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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.

Adult hematopoiesis takes place in the perivascular zone of the bone cavity, where endothelial cells, mesenchymal stromal/stem cells and their derivatives such as osteoblasts are key components of bone marrow (BM) niches. Defining the contribution of BM adipocytes to the hematopoietic stem cell niche remains controversial. While an excess of medullar adiposity is generally considered deleterious for hematopoiesis, an active role for adipocytes in shaping the niche has also been proposed. We thus investigated the consequences of total adipocyte deletion, including in the BM niche, on adult hematopoiesis using mice carrying a constitutive deletion of the gene coding for the nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ). We show that PpargΔ/Δ lipodystrophic mice exhibit severe extramedullary hematopoiesis (EMH), which we found to be non-cell autonomous, as it is reproduced when wild-type donor BM cells are transferred into PpargΔ/Δ recipients. This phenotype is not due to a specific alteration linked to Pparg deletion, such as chronic inflammation, since it is also found in AZIPtg/+ mice, another lipodystrophic mouse model with normal PPARγ expression, that display only very moderate levels of inflammation. In both models, the lack of adipocytes alters subpopulations of both myeloid and lymphoid cells. The CXCL12/CXCR4 axis in the BM is also dysregulated in an adipocyte deprived environment supporting the hypothesis that adipocytes are required for normal hematopoietic stem cell mobilization or retention. Altogether, these data suggest an important role for adipocytes, and possibly for the molecular interactions they provide within the BM, in maintaining the appropriate microenvironment for hematopoietic homeostasis.

Men with nonalcoholic fatty liver disease (NAFLD) are more exposed to nonalcoholic steatohepatitis (NASH) and liver fibrosis than women. However, the underlying molecular mechanisms of NALFD sex dimorphism are unclear. We combined gene expression, histological and lipidomic analyses to systematically compare male and female liver steatosis. We characterized hepatosteatosis in three independent mouse models of NAFLD, ob/ob and lipodystrophic fat-specific (PpargFΔ/Δ) and whole-body PPARγ-null (PpargΔ/Δ) mice. We identified a clear sex dimorphism occurring only in PpargΔ/Δ mice, with females showing macro- and microvesicular hepatosteatosis throughout their entire life, while males had fewer lipid droplets starting from 20 weeks. This sex dimorphism in hepatosteatosis was lost in gonadectomized PpargΔ/Δ mice. Lipidomics revealed hepatic accumulation of short and highly saturated TGs in females, while TGs were enriched in long and unsaturated hydrocarbon chains in males. Strikingly, sex-biased genes were particularly perturbed in both sexes, affecting lipid metabolism, drug metabolism, inflammatory and cellular stress response pathways. Most importantly, we found that the expression of key sex-biased genes was severely affected in all the NAFLD models we tested. Thus, hepatosteatosis strongly affects hepatic sex-biased gene expression. With NAFLD increasing in prevalence, this emphasizes the urgent need to specifically address the consequences of this deregulation in humans.

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