Hypothalamic BMP9 suppresses glucose production by central PI3K/Akt/mTOR pathway

Area of Science:

• Endocrinology
• Neuroscience
• Metabolic Research

Background:

• Bone morphogenetic proteins (BMPs), part of the TGF-β superfamily, include BMP7, known for roles in obesity and appetite regulation.
• The central role of BMP9 in glucose metabolism and insulin sensitivity remains largely unexplored.
• Hypothalamic BMP9 expression is reduced in obese and insulin-resistant states.

Purpose of the Study:

• To investigate the impact of central BMP9 signaling on glucose metabolism and insulin sensitivity.
• To elucidate the underlying molecular mechanisms, including the route of transmission and signaling pathways involved.

Main Methods:

• Intracerebroventricular (ICV) injection of adenovirus expressing BMP9 (Ad-BMP9) in mice.
• Metabolic analysis, hyperinsulinemic-euglycemic clamp tests, and assessment of phosphatidylinositol 3,4,5-trisphosphate (PIP3) formation.
• Gene expression and pathway analysis using real-time PCR and Western blotting; use of rapamycin to inhibit mTOR signaling.

Main Results:

• Central BMP9 overexpression reduced food intake, body weight, and blood glucose, while increasing energy expenditure in high-fat diet-fed mice.
• BMP9 treatment improved hepatic insulin resistance and inhibited hepatic glucose production.
• BMP9 activated the hypothalamic insulin receptor/PI3K/Akt pathway, an effect blocked by rapamycin, indicating mTOR involvement.

Conclusions:

• Central BMP9 signaling ameliorates hepatic glucose metabolism and insulin resistance.
• The mechanism involves the activation of the hypothalamic mTOR/PI3K/Akt pathway.
• BMP9 represents a potential therapeutic target for metabolic disorders like obesity and insulin resistance.