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

Abstract

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 receptor bypasses deleterious effects of dexamethasone on glucose handling, bone integrity, and hypothalamus-pituitary-adrenal axis activity. Thus, GLP-1-directed glucocorticoid pharmacology represents a safe and efficacious therapy option for diet-induced immunometabolic derangements and the resulting obesity.

The influence of peptide context on signalling and trafficking of glucagon-like peptide-1 receptor biased agonists

“…It could be speculated that different GLP-1RAs might therefore behave differently in beta cells and anorectic neurons, for example, although further experiments using primary neurons and beta cells would be required to substantiate this. Moreover, there is current interest in using GPCR-targeting peptides to deliver cargo to metabolically important tissues (44)(45)(46) In summary, this work provides a systematic evaluation of a panel of GLP-1RAs with varying homology to GLP-1 and exendin-4. We identified marked differences in signalling, endocytosis and trafficking characteristics, which may be informative for the development of improved GLP-1RAs for T2D and obesity.…”

Peptide‐based multi‐agonists: a new paradigm in metabolic pharmacology

“…In the context of metabolic therapy, GLP‐1 is an ideal nuclear hormone conjugation partner since GLP‐1 targets mainly the endocrine pancreas and central nervous system, thus potentially delivering nuclear hormones preferentially to these tissues. So far GLP‐1 has been conjugated to oestrogen and dexamethasone (Fig. ).…”

“…A conjugate of GLP‐1 and dexamethasone utilizes the anti‐inflammatory properties of dexamethasone to target the chronic, low‐grade inflammation that is typically observed under conditions of obesity . Unaltered dexamethasone induces hyperglycaemia, hyperphagia and reduces bone density . In mice, a GLP‐1/dexamethasone conjugate at a dose of 100 nmol kg −1 for 2 weeks reduced food intake and induced a 25% body weight loss, relative to baseline, predominately a result of loss in fat mass.…”

Anti-Obesity Therapy: from Rainbow Pills to Polyagonists

“…In line with its action on key hypothalamic neurocircuits, weight loss induced by GLP-1/dexamethasone was a result of decreased food intake and increased energy expenditure and was associated with improved glucose metabolism and restored insulin sensitivity. Notably, the targeted delivery of dexamethasone to GLP-1R-positive cells prevented typical dexamethasone off-target effects on glucose handling, bone integrity, and hypothalamus-pituitary-adrenal axis activity (Quarta et al, 2017).…”

“…Glucocorticoids are known for decades for their anti-inflammatory properties, but, as with other nuclear-acting hormones, their ubiquitous action profile limits their therapeutic utility and can lead to off-target effects. Expanding the concept of peptide-mediated nuclear hormone delivery, collaborative research of the DiMarchi/Tschöp laboratories recently let to the development of a molecule, which selectively restricts the action of dexamethasone to cells expressing the receptor for GLP-1, such as brain and the pancreas (Quarta et al, 2017) (Fig. 5).…”