Abstract
Leptin is an adipocyte-derived hormone that regulates appetite and energy expenditure via the hypothalamus. Since the majority of obese subjects are leptin resistant, leptin sensitizers, rather than leptin itself, are expected to be anti-obesity drugs. Endoplasmic reticulum (ER) stress in the hypothalamus plays a key role in the pathogenesis of leptin resistance. ATP-deficient cells are vulnerable to ER stress and ATP treatment protects cells against ER stress. Thus, we investigated the therapeutic effects of oral 1,3-butanediol (BD) administration, which increases plasma β-hydroxybutyrate and hypothalamic ATP concentrations, in diet induced obese (DIO) mice with leptin resistance. BD treatment effectively decreased food intake and body weight in DIO mice. In contrast, BD treatment had no effect in leptin deficient ob/ob mice. Co-administration experiment demonstrated that BD treatment sensitizes leptin action in both DIO and ob/ob mice. We also demonstrated that BD treatment attenuates ER stress and leptin resistance at the hypothalamus level. This is the first report to confirm the leptin sensitizing effect of BD treatment in leptin resistant DIO mice. The present study provides collateral evidence suggesting that the effect of BD treatment is mediated by the elevation of hypothalamic ATP concentration. Ketone bodies and hypothalamic ATP are the potential target for the treatment of obesity and its complications.
Highlights
Leptin is an adipocyte-derived hormone that regulates appetite and energy expenditure via the hypothalamus
Co-administration experiment of BD and leptin demonstrated that BD treatment sensitizes leptin action in both diet induced obese (DIO) and ob/ob mice. These results indicate that leptin is necessary for BD treatment to exert its effects, and that leptin sensitization is the primary effect of BD treatment on body weight
Plasma β-hydroxybutyrate concentrations in DIO mice treated with water tended to be higher than in lean control mice but there was no statistically significant difference (Fig. 1E)
Summary
Leptin is an adipocyte-derived hormone that regulates appetite and energy expenditure via the hypothalamus. We investigated the therapeutic effects of oral 1,3-butanediol (BD) administration, which increases plasma β-hydroxybutyrate and hypothalamic ATP concentrations, in diet induced obese (DIO) mice with leptin resistance. We demonstrated that BD treatment attenuates ER stress and leptin resistance at the hypothalamus level This is the first report to confirm the leptin sensitizing effect of BD treatment in leptin resistant DIO mice. ATP-deficient cells are vulnerable to ER stress, and ATP treatment protects cells against ER stress[13] For these reasons, increased hypothalamic ATP concentration might have a protective effect against ER stress and leptin resistance in the hypothalamus. If the elevation of hypothalamic ATP concentration has a protective effect against ER stress and leptin resistance in the hypothalamus, ketone bodies should reduce food intake and body weight in obese subjects with leptin resistance. The effects of ketone bodies on hypothalamic ER stress and leptin resistance have not been reported
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