Glucose metabolism in adipocytes from 6 week old lean and obese Zucker rats were sensitive to direct and chronic treatment with insulin and triidothyronine (T(,3)). Insulin had a large stimulatory effect on glucose metabolism in acutely isolated adipocytes. This effect was greater in the lean than in the obese. Fatty acid, CO(,2) and glycerol-glyceride formation from radiolabeled glucose was elevated, 12 fold, 8 fold and 2 fold, respectively, in the obese over the leans. Pretreatment of isolated adipocytes with pharmacological concentrations of T(,3) for 30 minutes prior to the measurement of glucose metabolism had a greater effect on lean than obese adipocytes. This is indicative of a possible T(,3) resistance by obese adipocytes. The presence of insulin was required to observe the acute effects of T(,3). The effect of a 2 hour pre-treatment of isolated adipocytes with T(,3) dramatically exemplifies the alterations in glucose metabolism that occur depending upon the in vivo insulin and T(,3) status and the in vitro insulin status. The 2 hour effect of physiological levels of T(,3) in the presence of insulin in both lean and obese adipocytes was to decrease lipogenesis. In the absence of insulin, the effect of a 2 hour pretreatment with physiological levels of T(,3) in tissue from a euthyroid animal was to increase lipogenesis. The effect of T(,3) on glucose utilization is due to a post-receptor action, as glucose transport into the adipocytes was unaltered by T(,3) treatment;Adipose tissue explants were utilized to investigate the 18 hour effects of T(,3) and insulin treatment on glucose metabolism in fat cells. Adipocytes isolated from tissue explants were insensitive to the acute effects of insulin. At physiological concentrations of T(,3) and without insulin in the media, lipogenesis was increased in explants from lean rats. Under the same conditions, lipogenesis was stimulated in obese explants at pharmacological concentrations of T(,3). When insulin and T(,3) are both present at physiological through pharmacological concentrations in the explant media, fatty acid synthesis is decreased and reesterification of triglycerides may be accelerated. These results suggest that thyroid hormones might modulate a critical regulatory step(s) common to lipogenesis and lipolysis.