Objective: Obesity, smoking, and estrogen deficiency lead toalterations in lipid and glucose homeostasis. On the other hand, estrogensupplementation as well as regular physical exercise training promotesglucose uptake and makes the working skeletal muscles more sensitive toinsulin. Our purpose is to study the role of -obesity whether due togenetic defects (Zucker rats) or induced by high fat diet, exposure topassive smoking, exercise, estrogen deficiency induced by ovariectomyand estrogen supplementation- on the insulin sensitive tissues whetherthrough alteration of insulin receptor function (insulin sensitivity) or postreceptor events (insulin responsivity) and determination of : (PI3K) gene(PPAR-γ) Methods : Female rats were divided into seven groups.The visceral adipose tissue, muscle (diaphragm) and the liver wereobtained to clarify the mechanism through which each factor affects thesetarget tissues, whether by alteration of insulin sensitivity (receptorfunction) or responsivity (post receptor function). Accordingly, the effectof in vitro addition to the incubating medium of sub maximal andmaximal insulin concentrations, on the glucose uptake by visceral adiposetissue and muscle (diaphragm) as well as the glucose release from theliver in each of these seven groups were investigated. Parts of the isolatedtissues were frozen for further measurement of PI3K and PPARγexpression Results: Obesity resulted in reduced receptor function inboth groups. In addition HFD group revealed a reduced post receptorfunction as well. Passive smoking group revealed impaired receptor andpost receptor functions which was supported by reduction in PI3K level.Estrogen deficiency resulted in variable effects on receptor and postreceptor functions Administration of E2 improved insulin resistancepossibly by enhancing the expression of PPAR γ Conclusion :avoiding obesity mainly by controlling quality and quantity of food aswell as practicing exercise regularly, in addition to avoiding exposure totobacco smoke and supplementation of estrogen to the idealpostmenopausal candidates would improve the function of insulinsensitive tissues that in turn would help to achieve a normal glucosehomeostasis.