Hypothalamic Angptl4/Fiaf Is a Novel Regulator of Food Intake and Body Weight

  1. Min-Seon Kim3
  1. 1Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul, Korea;
  2. 2AdipoGen Inc., Incheon, Korea;
  3. 3Department of Internal Medicine, Asan Medical Center, Seoul, Korea;
  4. 4Department of Anatomy, Kangwon National University School of Medicine, Chuncheon, Korea;
  5. 5College of Life Sciences and Biotechnology, Korea University, Seoul, Korea;
  6. 6Department of Biophysics and Chemical Biology, School of Biological Sciences, Institute of Molecular Biology and Genetics, Seoul National University, Seoul, Korea;
  7. 7Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.
  1. Corresponding author: Min-Seon Kim, mskim{at}amc.seoul.kr.
  1. H.-K.K. and B.-S.Y. contributed equally to this work.

Abstract

OBJECTIVE The angiopoietin-like protein 4 (Angptl4)/fasting-induced adipose factor (Fiaf) is known as a regulator of peripheral lipid and glucose metabolism. In the present study, we investigated the physiological role of Angptl4 in central regulation of body weight homeostasis.

RESEARCH DESIGN AND METHODS Hypothalamic Angptl4 expression levels were measured using immunoblot assay during feeding manipulation or after administration of leptin, insulin, and nutrients. The effects of Angptl4 on food intake, body weight, and energy expenditure were determined following intracerebroventricular (ICV) administration of Angptl4 in C57BL/6 mice. Food intake, energy metabolism, and feeding responses to leptin, insulin, and nutrients were compared between Angptl4-null mice and their wild littermates. Finally, the relationship of hypothalamic AMP-activated protein kinase (AMPK) and Angptl4 was studied.

RESULTS Hypothalamic Angptl4 expression levels were increased upon food intake or administration of leptin, insulin, and nutrients. Furthermore, central administration of Angptl4 suppressed food intake and body weight gain but enhanced energy expenditure. These effects were mediated via suppression of hypothalamic AMPK activities. Consistently, Angptl4-null mice displayed increased body weight and hypothalamic AMPK activity but reduced energy expenditure. Food intake following a fast was significantly greater in Angptl4-null mice, which was normalized by centrally administered Angptl4. Moreover, anorectic responses to leptin, insulin, and glucose were diminished in Angptl4-null mice. In contrast, Angptl4-null mice were resistant to diet-induced obesity, indicating obesity-promoting effects of Angptl4 under the condition of fat-enriched diet.

CONCLUSIONS We have demonstrated that hypothalamic Angptl4 is regulated by physiological appetite regulators and mediates their anorexigenic effects via inhibition of hypothalamic AMPK activity. Therefore, Angptl4 appears to have an important role in central regulation of energy metabolism.

Footnotes

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  • Received January 28, 2010.
  • Accepted August 19, 2010.

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  1. Diabetes vol. 59 no. 11 2772-2780
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