Early obesity and late-onset of insulin resistance associated with hormonal imbalances occur in FSH receptor deficient FORKO female mice. This study tests the hypothesis that chronic high fat diet aggravates obesogenic changes in a depot specific manner and explores some molecular links of hormone imbalances with insulin resistance. In SV 129 mice, hormonal imbalances seem obligatory for exacerbation of diet induced obesity. Visceral adiposity, glucose intolerance and lipid disturbances in 9-month FORKO females were associated with decrease in adiponectin signaling. High molecular weight plasma adiponectin and adipose tissue adiponectin mRNA were decreased. Adiponectin receptors R1 and R2 mRNA were selectively altered in mesenteric fat but not periuterine fat. R2 decreased in the liver and R1 was higher in muscle. Whereas hepatic adenosine monophosphate kinase (AMPK) activity was down-regulated, both phosphoenolpyruvate carboxykinase (PEPCK) and Glucose-6-Phosphatase (G6Pase) enzymes were up-regulated. Longitudinally, diminishing sex hormone signaling in adipose tissue was associated with progressive down-regulation of adiponectin activity and gradual impaired glucose tolerance. Chronic high-fat diet in SV129 wild type mice did not produce overt obesity but induced visceral fat depot changes accompanied by liver lipid accumulation, high cholesterol, and up-regulation of inflammation gene mRNAs. Thus tumor necrosis factor-, C-C motif chemokine receptor-2, C-C motif chemokine ligand-2 were selectively elevated in mesenteric fat without altering glucose tolerance and adiponectin signaling. Our study highlights adiponectin signaling and regulation to be involved in hormone imbalance induced insulin resistance and demonstrates selective visceral adipose depot alterations by chronic high fat diet and induction of inflammatory genes.