An Adcy3 coding mutation causes partial loss of enzymatic function, contributing to obesity in a rat model by reducing lipolysis

We previously showed that rats with a protein-coding mutation in Adenylate cyclase 3 (Adcy3) (Adcy3 ^mut/mut ) have increased adiposity. ADCY3 catalyzes the production of cyclic AMP (cAMP), a key secondary messenger that regulates lipolysis and thermogenesis. Here, we assessed how Adcy3 ^mut/mut affects lipolysis, thermogenesis, and cAMP signaling. Adcy3 ^mut/mut and wild-type (WT) males and female rats were fed a high-fat diet for 12 weeks. We measured body weight, fat mass, serum free fatty acids (FFA) during a 48-hour fast, body temperature during acute cold exposure, and triglyceride lipase gene expression after a 48-hour fast and after prolonged cold exposure. We also measured cAMP production in response to a β-3 adrenergic receptor agonist (CL 316,243) in adipose tissue ex vivo . Adcy3 ^mut/mut rats displayed increased adiposity, decreased serum FFA, and downregulated adipose triglyceride lipase gene expression. Additionally, cAMP production was decreased in Adcy3 ^mut/mut adipose tissue compared with WT adipose tissue in response to ex vivo stimulation with CL 316,243. Adcy3 ^mut/mut females, but not males, showed a trend toward decreased body temperature during acute cold exposure. These findings demonstrate that a mutation in the transmembrane domain of ADCY3 results in partial loss of enzymatic function, decreasing lipolytic responsiveness and contributing to increased adiposity.