In its initial encounter with growth hormone (GH) in vitro, epididymal fat excised from GH-deficient rats responds with an insulin-like increase in glucose metabolism. Tissues freshly excised from normal rats are refractory to the insulin-like effects of GH, but become sensitive immediately after surgical stress. Reversal of refractoriness is prevented by administration of the opioid antagonist, naloxone, just prior to stress, suggesting a possible role of β-endorphin or related peptides. These experiments were undertaken to determine the source of these peptides which might equally well be released from the pituitary, adrenal medullae, or nerve endings in response to stress. Since adrenalectomy, like stress, also results in increased secretion of adrenocorticotropic hormone (ACTH) and related peptides, we studied the effects of GH on glucose oxidation in adipose tissue obtained from adrenalectomized rats and found a significant insulin-like response to GH in tissues studied 4 days after adrenalectomy. This effect was not due to GH deficiency, since plasma concentrations were only slightly reduced by adrenalectomy. Administration of naloxone (250 µg/rat), 30 or 60 min before sacrifice, or dexamethasone (100 µg/injection), 60 and 120 min before sacrifice, prevented a response to GH without affecting circulating levels of GH. The effects of adrenalectomy could not be reproduced by preincubation of adipose tissue from normal nonstressed rats with ACTH and β-endorphin, but were duplicated by preincubation of adipose tissue for 15 min in medium in which pituitary glands had previously incubated in the presence of corticotropin-releasing hormone (0.1 µM) and arginine vasopressin (0.2 µM). Addition of naloxone (250 µg/ml) blocked this effect. Neither medium, in which pituitary glands had been incubated in the absence of hypothalamic peptides, nor the hypothalamic peptides alone were effective in inducing an insulin-like response to GH in adipose tissue of normal rats. The pituitary glands used for these studies were obtained from rats that had been thyroidectomized 3–5 weeks earlier and hence were virtually devoid of GH. The data suggest that substances released along with ACTH in the adrenalectomized or stressed rat can acutely reverse the refractoriness of normal adipose tissue to the insulin-like effec