TY  - CONF
AB  - Obesity and its comorbidities such as type 2 diabetes constitute major worldwide health threats, and the identification of an effective medical intervention has emerged as a global priority. The limited effectiveness of historical, anti-obesity treatments is commonly attributed to the complexity of the disease and the redundancy of metabolic regulatory mechanisms that sustain body weight. At the forefront of obesity research is the development of combinational drug therapies that simultaneously target multiple regulatory pathways, which promote dysfunctional metabolism. Recently, molecularly crafted unimolecular "multi-agonism" of balanced activity at 3 key receptors involved in metabolism and specifically the glucagon-like peptide (GLP)-1 receptor, glucose-dependent insulinotropic polypeptide (GIP) receptor and glucagon receptor was reported as superior to conventional monoagonist therapy. These mixed peptide agonists are designed to pharmacologically integrate the insulinotropic and anorexigenic effects of GLP-1, the thermogenic and lipolytic activities of glucagon, and the insulinotropic and insulin sensitizing properties of GIP. The molecular mechanism of these purposefully promiscuous ligands is not completely understood, however, recent studies in pancreatic beta cells point to the prospect of a complex signaling network that can magnify the signaling of multi-agonist ligands. The activation of this signalosome might explain the additional therapeutic benefit inherent to simultaneous cellular activation through multiple metabolic receptors.
AU  - Khajavi, N.*
AU  - Biebermann, H.*
AU  - Tschöp, M.H.
AU  - DiMarchi, R.*
C1  - 51750
C2  - 43436
SP  - 165-182
TI  - Treatment of diabetes and obesity by rationally designed peptide agonists functioning at multiple metabolic receptors.
JO  - Endocr. Dev.
VL  - 32
PY  - 2017
SN  - 1421-7082
ER  - 

TY  - JOUR
AB  - The gastrointestinal peptide hormone ghrelin was discovered in 1999 as the endogenous ligand for the growth hormone secretagogue receptor (GHSR-1a). Since its discovery tremendous research efforts have been directed at unraveling ghrelin's mechanisms of action, revealing that ghrelin is a pleiotropic hormone implicated in myriad of molecular signaling mechanisms. Accordingly, ghrelin is the only known circulating peripheral hormone with the ability to promote a positive energy balance by stimulating food intake while decreasing energy expenditure and body fat utilization. Moreover, beyond its ability to promote the release of growth hormone from the anterior pituitary, ghrelin stimulates gut motility and gastric acid secretion, modulates sleep, taste sensation and behavior, and regulates glucose metabolism. Due to ghrelin's ability to promote body weight gain and adiposity via centrally mediated signaling mechanisms, modulation of the endogenous ghrelin system is considered a promising strategy to treat individuals with pathologically reduced body weight, such as patients with anorexia nervosa or cachexia. The aim of this chapter is to summarize the current knowledge of how ghrelin affects systemic energy metabolism.
AU  - Müller, T.D.
AU  - Tschöp, M.H.
C1  - 28195
C2  - 33007
SP  - 91-100
TI  - Ghrelin - a key pleiotropic hormone-regulating systemic energy metabolism.
JO  - Endocr. Dev.
VL  - 25
PB  - Karger
PY  - 2013
SN  - 1421-7082
ER  -