Regulation of energy balance by the hypothalamic lipoprotein lipase regulator Angptl3.

Abstract

Hypothalamic lipid sensing is important for the maintenance of energy balance. Angiopoietin-like protein 3 (Angptl3) critically regulates the clearance of circulating lipids by inhibiting lipoprotein lipase (LPL). The current study demonstrated that Angptl3 is highly expressed in the neurons of the mediobasal hypothalamus, an important area in brain lipid sensing. Suppression of hypothalamic Angptl3 increased food intake but reduced energy expenditure and fat oxidation, thereby promoting weight gain. Consistently, intracerebroventricular (ICV) administration of Angptl3 caused the opposite metabolic changes, supporting an important role for hypothalamic Angptl3 in the control of energy balance. Notably, ICV Angptl3 significantly stimulated hypothalamic LPL activity. Moreover, coadministration of the LPL inhibitor apolipoprotein C3 antagonized the effects of Angptl3 on energy metabolism, indicating that LPL activation is critical for the central metabolic actions of Angptl3. Increased LPL activity is expected to promote lipid uptake by hypothalamic neurons, leading to enhanced brain lipid sensing. Indeed, ICV injection of Angptl3 increased long-chain fatty acid (LCFA) and LCFA-CoA levels in the hypothalamus. Furthermore, inhibitors of hypothalamic lipid-sensing pathways prevented Angptl3-induced anorexia and weight loss. These findings identify Angptl3 as a novel regulator of the hypothalamic lipid-sensing pathway.

• Authors: Hyun-Kyong Kim, Mi-Seon Shin, Byung-Soo Youn, Gil Myoung Kang, So Young Gil, Chan Hee Lee, Jong Han Choi, Hyo Sun Lim, Hyun Ju Yoo, Min-Seon Kim
• Journal: Diabetes (Diabetes) Vol. 64 Issue 4 Pg. 1142-53 (Apr 2015) ISSN: 1939-327X [Electronic] United States
• PMID: 25338813 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Chemical References

• Angiopoietin-Like Protein 3
• Angiopoietin-like Proteins
• Angiopoietins
• Angptl3 protein, mouse
• Fatty Acids
• Lipoprotein Lipase

Topics

• Angiopoietin-Like Protein 3
• Angiopoietin-like Proteins
• Angiopoietins (genetics, metabolism, pharmacology)
• Animals
• Avoidance Learning (drug effects, physiology)
• Conditioning, Operant (drug effects, physiology)
• Eating (drug effects, physiology)
• Energy Metabolism (drug effects, physiology)
• Fatty Acids (metabolism)
• Hypothalamus (drug effects, metabolism)
• Lipoprotein Lipase (metabolism)
• Male
• Mice
• RNA Interference
• Rats
• Rats, Sprague-Dawley