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LIVER AND BILIARY TRACT

Uncoupling protein-2 modulates the lipid metabolic response to fasting in mice

¹Division of Gastroenterology and Liver Research Center, ³Department of Pathology, Brown Medical School and Rhode Island Hospital, Providence, Rhode Island; and ²First Department of Medicine, University of Debrecen Medical and Health Science Center, Debrecen, Hungary

Submitted 11 January 2008 ; accepted in final form 20 February 2008

Uncoupling protein-2 (UCP2) regulates insulin secretion by controlling ATP levels in β-cells. Although UCP2 deficiency improves glycemic control in mice, increased expression of UCP2 interferes with glucose-stimulated insulin secretion. These observations link UCP2 to β-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.

prolonged fasting; lipolysis; steatosis; insulin secretion

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