The Role of Liver Fructose-1,6-Bisphosphatase in Regulating Appetite and Adiposity
- Sherley Visinoni1,
- Nurul Fathiah Izzati Khalid1,
- Christos N. Joannides1,
- Arthur Shulkes2,
- Mildred Yim2,
- Jon Whitehead3,
- Tony Tiganis4,
- Benjamin J. Lamont1,
- Jenny M. Favaloro1,
- Joseph Proietto1,
- Sofianos Andrikopoulos1 and
- Barbara C. Fam1⇓
- 1Department of Medicine, University of Melbourne, Heidelberg, Victoria, Australia
- 2Department of Surgery, Austin Health, University of Melbourne, Heidelberg, Victoria, Australia
- 3Mater Medical Research Institute, Brisbane, Queensland, Australia
- 4Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia
- Corresponding author: Barbara C. Fam, .
S.A. and B.C.F. contributed equally to this study.
Liver fructose-1,6-bisphosphatase (FBPase) is a regulatory enzyme in gluconeogenesis that is elevated by obesity and dietary fat intake. Whether FBPase functions only to regulate glucose or has other metabolic consequences is not clear; therefore, the aim of this study was to determine the importance of liver FBPase in body weight regulation. To this end we performed comprehensive physiologic and biochemical assessments of energy balance in liver-specific transgenic FBPase mice and negative control littermates of both sexes. In addition, hepatic branch vagotomies and pharmacologic inhibition studies were performed to confirm the role of FBPase. Compared with negative littermates, liver-specific FBPase transgenic mice had 50% less adiposity and ate 15% less food but did not have altered energy expenditure. The reduced food consumption was associated with increased circulating leptin and cholecystokinin, elevated fatty acid oxidation, and 3-β-hydroxybutyrate ketone levels, and reduced appetite-stimulating neuropeptides, neuropeptide Y and Agouti-related peptide. Hepatic branch vagotomy and direct pharmacologic inhibition of FBPase in transgenic mice both returned food intake and body weight to the negative littermates. This is the first study to identify liver FBPase as a previously unknown regulator of appetite and adiposity and describes a novel process by which the liver participates in body weight regulation.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db11-1511/-/DC1.
- Received October 26, 2011.
- Accepted January 26, 2012.
- © 2012 by the American Diabetes Association.
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