Discovery and characterization of novel peptide modulators targeting membrane proteins

Abstract

The prevalence of severe obesity is a major risk factor for metabolic disorders such as type 2 diabetes, hypertension, dyslipidemia, and cardiovascular disease. In this study, I designed the conjugate of exendin-4 analog and glucagon (Exa-Gcg), as an attractive approach using click chemistry, and characterized its interesting functional roles. The Exa-Gcg conjugate promotes weight loss, reduces fat mass, and alleviates the development of obesity-related metabolic syndromes such as insulin resistance and hepatic steatosis in diet-induced obese mice. Analysis of tissues from the Exa-Gcg-treat mice exhibits not only the increased expression of UCP-1 in brown adipose tissue, resultung in a PKA-mediated lipolysis of visceral fat and the suppression of lipogenesis of subcutaneous fat, but also the stimulation of substrate utilization such as fatty acid β-oxidation and thermogenesis in brown adipocytes and skeletal muscle. Consistent with increased fatty acid oxidation and thermogenesis, Exa-Gcg conjugate activated AMPK-mediated signaling pathway in C2C12 skeletal myotubes and thus the palmitate-induced oxidative stress is prevented. Taken together, in this study I propose that by increasing energy expenditure, Exa-Gcg conjugate might be a valuable treatment for obesity and associated metabolic disorders in human.