Identification of a plant-derived small molecule with potent
anti-obesity and anti-diabetic activities in type 2 diabetic mice
Abstract
Insulin resistance and progressive decline in functional β-cell mass are
two key factors for developing T2D, which is largely driven by
overweight and obesity, a significant obstacle for effective metabolic
control in many patients with T2D. Thus, agents that simultaneously
ameliorate obesity and promote insulin sensitivity and β-cell function
could be more effective for treating T2D. Here, we report that elenolic
acid (EA), a small molecule, is such a dual-action agent. Oral
administration of EA restored glucose homeostasis and other metabolic
disorders in diet-induced obese mice, which were associated with
increased circulating GLP-1, PYY, and GIP concentrations. EA slowed
gastric emptying, downregulated hypothalamic agouti-related peptide, and
reduced food intake and obesity in obese mice. EA also exerted potent
anti-hyperglycemic effect in db/db mice that was comparable to that of
liraglutide but greater than that of metformin, and it was more
effective in promoting weight loss relative to these two drugs.
Mechanistically, EA directly stimulated GLP-1 and PYY secretion from
L-cells, and its induction of GLP-1 release is mediated via
Gαq/phospholipase C-mediated pathway. EA also directly suppresses
glucose production in liver cells. These results suggest that EA is a
novel, dual-action agent for developing drug to treat both T2D and
obesity.