AB0172 PGC-1Α REGULATES AUTOPHAGY TO PROMOTE FIBROBLAST ACTIVATION AND TISSUE FIBROSIS

Background:Peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) is the best studied member of the family of coactivators. PGC-1α was initially identified through its interaction with PPARγ in brown adipose tissue. Recent evidence further indicates that PGC-1α may also modulate the transcription of autophagy-related genes, which has recently been shown to be required for fibroblast-to-myofibroblast differentiation under fibrotic conditions. However, the role of PGC-1α in the pathogenesis of SSc has not been investigated.Objectives:The aim of the present study was to evaluate the role of the coactivator PGC-1α on autophagy and to evaluate its role in the pathologic activation of fibroblasts in SSc.Methods:Expression of PGC-1α was analyzed by RT-PCR, Western blot and immunofluorescence. Modulation of autophagy was analyzed by reporter studies by expression of autophagy related genes. The effects of PGC-1α knockdown on collagen production and myofibroblast differentiation were analyzed in cultured human fibroblasts and in two mouse models with fibroblast-specific knockout of PGC-1α.Results:PGC-1α overexpression was detected by immunohistochemistry in skin sections of SSc patients and in experimental fibrotic murine skin, particularly in fibroblasts. Knockdown of PGC-1α inhibited the stimulatory effects of TGFβ on fibroblast activation with impaired induction of collagen as compared to control fibroblasts. Fibroblasts specific knockout of PGC-1α ameliorates experimental fibrosis in bleomycin-induced and adTBR-induced murine dermal fibrosis with decreased dermal thickness, hydroxyproline and myofibroblast counts compared to wild-type fibrotic mice. Incubation of dermal fibroblasts with TGFβ activated autophagy in control fibroblasts with increased expression of the autophagy-related genes ATG7 and BECLIN-1, enhanced conversion of LC3 I to LC3 II and decreased ratios of ILC3 I EGFP to LC3 II RFP in LC3 reporter assays. The expression levels of ATG7, BECLIN-1 and ILC3 II of TGFβ-stimulated PGC-1α knockout fibroblasts decreased compare to TGFβ stimulated wild-type fibroblasts. The ratio of ILC3 I EGFP to LC3 II RFP of TGFβ-stimulated PGC-1α knockout fibroblasts in reporter assays were comparable to unstimulated fibroblasts.Conclusion:PGC-1α is upregulated in SSc and promotes autophagy to foster TGFβ-induced fibroblast activation. Targeting of PGC-1α prevents aberrant autophagy, inhibits fibroblast activation and tissue fibrosis.References:[1]Finck BN, Kelly DP. PGC-1 coactivators: inducible regulators of energy metabolism in health and disease. The Journal of clinical investigation. 2006 Mar; 116(3):615-622[2]Lindholm D, Eriksson O, Makela J, Belluardo N, Korhonen L. PGC-1alpha: a master gene that is hard to master. Cellular and molecular life sciences: CMLS. 2012 Aug; 69(15):2465-2468.[3]Li SY, Susztak K. The Role of Peroxisome Proliferator-Activated Receptor gamma Coactivator 1alpha (PGC-1alpha) in Kidney Disease. Semin Nephrol. 2018 Mar; 38(2):121-126.[4]Vainshtein A, Tryon LD, Pauly M, Hood DA. Role of PGC-1alpha during acute exercise-induced autophagy and mitophagy in skeletal muscle. American journal of physiology Cell physiology. 2015 May 1; 308(9):C710-719.[5]Zehender A LN, Stefanica A, Chen CW, Soare A, Wohlfahrt T, Rauber S, Bergmann C, Ramming A, Distler O, Schett G, Distler J. TGFβ Promotes Fibrosis By MYST1-Dependent Epigenetic Regulation of Autophagy [abstract]. Arthritis Rheumatol 2017; 69 (suppl 10).Disclosure of Interests:Yun Zhang: None declared, Katja Dreißigacker: None declared, Diana Distler: None declared, Andrea-Hermina Györfi: None declared, Christina Bergmann: None declared, xiang zhou: None declared, Lichong Shen: None declared, Ingo Ludolph: None declared, Raymund Horch: None declared, Andreas Ramming Grant/research support from: Pfizer, Novartis, Consultant of: Boehringer Ingelheim, Novartis, Gilead, Pfizer, Speakers bureau: Boehringer Ingelheim, Roche, Janssen, Georg Schett Speakers bureau: AbbVie, BMS, Celgene, Janssen, Eli Lilly, Novartis, Roche and UCB, Jörg Distler Grant/research support from: Boehringer Ingelheim, Consultant of: Boehringer Ingelheim, Paid instructor for: Boehringer Ingelheim, Speakers bureau: Boehringer Ingelheim

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The Transcriptional Response to a Peroxisome Proliferator-activated Receptor α Agonist Includes Increased Expression of Proteome Maintenance Genes

Journal of Biological Chemistry ◽

10.1074/jbc.m409347200 ◽

2004 ◽

Vol 279 (50) ◽

pp. 52390-52398 ◽

Cited By ~ 64

Author(s):

Steven P. Anderson ◽

Paul Howroyd ◽

Jie Liu ◽

Xun Qian ◽

Rainer Bahnemann ◽

...

Keyword(s):

Oxidative Stress ◽

Stress Responses ◽

Transcriptional Response ◽

Lipid Homeostasis ◽

Peroxisome Proliferator ◽

Wild Type ◽

Peroxisome Proliferator Activated Receptor ◽

Proteasomal Genes ◽

Oxidative Stress Responses

The nuclear receptor peroxisome proliferator-activated receptor α (PPARα), in addition to regulating lipid homeostasis, controls the level of tissue damage after chemical or physical stress. To determine the role of PPARα in oxidative stress responses, we examined damage after exposure to chemicals that increase oxidative stress in wild-type or PPARα-null mice. Primary hepatocytes from wild-type but not PPARα-null mice pretreated with the PPAR pan-agonist WY-14,643 (WY) were protected from damage to cadmium and paraquat. The livers from intact wild-type but not PPARα-null mice were more resistant to damage after carbon tetrachloride treatment. To determine the molecular basis of the protection by PPARα, we identified by transcript profiling genes whose expression was altered by a 7-day exposure to WY in wild-type and PPARα-null mice. Of the 815 genes regulated by WY in wild-type mice (p≤ 0.001; ≥1.5-fold or ≤-1.5-fold), only two genes were regulated similarly by WY in PPARα-null mice. WY increased expression of stress modifier genes that maintain the health of the proteome, including those that prevent protein aggregation (heat stress-inducible chaperones) and eliminate damaged proteins (proteasome components). Although the induction of proteasomal genes significantly overlapped with those regulated by 1,2-dithiole-3-thione, an activator of oxidant-inducible Nrf2, WY increased expression of proteasomal genes independently of Nrf2. Thus, PPARα controls the vast majority of gene expression changes after exposure to WY in the mouse liver and protects the liver from oxidant-induced damage, possibly through regulation of a distinct set of proteome maintenance genes.

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The role of the amino-terminal domain in the interaction of unliganded peroxisome proliferator-activated receptor γ-2 with nuclear receptor co-repressor

Journal of Molecular Endocrinology ◽

10.1677/jme-10-0007 ◽

2010 ◽

Vol 45 (3) ◽

pp. 133-145 ◽

Cited By ~ 9

Author(s):

Sadako Suzuki ◽

Shigekazu Sasaki ◽

Hiroshi Morita ◽

Yutaka Oki ◽

Daisuke Turiya ◽

...

Keyword(s):

Insulin Resistance ◽

Nuclear Receptor ◽

Thyroid Hormone Receptor ◽

Dominant Negative ◽

Peroxisome Proliferator ◽

Wild Type ◽

Peroxisome Proliferator Activated Receptor ◽

Amino Terminal

Peroxisome proliferator-activated receptor γ-2 (PPARG2) is a ligand-dependent transcriptional factor involved in the pathogenesis of insulin resistance. In the presence of a ligand, PPARG2 associates with co-activators, while it recruits co-repressors (CoRs) in the absence of a ligand. It has been reported that the interaction of liganded PPARG2 with co-activators is regulated by the amino-terminal A/B domain (NTD) via inter-domain communication. However, the role of the NTD is unknown in the case of the interaction between unliganded PPARG2 and CoRs. To elucidate this, total elimination of the influence of ligands is required, but the endogenous ligands of PPARG2 have not been fully defined. PPARG1-P467L, a naturally occurring mutant of PPARG1, was identified in a patient with severe insulin resistance. Reflecting its very low affinity for various ligands, this mutant does not have transcriptional activity in the PPAR response element, but exhibits dominant negative effects (DNEs) on liganded wild-type PPARG2-mediated transactivation. Using the corresponding PPARG2 mutant, PPARG2-P495L, we evaluated the role of the NTD in the interaction between unliganded PPARG2 and CoRs. Interestingly, the DNE of PPARG2-P495L was increased by the truncation of its NTD. NTD deletion also enhanced the DNE of a chimeric receptor, PT, in which the ligand-binding domain of PPARG2 was replaced with that of thyroid hormone receptor β-1. Moreover, NTD deletion facilitated the in vitro binding of nuclear receptor CoR with wild-type PPARG2, mutant P495L, and the PT chimera (PPARG2-THRB). Inter-domain communication in PPARG2 regulates not only ligand-dependent transactivation but also ligand-independent silencing.

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Evaluation of the role of peroxisome-proliferator-activated receptor α in the regulation of cardiac pyruvate dehydrogenase kinase 4 protein expression in response to starvation, high-fat feeding and hyperthyroidism

Biochemical Journal ◽

10.1042/bj20011841 ◽

2002 ◽

Vol 364 (3) ◽

pp. 687-694 ◽

Cited By ~ 46

Author(s):

Mark J. HOLNESS ◽

Nicholas D. SMITH ◽

Karen BULMER ◽

Teresa HOPKINS ◽

Geoffrey F. GIBBONS ◽

...

Keyword(s):

Protein Expression ◽

Pyruvate Dehydrogenase ◽

Fold Increase ◽

Pyruvate Dehydrogenase Kinase ◽

Peroxisome Proliferator ◽

Wild Type ◽

High Fat ◽

Peroxisome Proliferator Activated Receptor

Inactivation of cardiac pyruvate dehydrogenase complex (PDC) after prolonged starvation and in response to hyperthyroidism is associated with enhanced protein expression of pyruvate dehydrogenase kinase (PDK) isoform 4. The present study examined the potential role of peroxisome-proliferator-activated receptor α (PPARα) in adaptive modification of cardiac PDK4 protein expression after starvation and in hyperthyroidism. PDK4 protein expression was analysed by immunoblotting in homogenates of hearts from fed or 48h-starved rats, rats rendered hyperthyroid by subcutaneous injection of tri-iodothyronine and a subgroup of euthyroid rats maintained on a high-fat/low-carbohydrate diet, with or without treatment with the PPARα agonist WY14,643. In addition, PDK4 protein expression was analysed in hearts from fed, 24h-starved or 6h-refed wild-type or PPARα-null mice. PPARα activation by WY14,643 in vivo over the timescale of the response to starvation failed to up-regulate cardiac PDK4 protein expression in rats maintained on standard diet (WY14,643, 1.1-fold increase; starvation, 1.8-fold increase) or influence the cardiac PDK4 response to starvation. By contrast, PPARα activation by WY14,643 in vivo significantly enhanced cardiac PDK4 protein expression in rats maintained on a high-fat diet, which itself increased cardiac PDK4 protein expression. PPARα deficiency did not abolish up-regulation of cardiac PDK4 protein expression in response to starvation (2.9-fold increases in both wild-type and PPARα-null mice). Starvation and hyperthyroidism exerted additive effects on cardiac PDK4 protein expression, but PPARα activation by WY14,643 did not influence the response of cardiac PDK4 protein expression to hyperthyroidism in either the fed or starved state. Our data support the hypothesis that cardiac PDK4 protein expression is regulated, at least in part, by a fatty acid-dependent, PPARα-independent mechanism and strongly implicate a fall in insulin in either initiating or facilitating the response of cardiac PDK4 protein expression to starvation.

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Role of Mineralocorticoid Receptor in Adipogenesis and Obesity in Male Mice

Endocrinology ◽

10.1210/endocr/bqz010 ◽

2019 ◽

Vol 161 (2) ◽

Author(s):

Daniel Ferguson ◽

Irina Hutson ◽

Eric Tycksen ◽

Terri A Pietka ◽

Kevin Bauerle ◽

...

Keyword(s):

Metabolic Syndrome ◽

Fat Mass ◽

Mineralocorticoid Receptor ◽

Peroxisome Proliferator ◽

Sequencing Analysis ◽

Wild Type ◽

Peroxisome Proliferator Activated Receptor ◽

Pparγ Agonist ◽

Brown Adipose

Abstract Increased visceral adiposity and hyperglycemia, 2 characteristics of metabolic syndrome, are also present in conditions of excess glucocorticoids (GCs). GCs are hormones thought to act primarily via the glucocorticoid receptor (GR). GCs are commonly prescribed for inflammatory disorders, yet their use is limited due to many adverse metabolic side effects. In addition to GR, GCs also bind the mineralocorticoid receptor (MR), but there are many conflicting studies about the exact role of MR in metabolic disease. Using MR knockout mice (MRKO), we find that both white and brown adipose depots form normally when compared with wild-type mice at P5. We created mice with adipocyte-specific deletion of MR (FMRKO) to better understand the role of MR in metabolic dysfunction. Treatment of mice with excess GCs for 4 weeks, via corticosterone in drinking water, induced increased fat mass and glucose intolerance to similar levels in FMRKO and floxed control mice. Separately, when fed a high-fat diet for 16 weeks, FMRKO mice had reduced body weight, fat mass, and hepatic steatosis, relative to floxed control mice. Decreased adiposity likely resulted from increased energy expenditure since food intake was not different. RNA sequencing analysis revealed decreased enrichment of genes associated with adipogenesis in inguinal white adipose of FMRKO mice. Differentiation of mouse embryonic fibroblasts (MEFs) showed modestly impaired adipogenesis in MRKO MEFs compared with wild type, but this was rescued upon the addition of peroxisome proliferator-activated receptor gamma (PPARγ) agonist or PPARγ overexpression. Collectively, these studies provide further evidence supporting the potential value of MR as a therapeutic target for conditions associated with metabolic syndrome.

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The emerging role of COX-2, 15-LOX, and PPARγ in metabolic diseases and cancer: An introduction to novel multi-target directed ligands (MTDLs)

Current Medicinal Chemistry ◽

10.2174/0929867327999200820173853 ◽

2020 ◽

Vol 27 ◽

Cited By ~ 1

Author(s):

Rana A. Alaaeddine ◽

Perihan A. Elzahhar ◽

Ibrahim AlZaim ◽

Wassim Abou-Kheir ◽

Ahmed S.F. Belal ◽

...

Keyword(s):

Metabolic Diseases ◽

Biological Effects ◽

Arachidonic Acid Metabolism ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Cellular Targets ◽

Design And Synthesis ◽

Early Results ◽

Cox 2

: Emerging evidence supports an intertwining framework for the involvement of different inflammatory pathways in a common pathological background for a number of disorders. Of importance are pathways involving arachidonic acid metabolism by cyclooxygenase-2 (COX-2) and 15-lipoxygenase (15-LOX). Both enzyme activities and their products are implicated in a range of pathophysiological processes encompassing metabolic impairment leading to adipose inflammation and the subsequent vascular and neurological disorders, in addition to various pro-and anti-tumorigenic effects. A further layer of complexity is encountered by the disparate, and often reciprocal, modulatory effect COX-2 and 15-LOX activities and metabolites exert on each other or on other cellular targets, the most prominent of which is peroxisome proliferator-activated receptor gamma (PPARγ). Thus, effective therapeutic intervention with such multifaceted disorders requires the simultaneous modulation of more than one target. Here, we describe the role of COX-2, 15-LOX, and PPARγ in cancer and complications of metabolic disorders, highlight the value of designing multi-target directed ligands (MTDLs) modifying their activity, and summarize the available literature regarding the rationale and feasibility of design and synthesis of these ligands together with their known biological effects. We speculate on the potential impact of MTDLs in these disorders as well as emphasize the need for structured future effort to translate these early results facilitating the adoption of these, and similar, molecules in clinical research.

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The Nutraceutical N-Palmitoylethanolamide (PEA) Reveals Widespread Molecular Effects Unmasking New Therapeutic Targets in Murine Varicocele

Nutrients ◽

10.3390/nu13030734 ◽

2021 ◽

Vol 13 (3) ◽

pp. 734

Author(s):

Pietro Antonuccio ◽

Herbert Ryan Marini ◽

Antonio Micali ◽

Carmelo Romeo ◽

Roberta Granese ◽

...

Keyword(s):

Transforming Growth Factor ◽

Therapeutic Targets ◽

Sham Operation ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Pyrin Domain ◽

Age Related ◽

Extracellular Signal ◽

Morphometric Assessment

Varicocele is an age-related disease with no current medical treatments positively impacting infertility. Toll-like receptor 4 (TLR4) expression is present in normal testis with an involvement in the immunological reactions. The role of peroxisome proliferator-activated receptor-α (PPAR-α), a nuclear receptor, in fertility is still unclear. N-Palmitoylethanolamide (PEA), an emerging nutraceutical compound present in plants and animal foods, is an endogenous PPAR-α agonist with well-demonstrated anti-inflammatory and analgesics characteristics. In this model of mice varicocele, PPAR-α and TLR4 receptors’ roles were investigated through the administration of ultra-micronized PEA (PEA-um). Male wild-type (WT), PPAR-α knockout (KO), and TLR4 KO mice were used. A group underwent sham operation and administration of vehicle or PEA-um (10 mg/kg i.p.) for 21 days. Another group (WT, PPAR-α KO, and TLR4 KO) underwent surgical varicocele and was treated with vehicle or PEA-um (10 mg/kg i.p.) for 21 days. At the end of treatments, all animals were euthanized. Both operated and contralateral testes were processed for histological and morphometric assessment, for PPAR-α, TLR4, occludin, and claudin-11 immunohistochemistry and for PPAR-α, TLR4, transforming growth factor-beta3 (TGF-β3), phospho-extracellular signal-Regulated-Kinase (p-ERK) 1/2, and nucleotide-binding oligomerization domain-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) Western blot analysis. Collectively, our data showed that administration of PEA-um revealed a key role of PPAR-α and TLR4 in varicocele pathophysiology, unmasking new nutraceutical therapeutic targets for future varicocele research and supporting surgical management of male infertility.

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From Exercise to Cognitive Performance: Role of Irisin

Applied Sciences ◽

10.3390/app11157120 ◽

2021 ◽

Vol 11 (15) ◽

pp. 7120

Author(s):

Mirko Pesce ◽

Irene La Fratta ◽

Teresa Paolucci ◽

Alfredo Grilli ◽

Antonia Patruno ◽

...

Keyword(s):

The Elderly ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Beneficial Effects ◽

General Exercise ◽

Fibronectin Type Iii ◽

Exercise Induced ◽

Fibronectin Type Iii Domain ◽

The Brain

The beneficial effects of exercise on the brain are well known. In general, exercise offers an effective way to improve cognitive function in all ages, particularly in the elderly, who are considered the most vulnerable to neurodegenerative disorders. In this regard, myokines, hormones secreted by muscle in response to exercise, have recently gained attention as beneficial mediators. Irisin is a novel exercise-induced myokine, that modulates several bodily processes, such as glucose homeostasis, and reduces systemic inflammation. Irisin is cleaved from fibronectin type III domain containing 5 (FNDC5), a transmembrane precursor protein expressed in muscle under the control of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α). The FNDC5/irisin system is also expressed in the hippocampus, where it stimulates the expression of the neurotrophin brain-derived neurotrophic factor in this area that is associated with learning and memory. In this review, we aimed to discuss the role of irisin as a key mediator of the beneficial effects of exercise on synaptic plasticity and memory in the elderly, suggesting its roles within the main promoters of the beneficial effects of exercise on the brain.

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The Novel Role of PGC1α in Bone Metabolism

International Journal of Molecular Sciences ◽

10.3390/ijms22094670 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4670

Author(s):

Cinzia Buccoliero ◽

Manuela Dicarlo ◽

Patrizia Pignataro ◽

Francesco Gaccione ◽

Silvia Colucci ◽

...

Keyword(s):

Bone Metabolism ◽

Osteoblastic Differentiation ◽

In Vivo Studies ◽

Peroxisome Proliferator ◽

Sirtuin 3 ◽

Peroxisome Proliferator Activated Receptor ◽

Increased Risk

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) is a protein that promotes transcription of numerous genes, particularly those responsible for the regulation of mitochondrial biogenesis. Evidence for a key role of PGC1α in bone metabolism is very recent. In vivo studies showed that PGC1α deletion negatively affects cortical thickness, trabecular organization and resistance to flexion, resulting in increased risk of fracture. Furthermore, in a mouse model of bone disease, PGC1α activation stimulates osteoblastic gene expression and inhibits atrogene transcription. PGC1α overexpression positively affects the activity of Sirtuin 3, a mitochondrial nicotinammide adenina dinucleotide (NAD)-dependent deacetylase, on osteoblastic differentiation. In vitro, PGC1α overexpression prevents the reduction of mitochondrial density, membrane potential and alkaline phosphatase activity caused by Sirtuin 3 knockdown in osteoblasts. Moreover, PGC1α influences the commitment of skeletal stem cells towards an osteogenic lineage, while negatively affects marrow adipose tissue accumulation. In this review, we will focus on recent findings about PGC1α action on bone metabolism, in vivo and in vitro, and in pathologies that cause bone loss, such as osteoporosis and type 2 diabetes.

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The Potential Applications of Peroxisome Proliferator-Activated ReceptorδLigands in Assisted Reproductive Technology

PPAR Research ◽

10.1155/2008/794814 ◽

2008 ◽

Vol 2008 ◽

pp. 1-6 ◽

Cited By ~ 1

Author(s):

Jaou-Chen Huang

Keyword(s):

Assisted Reproductive Technology ◽

Reproductive Function ◽

Reproductive Technology ◽

Embryonic Cell ◽

Preimplantation Embryos ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Potential Applications ◽

And Function

Peroxisome proliferator-activated receptorδ(PPARδ, also known as PPARβ) has ubiquitous distribution and extensive biological functions. The reproductive function of PPARδwas first revealed in the uterus at the implantation site. Since then, PPARδand its ligand have been discovered in all reproductive tissues, including the gametes and the preimplantation embryos. PPARδin preimplantation embryos is normally activated by oviduct-derived PPARδligand. PPARδactivation is associated with an increase in embryonic cell proliferation and a decrease in programmed cell death (apoptosis). On the other hand, the role of PPARδand its ligand in gamete formation and function is less well understood. This review will summarize the reproductive functions of PPARδand project its potential applications in assisted reproductive technology.

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Adverse Adipose Phenotype and Hyperinsulinemia in Gravid Mice Deficient in Placental Growth Factor

Endocrinology ◽

10.1210/en.2007-1272 ◽

2008 ◽

Vol 149 (5) ◽

pp. 2176-2183 ◽

Cited By ~ 19

Author(s):

Bianca Hemmeryckx ◽

Rita van Bree ◽

Berthe Van Hoef ◽

Lisbeth Vercruysse ◽

H. Roger Lijnen ◽

...

Keyword(s):

Growth Factor ◽

Adrenergic Receptors ◽

Growth Factor Receptor ◽

Placental Growth Factor ◽

Peroxisome Proliferator ◽

Vascular Endothelial ◽

Wild Type ◽

Peroxisome Proliferator Activated Receptor ◽

Adipocyte Hypertrophy ◽

Endothelial Growth Factor

Pregnancy-induced metabolic changes are regulated by signals from an expanded adipose organ. Placental growth factor (PlGF), acting through vascular endothelial growth factor receptor-1, may be among those signals. There is a steep rise in circulating PlGF during normal pregnancy, which is repressed in gravidas who develop preeclampsia. PlGF-deficiency in mice impairs adipose vascularization and development. Here we studied young-adult PlGF-deficient (PlGF−/−) and wild-type mice on a high-fat diet in the nongravid state and at embryonic day (E) 13.5 or E18.5 of gestation. Litter size and weight were normal, but E18.5 placentas were smaller in PlGF−/− pregnancies. PlGF−/− mice showed altered intraadipose dynamics, with the following: 1) less blood vessels and fewer brown, uncoupling protein (UCP)-1-positive, adipocytes in white sc and perigonadal fat compartments and 2) white adipocyte hypertrophy. The mRNA expression of β3-adrenergic receptors, peroxisome proliferator-activated receptor-γ coactivator-1α, and UCP-1 was decreased accordingly. Moreover, PlGF−/− mice showed hyperinsulinemia. Pregnancy-associated changes were largely comparable in PlGF−/− and wild-type dams. They included expanded sc fat compartments and adipocyte hypertrophy, whereas adipose expression of key angiogenesis/adipogenesis (vascular endothelial growth factor receptor-1, peroxisome proliferator-activated receptor-γ2) and thermogenesis (β3-adrenergic receptors, peroxisome proliferator-activated receptor-γ coactivator-1α, and UCP-1) genes was down-regulated; circulating insulin levels gradually increased during pregnancy. In conclusion, reduced adipose vascularization in PlGF−/− mice impairs adaptive thermogenesis in favor of energy storage, thereby promoting insulin resistance and hyperinsulinemia. Pregnancy adds to these changes by PlGF-independent mechanisms. Disturbed intraadipose dynamics is a novel mechanism to explain metabolic changes in late pregnancy in general and preeclamptic pregnancy in particular.

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