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Macrophages are involved in the immune and the inflammatory response. The deregulation of their physiological properties is associated with several pathologies such as atherosclerosis and some cancers. Cytokines action on this blood lineage modulates p21WAF1/CIP1 expression. It appears that this protein may play a role in the inflammation regulation through PPAR (peroxysome proliferator-activated receptors) transcription factors, strongly linked to lipid metabolism. It could also be involved in the control of the proliferation of monocytes/macrophages, even if these cells are classically described as devoided of any proliferative capacity.

International audience; Peroxisome proliferators activated receptors (PPAR) are ligand-inducible nuclear transacting factors comprising three subtypes, PPARα, PPARβ/δ and PPARγ, which play a key role in lipids and glucose homeostasis. All PPAR subtypes have been identified in joint or inflammatory cells and their activation resulted in a transcriptional repression of pro-inflammatory cytokines (IL-1, TNFα), early inflammatory genes (NOS2, COX-2, mPGES-1) or matrix metalloproteases (MMP-1, MMP-13), at least for the γ subtype. PPAR full agonists were also shown to stimulate IL-1 receptor antagonist (IL-1Ra) production by cytokine-stimulated articular cells in a subtype-dependent manner. These anti-inflammatory and anti-catabolic properties were confirmed in animal models of joint diseases where PPAR agonists reduced synovial inflammation while preventing cartilage destruction or inflammatory bone loss, although many effects required much higher doses than needed to restore insulin sensitivity or to lower circulating lipid levels. However, these promising effects of PPAR full agonists were hampered by their ability to reduce the growth factor-dependent synthesis of extracellular matrix components or to induce chondrocyte apoptosis, by the possible contribution of immunosuppressive properties to their anti-arthritic effects, by the increased adipocyte differentiation secondary to prolonged stimulation of PPARγ, and by a variable contribution of PPAR subtypes depending on the system. Clinical data are scarce in rheumatoid arthritis (RA) patients whereas thousands of patients worldwilde, treated with PPAR agonists for type 2 diabetes or dyslipidemia, are paradoxically prone to suffer from osteoarthritis (OA). Whereas high dosage of full agonists may expose RA patients to cardiovascular adverse effects, the proof of concept that PPAR agonists have therapeutical relevance to OA may benefit from an epidemiological follow-up of joint lesions in diabetic or hyperlipidemic patients treated for long periods of time with glitazones or fibrates. Additionally, cellular and animal studies are required to assess whether partial agonists of PPAR (SPPARMs) may preserve therapeutical properties with potentially less safety concern.; Les récepteurs activés par les proliférateurs de peroxysomes (PPAR) sont des facteurs de transcription inductibles par des ligands dont il existe trois sous-types, PPARα, PPARβ/δ et PPARγ jouant un rôle primordial dans le métabolisme des lipides et l'homéostasie du glucose. Ces trois sous-types sont également exprimés dans les cellules résidentes de l'articulation et celles de l'infiltrat inflammatoire, et leur activation réprime l'expression de cytokines pro-inflammatoires (IL-1, TNFα), de gènes précoces de l'inflammation (iNOS, COX-2, mPGES-1) ou de métalloprotéases matricielles (MMP-1, MMP-13), tout du moins pour le sous-type γ. Les agonistes de PPAR sont également capables de stimuler la production de l'antagoniste du récepteur à l'IL-1 (IL-1Ra) par les cellules articulaires soumises à un stimulus cytokinique. Ces potentialités anti-inflammatoires et anti-cataboliques ont été confirmées dans des modèles animaux d'arthropathie, dans lesquels les agonistes de PPAR diminuent l'inflammation synoviale et préviennent la destruction du cartilage ou la perte osseuse inflammatoire, même si les posologies requises sont très supérieures à celles permettant de normaliser les taux circulants de lipides ou de rétablir la sensibilité des tissus périphériques à l'insuline. Ces effets prometteurs des agonistes sont cependant pondérés par leur capacité à diminuer l'effet trophique des facteurs de croissance sur la biosynthèse des composants matriciels ou à provoquer une apoptose chondrocytaire, par leur effet immunosuppresseur responsable d'une surestimation des propriétés anti-inflammatoires dans les polyarthrites expérimentales, par le renforcement de la différenciation adipocytaire lors d'une stimulation prolongée de PPARγ, et par la contribution variable des sous-types selon le système expérimental. Les données cliniques restent anecdotiques dans la polyarthrite rhumatoïde alors que, paradoxalement, des milliers de patients qui sont traités quotidiennement par des agonistes de PPAR pour un diabète de type 2 ou une dyslipidémie, souffrent conjointement d'arthrose. Alors que les fortes posologies d'agonistes exposeraient les patients polyarthritiques à un risque important d'effets indésirables, notamment cardiovasculaires, la démonstration de l'intérêt des agonistes de PPAR dans l'arthrose pourrait être apportée par une étude épidémiologique de l'incidence ou de l'évolution de la maladie arthrosique chez les patients diabétiques et/ou dyslipidémiques traités par des glitazones ou des fibrates. Il sera également opportun d'étudier si des agonistes partiels de PPAR permettront de conserver certaines potentialités thérapeutiques tout en diminuant le risque d'effets indésirables.

The impact of nutrition and energy reserves on the reproductive functions is known for a very long time. However, the metabolic factors involved in the interactions between nutrition and reproduction are still poorly understood. These factors may be hormones or nutrients (glucose, protein and fatty acids). However, it remains to determine whether these factors act directly or indirectly on the reproductive tissues. In this issue, we briefly summarize the impact of fatty acids on the development of ovarian follicles, oocyte and embryo. We then discuss the current hypotheses about the mechanisms of action of these fatty acids on the ovarian functions. We describe more particularly the role of some receptors of fatty acids, Peroxisome Proliferator-Activated Receptors (PPAR) and Liver X Receptors (LXR) and two adipokines, leptin and adiponectin on ovarian cells.

In last few years, the topic of nuclear receptor has been developed in the field of hepatology allowing envisaging therapeutic strategies for the most frequent chronic liver diseases. Peroxysome proliferator-activated receptors (PPAR) contribute to wide physiological processes within the liver such as lipid/glucid metabolisms, inflammatory response, cell differenciation and cell cycle. In vitro experiments and animal studies showed that PPARalpha discloses anti-inflammatory property and PPARgamma discloses anti-inflammatory, antifibrogenic and antiproliferative properties in the liver. Main available agonists are fibrates (PPARalpha) used for 20 years in cases of lipid metabolism abnormalities and glitazones (PPARgamma) used since 2000 for type 2 diabetes. In terms of therapy, animal studies and human trials have been conducted in steatopathies. However, clinicians have to be aware of potential specific side effects related to glitazones especially on cardiovascular system.

The peroxisome proliferator-activated receptors (PPARs) are transcription factors and belong to the superfamily of nuclear receptors. They are encoded by three genes located on different chromosomes: PPARalpha, PPARbeta/delta and PPARgamma. PPARalpha plays a key role in the control of lipid metabolism and homeostasis. PPARbeta/delta is expressed ubiquitously and participates in skeletal muscle physiology. PPARbeta/delta and PPARgamma are important factors for placental development and function as well as for embryo implantation. In addition, PPARgamma is mainly involved in adipogenesis. PPARs also participate more or less to cell proliferation, differentiation and apoptosis. Surprisingly, the involvement of these transcription factors in cell-cell and/or cell-matrix interactions has not yet been reviewed except for their role as therapeutic agents in inflammation. Nevertheless, several pioneer reports have recently provided some new insights in this research field, by suggesting that PPARs are involved, directly or indirectly, in these interactions and that their activation by specific ligands may lead to potential therapeutic approaches.

The nuclear receptors PPAR (Peroxisome Proliferator-Activated Receptors) are transcription factors which form with the retinoid receptor RXR, a PPAR/RXR heterodimer, the functional transcription factor within cells. PPAR receptors are activated by their ligands, either naturals or synthetics, and modulate target gene transcription. There are three PPAR subtypes (PPARalpha, PPARbeta/delta et PPARgamma) coded by different genes, and two isoforms of PPARgamma proteins have been detected in humans (PPARgamma1 and PPARgamma2). PPAR are mainly modulators of lipid metabolism, but each receptor subtype is pharmacologically distinct, and development of synthetic PPAR agonists has shown their role in cellular (mainly adipocyte) differentiation and in glucose homeostasis. This review summarise the main data, currently available, on expression, biological functions, natural and synthetic (activators) ligands for the PPAR receptor subtypes. PPAR receptors key-role in lipid and glucose métabolisms, has lead to a large clinical use of pharmacological agents acting as PPAR ligands: fibrates, PPARalpha agonists as hypolipidaemic treatment, thiazolidinediones (glitazones), PPARalpha agonists as antidiabetics. Lipid metabolism is impaired in insulin resistant skeletal muscles, fatty acids role in the pathophysiology of insulin resistance generates several hypothesis we briefly describe. Finally, we present and discuss experimental data, suggesting the activation of PPARbeta/delta in skeletal muscle to be a potential new approach in the treatment of insulin resistance and metabolic syndrome.