Using GLP-1 to carry dexamethasome to treat hypothalamic inflammation and metabolic diseases.

It has been recently demonstrated that an obesogenic diet induces a degree of hypothalamic inflammation and neuronal injury in rodents and humans. Despite the recognized negative impact of systemic and central inflammation on metabolic control, a scarcity of efficacious drugs targeting this particular pathogenic mechanism exists because a majority of the steroid-based anti-inflammatory drugs are fraught with adverse off-target effects that restrict their use in chronic studies. We developed a new series of peptide/nuclear hormone conjugates with the aim to selectively deliver an anti-inflammatory effect to tissues entwined in metabolic inflammation, including the hypothalamus. We show here that GLP-1 mediated delivery of the synthetic glucocorticoid dexamethasone drives substantial weight loss in diet-induced obese mice, which is greater than the weight-loss achieved by equivalent GLP-1 or dexamethasone treatment alone. Chronic treatment with plasma-stable, yet intracellularly-labile GLP-1/dexamethasone conjugates results in decreased levels of surrogate markers for hypothalamic inflammation compared to vehicle and pair-fed controls, including decreased expression of TNF alpha, decreased hypothalamic microglia activation (as measured by Iba1 immunoreactivity), and restored POMC tone, all of which are perturbed after prolonged exposure to high-fat, high-sugar diets. Importantly in these rodent studies, we do not observe several of the hallmark drawbacks associated with chronic dexamethasone treatment in tissues that do not house the GLP-1 receptor, including: (i) a lack of glucocorticoid signaling in the thymus, (ii) no observation of muscle wasting, (iii) no indication of a negative impact on bone turnover, and (iv) an avoidance of the diabetogenic liability of hepatic glucocorticoid action. These preclinical studies imply that a peptide carrier with the capability to circumvent the unwanted systemic effects of glucocorticoid pharmacology has the promise to safely treat the inflammatory state associated with metabolic diseases, most notably that observed in the hypothalamus