggests beta cell secretion partly corrects the mild insulin resistance in Ubc9 a-KO mice. Our model resembles many features of progressive lipoatrophy observed in PPAR knockout models [4,8]. Lipoatrophy in fatspecific PPAR knockout mice occurs because adipocytes lost lipids and shrank, consistent with the pivotal roles of PPAR as a master regulator of adipose tissue formation [4,29].…”

“…Lipoatrophy in fatspecific PPAR knockout mice occurs because adipocytes lost lipids and shrank, consistent with the pivotal roles of PPAR as a master regulator of adipose tissue formation [4,29]. PPAR ablation in Sox2-expressing cells (PPAR / skirts embryonic lethality and mice survive without WAT and BAT [8]. PPAR / show a hypermetabolic phenotype accompanied by higher energy expenditure and hyperphagia.…”

“…Adipocyte differentiation requires PPAR [4] to partner with distinct transcriptional co-regulators that coordinate brown and white adipocyte-specific gene expression [5,6]. Gene deletion or tissue-specific disruption of PPAR impairs adipogenesis and results in severe lipodystrophy [4,[7][8][9]. The mechanisms that enable adipose tissue development carry broad basic research and clinical implications for understanding energy balance disorders.…”

PPARγ and Its Agonists in Chronic Kidney Disease

“…More TFs have been reported to be coregulated by PPARc, and these include the CCAAT/enhancer binding protein (C/ EBP) family [11], SREBP [12], REV-ERBa [13], and GATA3 [14]. Due to its wide-spectrum of regulatory effects, mutations in PPARc have been identified in the humans and led to dysfunctional lipid and glucose metabolism, insulin resistance, which developed into obesity-induced T2DM, dyslipidemia, NAFLD, and cancer [15][16][17][18].…”

Lipoatrophy‐Associated Insulin Resistance and Hepatic Steatosis are Attenuated by Intake of Diet Rich in Omega 3 Fatty Acids

“…PPAR‐γ is not only essential to preadipocyte differentiation into mature adipocytes, but also a critical regulator of adipocyte metabolic and endocrine functions . Indeed, either whole‐body or adipocyte‐specific PPAR‐γ deletion results in complete loss of adipose tissue (generalized lipodystrophy), hyperlipidemia, insulin resistance, and organomegaly …”