Submitted on January 11, 2008
Accepted on February 20, 2008
UNCOUPLING PROTEIN-2 MODULATES THE LIPID METABOLIC RESPONSE
TO FASTING IN MICE
Anthony R Sheets1, Peter Fulop2, Zoltan Derdak1, Andrea Kassai3, Edmond Sabo4, Nicholas M Mark1, Gyorgy Paragh5, Jack R Wands1, and Gyorgy Baffy1*
1 Liver Research Center, Brown Medical School, Providence, Rhode Island, United States
2 Liver Research Center, Brown Medical School, Providence, Pennsylvania, United States; First Department of Medicine, University of Debrecen Medical and Health Science Center, Debrecen, Hungary
3 Liver Research Center, Brown Medical School, Providence, Rhode Island, United States; First Department of Medicine, University of Debrecen Medical and Health Science Center, Debrecen, Hungary
4 Department of Pathology, Brown Medical School, Providence, Rhode Island, United States
5 First Department of Medicine, University of Debrecen Medical and Health Science Center, Debrecen, Hungary
* To whom correspondence should be addressed. E-mail: gyorgy.baffy{at}va.gov.
Uncoupling protein-2 (UCP2) regulates insulin secretion by controlling ATP levels in 
cells. While UCP2 deficiency improves glycemic control in mice, increased expression of UCP2 interferes with glucose-stimulated insulin secretion. These observations link UCP2 to cell dysfunction in type 2 diabetes with a perplexing evolutionary role. We found higher residual serum insulin levels and blunted lipid metabolic responses in fasted ucp2-/- mice, supporting the concept that UCP2 evolved to suppress insulin effects and to accommodate the fuel switch to fatty acids during starvation. In the absence of UCP2, fasting initially promotes peripheral lipolysis and hepatic fat accumulation at less than expected rates, but culminates in protracted steatosis indicating diminished hepatic utilization and clearance of fatty acids. We conclude that UCP2-mediated control of insulin secretion is a physiologically relevant mechanism of the metabolic response to fasting.
