SUN-096 Hypothalamic ATP Has a Crucial Role in the Pathogenesis of Leptin Resistance: A Potential Mechanism for the Amelioration of Leptin Resistance by Celastrol and Withaferin A

Leptin is an adipocyte-derived hormone involved in the regulation of food intake and energy expenditure. Since obese subjects generally have leptin resistance, leptin sensitizers are expected as anti-obesity drugs. It has been reported that endoplasmic reticulum (ER) stress in the hypothalamus plays a key role in the pathogenesis of leptin resistance. Recently, two natural compounds, celastrol and withaferin A were reported to alleviate hypothalamic ER stress and restore the sensitivity to leptin (Cell 2015, Nat Med 2016). However, the molecular mechanism remains completely unknown. Under ER stress, cells require appreciable amounts of ATP for unfolded protein response. ATP-deficient cells are vulnerable to ER stress and treatment of ATP protects cells against ER stress. For these reasons, we investigated the role of ATP in the development of hypothalamic ER stress and leptin resistance. High fat diet induces ER stress and leptin resistance in the hypothalamus. We measured ATP concentrations in the hypothalamus of mice under high fat diet with or without celastrol and withaferin A treatment. Hypothalamic ATP concentrations were measured by luciferase activities. High fat diet decreased hypothalamic ATP concentrations. Celastrol and withaferin A suppressed body weight gain and food intake and increased hypothalamic ATP concentrations under high fat diet. Under standard diet, celastrol and withaferin A had no effect not only on body weight and food intake but also on hypothalamic ATP concentrations. In ob/obmice, celastrol and withaferin A increased hypothalamic ATP concentrations but showed only minimal effect on body weight and food intake, suggesting that increase of hypothalamic ATP concentrations by celastrol and withaferin A is not the secondary effect of metabolic improvement. Taken together, it is suggested that celastrol and withaferin A maintain leptin sensitivity by up-regulating hypothalamic ATP concentrations under high fat diet. Hypothalamic ATP has a crucial role in the pathogenesis of leptin resistance.