Molecular Integration of Incretin and Glucocorticoid Action Reverses Immunometabolic Dysfunction and Obesity

Chronic inflammation has been proposed to contribute to the pathogenesis of diet-induced obesity. However, scarce therapeutic options are available to treat obesity and the associated immunometabolic complications. Glucocorticoids are routinely employed for the management of inflammatory diseases, but their pleiotropic nature leads to detrimental metabolic side effects. We developed a glucagon-like peptide-1 (GLP-1)-Dexamethasone co-agonist in which GLP-1 selectively delivers Dexamethasone to GLP-1 receptor-expressing cells. GLP-1-Dexamethasone lowers body weight up to 25% in obese mice by targeting the hypothalamic control of feeding and by increasing energy expenditure. This strategy reverses hypothalamic and systemic inflammation while improving glucose tolerance and insulin sensitivity. The selective preference for GLP-1 receptors bypasses deleterious effects of Dexamethasone on glucose handling, bone integrity, and hypothalamus-pituitary-adrenal axis activity. Thus, GLP-1-directed glucocorticoid pharmacology represents an efficacious therapy option for diet-induced immunometabolic derangements and the resulting obesity. To elucidate the in vivo signaling properties of GLP-1/Dexa, we performed unbiased transcriptional profiling (mRNA-seq) of hypothalami from DIO mice treated for 5 days with vehicle, GLP-1/Dexa, Dexamethasone (Dexa) or with GLP-1 at the equimolar doses of 100 nmol/kg. A group of calorie restricted mice with body weight matched to that of GLP-1/Dexa-treated mice was included in order to dissect whether the molecular signatures governed by the conjugate are independent from the induced weight loss. N=5 hypothalamic samples per experimental group were used.