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

Abstract

Sheets AR, Fülöp P, Derdák Z, Kassai A, Sabo E, Mark NM, Paragh G, Wands JR, Baffy G. Uncoupling protein-2 modulates the lipid metabolic response to fasting in mice. Am J Physiol Gastrointest Liver Physiol 294: G1017-G1024, 2008. First published February 21, 2008 doi:10.1152/ajpgi.00016.2008.-Uncoupling protein-2 (UCP2) regulates insulin secretion by controlling ATP levels in ␤-cells. Although 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 Ϫ/Ϫ 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 UNCOUPLING PROTEIN (UCP) 2, a member of the anion carrier protein superfamily, is a widely distributed constituent of the mitochondrial inner membrane (6, 35). Although UCP2 was identified over 10 years ago by molecular cloning, its biological role and evolutionary aspects remain debated (6,29,35,40). Based on its significant homology with the brown adipose tissue-specific UCP1 (thermogenin), UCP2 was predicted to regulate energy balance. Subsequent observations did not confirm this prediction, and UCP2 appears to have a complex function yet to be fully explored (6,29,35,40). Similar to other uncoupling proteins, UCP2 lowers the mitochondrial membrane potential by mediating proton leak across the inner membrane (6). As a result, UCP2 has the ability to interfere with the function of F 1 F 0 ATP synthase and to alter the matrix ATP-to-ADP ratio (6).Soon after its discovery, the importance of UCP2 was recognized in pancreatic ␤-cells, where UCP2 acts as a negative regulator of glucose-stimulated insulin secretion (GSIS) (30, 51). Pancreatic ␤-cells sense blood glucose through its metabolism that results in increased levels of intracellular ATP and triggers GSIS to maintain glucose homeostasis (41). Because of more efficient oxidative phosphorylation and increased rates of mitochondrial ATP synthesis, UCP2 deficiency is associated with enhanced ␤-cell insulin secretory capacity in ucp2 Ϫ/Ϫ mice and allows the partial correction of diabetes in leptin-deficient ob/ob mice (51). In contrast, overexpression of UCP2 in ␤-cells reduces intracellular ATP levels, leading to diminished GSIS (21). Because increased UCP2 expression of ␤-cells is associated with obesity, UCP2 has been linked to impaired insulin production in typ...

Ghrelin and lipid metabolism: key partners in energy balance

“…The molecular mechanisms under this effect are not fully understood, but UCP2 KO mice display high expression of lipogenic enzymes, such as FAS, SCD1, and LPL, and decreased expression of CPT1a in WAT (Andrews et al 2010). These data correlate with the higher susceptibility to gain weight in an HFD observed in this model (Joseph et al 2002), as well as with that well-established UCP2-mediated increase in fatty acid oxidation under fasting (Andrews et al 2008, Pecqueur et al 2008, Sheets et al 2008. These data identify UCP2 as a common factor modulating energy homeostasis at hypothalamic (Andrews et al 2008) and peripheral level (Andrews et al 2010).…”

TRPV1 activation prevents nonalcoholic fatty liver through UCP2 upregulation in mice

“…Exercise can upregulate the hepatic UCP2 mRNA and increase fatty acid β oxidation and decrease body weight and fat mass [15]. In contrast, in UCP2 deficiency, efficient breakdown, conversion, and redistribution of fatty acids were perturbed, then blunted peripheral lipolysis and hepatic lipid were utilized [19]. Our previous study showed that capsaicin significantly increased UCP2 expression in adipose tissue [6].…”

UCP2-induced fatty acid synthase promotes NLRP3 inflammasome activation during sepsis

“…Since UCP2 can regulate the lipid metabolic response to fasting in mice through the expression of key lipid regulatory enzymes (29,33), we analyzed whether UCP2 regulates lipogenic enzymes in the lipid synthesis pathway in macrophages. Lipid synthesis is regulated by the expression of key lipogenic enzymes, including FASN, acetyl-CoA carboxylase (ACACA), and ATP citrate lyase (ACLY).…”