A unique mechanism of desensitization to lipolysis mediated by β₃- adrenoceptor in rats with thermal injury

Thermal injury causes a hypermetabolic state associated with increased levels of catabolic hormones, but the molecular bases for the metabolic abnormalities are poorly understood. We investigated the lipolytic responses after β₃-adrenoceptor (β₃-AR) agonists and evaluated the associated changes in β-AR and its downstream signaling molecules in adipocytes isolated from rats with thermal injury. Maximal lipolytic responses to a specific β₃-AR agonist, BRL-37344, were significantly attenuated at post burn days (PBD) 3 and 7. Despite significant reduction of the cell surface β₃-AR number and its mRNA at PBD 3 and 7, BRL-37344 and forskolin- stimulated cAMP levels were not decreased. Glycerol production in response to dibutyryl cAMP, a direct stimulant of hormone-sensitive lipase (HSL) via protein kinase A (PKA), was significantly attenuated. Although immunoblot analysis indicated no differences in the expression and activity of PKA or in the expression of HSL, HSL activity showed significant reductions. Finally, β₃-AR-induced insulin secretion was indeed attenuated in vivo. These studies indicate that the β₃-AR system is desensitized after burns, both in the adipocytes and in β₃-AR-induced secretion of insulin. Furthermore, these data suggest a complex and unique mechanism underlying the altered signaling of lipolysis at the level of HSL in animals after burns.