Adult obese Zucker rats (fa.fa) are hyperinsulinemic and insulin resistant. Specific insulin binding to crude membranes prepared from livers was 2.8% (per mg protein) in fatty animals compared with 7.9%in homozygous lean (Fa, Fa) and 9.0.% in heterozygous lean (Fa.fa) animals. Insulin binding increased in liver membranes from fatty animals after a 72-h fast to 6.4%. The reduced insulin binding in livers from fatty rats was associated with elevated insulin-sensitive tyrosine kinase activity, which fell towards control values after the fast. The elevated tyrosine kinase activity was associated with an increased maximum velocity (Vmaxwithout a change in Michaelis- Menten constant (Km) for its substrates, ATP and poly(Glu, Tyr)4:l. These findings suggest that, in adult fatty rats, insulin-sensitive tyrosine kinase has increased intrinsic activity. Further, the effect of the prolonged fast on both insulin binding and kinase activity, suggest that in this model environmental factors, and not necessarily a genetic abnormality, may regulate liver insulin receptors and their kinase. Whether the inverse relationship of the kinase and insulin receptor number is the result of a compensatory mechanism remains to be elucidated.