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

## TL;DR

A mutation in the Adcy3 gene in rats reduces fat breakdown and increases obesity by impairing cAMP signaling.

## Contribution

A novel mutation in Adcy3 is shown to partially impair enzymatic function, linking it to obesity through reduced lipolysis.

## Key findings

- Adcy3mut/mut rats have increased adiposity and reduced serum free fatty acids.
- Adipose tissue from Adcy3mut/mut rats shows decreased cAMP production in response to stimulation.
- Female Adcy3mut/mut rats show reduced body temperature during cold exposure.

## Abstract

We previously showed that rats with a protein-coding mutation in Adenylate cyclase 3 (Adcy3) (Adcy3mut/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 Adcy3mut/mut affects lipolysis, thermogenesis, and cAMP signaling. Adcy3mut/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. Adcy3mut/mut rats displayed increased adiposity, decreased serum FFA, and downregulated adipose triglyceride lipase gene expression. Additionally, cAMP production was decreased in Adcy3mut/mut adipose tissue compared with WT adipose tissue in response to ex vivo stimulation with CL 316,243. Adcy3mut/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.