In this study we investigated (a) whether genetically obese Zucker rats exhibit higher levels of calcitonin gene-related peptide (CGRP) in the thyroid and plasma than lean controls, (b) if CGRP, like calcitonin (CT), increases in plasma in response to iv Ca or iv pentagastrin and (c) whether or not renal CT receptors exhibit 'downregulation' in fat rats compared to leans. Fat and lean rats 8-12 months old were used. Compared to leans, fat rats exhibited higher circulating levels of CGRP as well as CT. Also, the total thyroid content (micrograms per gland) and concentration (ng/mg wet weight) of CGRP were higher in fat rats. One minute after iv pentagastrin, both lean and fat rats showed a marked increase in plasma CT but not plasma CGRP. In another experiment involving only lean rats, iv Ca given 4 min earlier produced a massive increase in plasma CT but no detectable increase in plasma CGRP. Using renal membranes and 125I-sCT as the ligand, we found that renal CT receptors in fat rats appeared more abundant than in lean rats and exhibited the same KD (3-6 nM) for both. The findings show that, compared to leans, fat rats have higher levels of CGRP as well as CT in the thyroid gland and blood. However, stimulation of C-cell release of CT was not accompanied by a corresponding rise in plasma CGRP, suggesting that either (a) the plasma CGRP is derived largely from non-thyroidal sources and the adult rat thyroid releases only trivial amounts of CGRP or (b) Ca and pentagastrin are secretagogues for thyroidal CT but not CGRP. Examination of renal CT receptors in fat and lean rats provided no evidence for downregulation of receptors in fat rats exposed chronically to higher circulating levels of CT than leans.