Endocrine Abstracts

Abstract: Inflammation plays a contributing role in the pathogenesis of several metabolic disorders, including type 2 diabetes and obesity. Intriguingly, obesogenic diets induce markers of hypothalamic inflammation and neuronal injury in both rodents and humans, suggesting that targeting inflammatory pathways in the hypothalamus might represent a novel strategy to control energy metabolism. Unfortunately, the majority of steroid-based anti-inflammatory drugs are fraught with adverse off-target effects that restrict their use for the chronic treatment of metabolic diseases. We developed a new series of peptide/nuclear hormone conjugates with the aim to selectively deliver anti-inflammatory signals to tissues entwined in metabolic inflammation, including the hypothalamus. Our data show that GLP-1/dexamethasone conjugates allow selective delivery of dexamethasone to tissues expressing GLP-1 receptors. This pharmacological approach reduces markers of inflammation in the hypothalamus in a body weight-independent manner; it restores energy metabolic signalling and drives weight loss in diet-induced obese mice. Such positive metabolic effects are greater than those observed with equivalent GLP-1 or dexamethasone treatment alone. Intriguingly, mice bearing a genetic deletion of GLP-1R in the central nervous system, were only partially responsive to the compound-induced effects on energy metabolism, indicating that central delivery of anti-inflammatory signals is required for the positive metabolic effects of GLP-1/dexamethasone conjugates.

The GLP-1/dexamethasone conjugate does not induce glucocorticoid signalling in GLP-1R negative tissues and further, classical hallmark drawbacks associated with chronic dexamethasone treatment are circumvented with the peptide-medicated delivery approach, including: (i) muscle wasting, (ii) negative impact on bone turnover, and (iii) the diabetogenic liability of hepatic glucocorticoid action.

These preclinical studies imply that selective delivery of dexamethasone to GLP-1R expressing cells hold promise to safely treat metabolic inflammation and obesity, possibly by reversing inflammatory like processes in the hypothalamus.