Endocrine Abstracts

Obesity and its major consequence, type II diabetes mellitus (T2DM), is epidemic throughout Western society. T2DM accounts for 95% of the diabetes worldwide. One limitation to the development of new diabetes treatments has been a lack of effective animal models to use in research. There are no rodent models that recapitulate the pancreatic β-cell lesions of humans with T2DM. Moreover, animal models of obesity either require overfeeding which is expensive and takes weeks to months to establish, or specific genetic mutations that cause lifelong metabolic dysfunction. Thus the ability to rapidly induce obesity in healthy rat and mouse strains would be a major advance that could enhance research in diabetes and obesity and the development of novel therapies. We have recently developed superactive mouse leptin antagonist (D23L/L39A/D40A/F41A). Mono-pegylated antagonist (PEG-SMLA) is orexigenic, and when given to mice every 24–48 h for 2–3 weeks leads to weight gain of nearly 50% with primarily fat accumulation. PEG-SMLA -induced weight gain is accompanied by elevated fasting glucose and glucose intolerance with hyperinsulinemia, higher plasma cholesterol and TGs, and a dramatic rise of corticosterone. These changes were fully reversible with cessation of PEG-SMLA injections, and disappeared within 10–14 days. 1 month exposure to PEG-SMLA altered the expression of key regulatory genes in adipose tissue, muscle and brain. These findings indicate that leptin antagonism induces systemic dysmetabolism in a rapid, practical manner, and provides a valuable tool for research in obesity and diabetes.

Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.

Funding: This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.