Title:Mitochondrial Uncoupling and the Regulation of Glucose Homeostasis
Volume: 13
Issue: 4
Author(s): Marta Giralt and Francesc Villarroya*
Affiliation:
- Dept de Bioquimica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona. Av. Diagonal, 643. 08028-Barcelona, Catalonia,Spain
Keywords:
Brown adipose tissue, FGF21, glucose homeostasis, mitochondrial uncoupling, β-cells, UCP.
Abstract: Introduction: Mitochondrial uncoupling is a physiological process that has direct and indirect
consequences on glucose homeostasis. Non-shivering thermogenesis in brown adipose tissue, which
is the most well-recognized biological process related to the physiological uncoupling of mitochondria,
is caused by uncoupling protein-1 (UCP1), which mediates a regulated permeabilization of the mitochondrial
inner membrane to protons.
Conclusion: The uncoupled brown fat mitochondria are specialized to produce heat by oxidizing large
amounts of substrates, making brown fat a sink that can actively drain glucose from circulation. This has
been confirmed in human studies in which active brown fat was detected by glucose-derivative-based
positron emission tomography scans. Thus, UCP1-mediated activation of brown fat appears to be a
likely mechanism through which hyperglycemia could be ameliorated. In other tissues, mitochondria are
reported to be mildly uncoupled by the UCP1-like proteins, UCP2 and UCP3. The primary role of these
other UCPs does not appear to be the oxidation of a metabolic substrate (e.g., glucose) for heat production;
instead, they participate in other processes, such as regulating the production of reactive oxygen
species and transporting certain metabolites across the mitochondrial membrane. UCP2 activity influences
glucose homeostasis by fine tuning intracellular events related to the cellular energy status,
thereby controlling insulin secretion, food intake behavior and adiponectin secretion in pancreatic β -
cells, brain and white adipose tissue, respectively. UCP3 appears to be more specifically involved in
promoting fatty acid oxidation in muscle, and is thus likely to influence glucose metabolism indirectly.
Several genetic association studies have related polymorphisms in the genes encoding UCPs with obesity
and/or type 2 diabetes phenotypes. In this review, we will focus on what is known about the specific
role of mitochondrial uncoupling in glucose metabolism, and its implications in diabetes.
