Insulin signaling evaluation and the effects of activation of antiinflammatory cholinergic pathway in the offspring liver of obese dams

Abstract

The obesity has become a global epidemic and is related to a chronic, subclinical inflammatory condition. Result of the combination of several factors, the increased body fat can lead to many deleterious effects, including influencing the energy and hormone metabolism of offspring. The immune system and inflammatory processes are fundamental to the defense of the organism to pathogens and adverse conditions. The fine control of anti-inflammatory response is performed for the pathway cholinergic anti-inflammatory. When the nicotinic of acetylcholine receptor agonist binds to the ±7 subunit (±7nAChR) begins the signalling involving JAK2/STAT3, reducing the production of proinflammatory cytokines. However, where there is deficiency in this pathway, the control of the production of inflammatory molecules is impaired. Studies have shown that proteins called serine kinases are involved in signaling cascades triggered from inflammatory molecules such as free fat acids. The product of activation of pathways mediated by them are proinflammatory cytokines. Furthermore these proteins has capacity to modify the phosphorilation/activation of others proteins and cause damage in the pathway of insuline. When actives the serines kinases phosphorilate in serine residues the substrates of insuline receptor IRS1/2 and block the signaling downstream. Due to the central action in the energy expenditure and glucose homeostasis, the impaired their signaling may lead metabolic damage featuring an insuline resistance state. Studies have shown that activation of a7nAChR by farmacological agonist (nicotine) was able of decrease the inflammation and improve insuline sensibility in obeses mouse wild type but not in obeses and knoukout for a7nAChR. Studies conducted by our group showed that adult offspring of mothers fed with high fat diet during pregnancy and lactation has hyperinsuliemia, increased accumulation of body fat and increased inflammatory markers compared with control offspring. Still, the offspring showed greater weight gain and adiposity until the 28th day of life compared with her control. Too have observed decrease of a7AChR content proteic and increase of JNK phosphorilation after challenge with agonist receptor. Thus, our study hypotesis is that offspring of mothers fed with high fat diet during pregnancy and lactation feature damages in the cholinergic anti-inflammatory pathway and that this is related to the development os insulin resistance in this animals. To investigate this hypothesis will be used male offspring of mothers fed high fat diet during pregnancy and lactation with 28th day of life.Hepatic expression of macrophages for RT-PCR and immunofluorescense, proteic content of p-AKT after insuline administration intraperitonial for Western blot before or after inflammatory substance exposition will be assessed. (AU)