Similarly Cota et al, and Martin et al, reported alteration in AMPK and mTOR pathway but not the STAT3 pathway during development of DIO in FVB/N mice. Therefore in absence of significant difference in hypothalamic leptin induced STAT3 activation in RC and RR rats compared to CC rats, we PCI-32765 investigated others cellular pathways. The absence of activation and furthermore the inhibition of pAKT signal measured in RC rats could suggest a role of this pathway in leptin resistance since leptin-stimulated activation of hypothalamic PI3-kinase/AKT pathway is impaired in DIO mice. Furthermore inhibition of the PI3-kinase pathway in the brain blocks the ability of leptin to reduce food intake and weight gain. Leptin stimulates phosphorylation of ribosomal S6 kinase, a major physiological substrate for mTOR kinase in the hypothalamus but fasting inhibits it. Inhibition of mTOR by rapamycin or deletion of S6K1 attenuates leptin acute anorexigenic action. The high increase of hypothalamic mTOR phosphorylation that we found in RC rats after leptin challenge is not easy to explain in the context of leptin resistance. However in mice, chronic activation of the mTOR/S6K pathway by POMC neuron-specific deletion of TSC1, demonstrate leptin resistance, hyperphagia and obesity, presumably due to an alteration of the hypothalamic neurocircuitry of energy balance. The strong pmTOR signal measured in RC rats could be a major mechanism of leptin resistance but this finding will deserve a better immunohistochemical and anatomical localization in order to phenotype the target cells as well as comparison between the fed and fast state. In addition to alteration of signalling pathways RR rats hypothalami displayed a significant reduction of the long form leptin receptor mRNA and leptin transporter mRNA. This could result in an impaired response to leptin challenge by leptin failure to cross the blood–brain barrier and low cerebral binding capacity. In summary, we observed that IUGR rats, with programmed adipocytes hypertrophy by rapid catch-up growth, were leptin resistant prior to the development of obesity. This leptin resistance could involve low activation of the JAK2/STAT3 hypothalamic pathway, deregulation of Akt/mTOR pathway or leptin receptors availability. Leptin resistance represents an early marker of metabolic disorders whose mechanisms could depend of nutritional environment of the perinatal period. The NLR family of proteins has been increasingly associated with various aspects of innate and adaptive immune system regulation, inflammation, and autoimmunity. Several prototypic NLR family members, including CIITA, NLRP3 and NOD2, have emerged as major contributing factors in a variety of human diseases. To date, the majority of NLR studies have focused on a subgroup of NLR family members that are capable of forming a multiprotein complex, termed the inflammasome, with the NLR adaptor protein PYCARD and Caspase-1. The inflammasome functions to cleave pro-IL-1b and pro-IL-18 into their active cytokines. NLRs that are associated with this subgroup are inherently proinflammatory and include NLRP3 and NLRC4. In addition to the inflammasome forming NLRs, recent studies have also revealed a second subgroup of NLRs that have anti-inflammatory functions, which dampen overzealous immune responses. The members of this subgroup include NLRP12, NLRX1, NLRC3 and NLRC5.