Uncoupling protein-2: a novel gene linked to obesity and hyperinsulinemia

Abstract

A mitochondrial protein called uncoupling protein (UCP1) plays an important role in generating heat and burning calories by creating a pathway that allows dissipation of the proton electrochemical gradient across the inner mitochondrial membrane in brown adipose tissue, without coupling to any other energy-consuming process. This pathway has been implicated in the regulation of body temperature, body composition and glucose metabolism. However, UCP1-containing brown adipose tissue is unlikely to be involved in weight regulation in adult large-size animals and humans living in a thermoneutral environment (one where an animal does not have to increase oxygen consumption or energy expenditure to lose or gain heat to maintain body temperature), as there is little brown adipose tissue present. We now report the discovery of a gene that codes for a novel uncoupling protein, designated UCP2, which has 59% amino-acid identity to UCP1, and describe properties consistent with a role in diabetes and obesity. In comparison with UCP1, UCP2 has a greater effect on mitochondrial membrane potential when expressed in yeast. Compared to UCP1, the gene is widely expressed in adult human tissues, including tissues rich in macrophages, and it is upregulated in white fat in response to fat feeding. Finally, UCP2 maps to regions of human chromosome 11 and mouse chromosome 7 that have been linked to hyperinsulinaemia and obesity. Our findings suggest that UCP2 has a unique role in energy balance, body weight regulation and thermoregulation and their responses to inflammatory stimuli.

Molecular mechanisms for hyperinsulinaemia induced by overproduction of selenium-dependent glutathione peroxidase-1 in mice

“…The transcriptional factor pancreatic duodenal homeobox 1 (PDX1) plays a pivotal role in pancreatic beta cell differentiation as well as insulin gene expression and synthesis [14][15][16][17]. Uncoupling protein 2 (UCP2) serves as a negative regulator of mitochondrial membrane potential (Δ= m ) [18], which positively correlates with glucosestimulated insulin secretion (GSIS) [19]. Levels and function of PDX1 and UCP2 are affected by intracellular ROS status [20,21], glucotoxicity [22] and antioxidants [6,23,24].…”

Muscle UCP-3 mRNA levels are elevated in weight loss associated with gastrointestinal adenocarcinoma in humans

“…UCP-1 is restricted to brown adipose tissue (BAT) where it uncouples oxidative phosphorylation and generates heat instead of ATP (Klaus et al, 1991). Other UCPs include UCP-2 (found in many tissues) and UCP-3 (expressed in BAT and skeletal muscle) (Boss et al, 1997;Fleury et al, 1997). Both have uncoupling activity in vitro and may mediate the increased energy expenditure implicated in energy balance.…”

Time-Dependent Effects of a High-Energy-Yielding Diet on the Regulation of Specific White Adipose Tissue Genes

“…In this sense, the description of several uncoupling proteins, such as UCP1, 2 and 3, in adipose tissue (11)(12)(13) provides new molecular targets to understand adipocyte metabolism (14).…”