Evaluation of the potential of prolactin antagonists to the treatment of obesity and Diabetes mellitus 2

Abstract

Recently the entity Food and Drug Administration (FDA) approved the commercial use in the United States of bromocriptine mesylate (trade name Cycloset®) to improve glycemic control in adults with type 2 diabetes mellitus (T2DM). Cycloset® represents a new class of drugs to treat T2DM and acts as an agonist of dopamine D2 receptors. It is worth noting that many studies have also demonstrated that administration of bromocriptine causes a reduction in food intake and body weight. Notably, the mechanisms of action of bromocriptine to affect glucose homeostasis and energy balance are unknown. By acting as a dopamine agonist, bromocriptine may affect numerous physiological systems, broadening the spectrum of possible side effects. A relevant fact is that bromocriptine has been used for decades in the treatment of hyperprolactinemia. In addition to its classical effects on milk production, prolactin has numerous metabolic effects that have not yet been well studied. Several studies show that hyperprolactinemia increases the risk of metabolic diseases such as obesity and T2DM. These metabolic abnormalities are observed both in prolactinomas and during the use of antipsychotic drugs that antagonize dopamine D2 receptors. Thus, it is plausible to assume that prolactin exerts an important role in the modulation of glucose homeostasis and energy balance. Therefore, the overall objective of this proposal is to investigate the potential of prolactin antagonists for the treatment of obesity and T2DM. More specifically, this proposal will: 1) assess whether the beneficial effects of bromocriptine on metabolism are mediated by prolactin, 2) produce in mammalian cells (CHO) two types of hPRL antagonists (hPRL-G129R-and S179D hPRL) in sufficient quantities for in vivo testing, 3) assess whether the administration of such antagonists recapitulates the beneficial effects of bromocriptine in mouse models of obesity and diabetes. (AU)