Ketone Body β-Hydroxybutyrate Enhances Hypothalamic Leptin and Insulin Responsiveness

Area of Science:

• Metabolic signaling
• Neuroendocrinology
• Obesity research

Background:

• Obesity involves impaired hypothalamic energy balance and reduced responsiveness to leptin and insulin.
• Beta-hydroxybutyrate (β-HB), a ketone body, is recognized as a signaling metabolite with unclear effects on hypothalamic hormone sensitivity.

Purpose of the Study:

• To investigate the impact of β-HB on hypothalamic leptin and insulin responsiveness in diet-induced obese mice.
• To elucidate the molecular mechanisms underlying β-HB's effects on hypothalamic function.

Main Methods:

• High-fat diet (HFD) induced obesity in mice, followed by oral or intracerebroventricular (ICV) β-HB administration.
• Assessed anorexigenic hormone responses, hypothalamic STAT3 and Akt signaling pathways, and gene expression (inflammation, appetite regulation).
• Chronic ICV β-HB administration in HFD-fed mice monitored body weight and food intake.

Main Results:

• β-HB administration (oral and ICV) improved anorexigenic responses to leptin and insulin in obese mice.
• Enhanced hypothalamic phosphorylation of STAT3 (leptin) and Akt (insulin) was observed.
• Reduced expression of SOCS3 and TNFα, and increased POMC expression were noted.
• Chronic ICV β-HB suppressed body weight gain and food intake in HFD-fed mice.

Conclusions:

• β-HB administration enhances hypothalamic leptin and insulin sensitivity in obese mice.
• β-HB modulates the hypothalamic molecular environment, reducing inflammation and improving appetite regulation.
• β-HB acts as a signaling molecule regulating hypothalamic function, suggesting potential as an anti-obesity intervention.