Major Urinary Protein-1 Increases Energy Expenditure and Improves Glucose Intolerance through Enhancing Mitochondrial Function in Skeletal Muscle of Diabetic Mice

Abstract

Major urinary protein-1 (MUP-1) is a low molecular weight secreted protein produced predominantly from the liver. Structurally it belongs to the lipocalin family, which carries small hydrophobic ligands such as pheromones. However, the physiological functions of MUP-1 remain poorly understood. Here we provide evidence demonstrating that MUP-1 is an important player in regulating energy expenditure and metabolism in mice. Both microarray and real-time PCR analysis demonstrated that the MUP-1 mRNA abundance in the liver of db/db obese mice was reduced by ϳ30-fold compared with their lean littermates, whereas this change was partially reversed by treatment with the insulin-sensitizing drug rosiglitazone. In both dietary and genetic obese mice, the circulating concentrations of MUP-1 were markedly decreased compared with the lean controls. Chronic elevation of circulating MUP-1 in db/db mice, using an osmotic pump-based protein delivery system, increased energy expenditure and locomotor activity, raised core body temperature, and decreased glucose intolerance as well as insulin resistance. At the molecular level, MUP-1-mediated improvement in metabolic profiles was accompanied by increased expression of genes involved in mitochondrial biogenesis, elevated mitochondrial oxidative capacity, decreased triglyceride accumulation, and enhanced insulin-evoked Akt signaling in skeletal muscle but not in liver. Altogether, these findings raise the possibility that MUP-1 deficiency might contribute to the metabolic dysregulation in obese/diabetic mice, and suggest that the beneficial metabolic effects of MUP-1 are attributed in part to its ability in increasing mitochondrial function in skeletal muscle.The liver is the primary organ for carbohydrate and lipid metabolism, including gluconeogenesis, glycogenesis, cholesterol biosynthesis, and lipogenesis (1, 2). These metabolic events in the liver are tightly controlled by several pancreatic hormones including insulin and glucagon. In addition, the liver itself is one of the largest endocrine organs in the body, secreting numerous humoral factors involved in the regulation of systemic glucose and lipid homeostasis. The importance of the liver-derived humoral factors in maintaining glucose metabolism is highlighted by the observation that glucose uptake by skeletal muscle is severely impaired by surgical or pharmacological blockade of hepatic parasympathetic nerves (3). In the past several years, a number of liver-derived humoral metabolic factors, including bone morphogenetic protein-9 (BMP-9) (4), fibroblast growth factor 21 (FGF21) (5-7), retinol-binding protein 4 (RBP4) (8, 9), adropin (10), and angiopoietin-like proteins (Angptl) 3, 4, and 6 (11-13), have been identified, and their roles in glucose and lipid metabolism have been characterized in great detail. Noticeably, BMP-9, FGF21, and Angptl6 exhibit potent insulin-sensitizing and glucose-lowering effects in animal models, and they have been proposed as potential candidates for the treatment of insulin resistance and ty...

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“…Antimouse A-FABP was produced in-house by immunizing female New Zealand rabbits with recombinant mouse A-FABP expressed in Escherichia coli and was affinity-purified as described previously (24). TRIzol reagent, SYBR Green, and cell culture medium were purchased from Invitrogen.…”

“…1 g of total RNA was reverse-transcribed into cDNA using Improm-II reverse. Each cDNA sample was analyzed for gene expression by quantitative real time PCR using the SYBR Green reagent on an Applied Biosystems Prism 7000 sequence detection system as described previously (24). Analysis was performed with ABI Prism 7000 SDS software.…”

“…The proteins were visualized by chemiluminescence detection, and the relative band densities were quantified using the MultiAnalyst software package (Bio-Rad) as described previously (24).…”

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Lipocalin 13 Protein Protects against Hepatic Steatosis by Both Inhibiting Lipogenesis and Stimulating Fatty Acid β-Oxidation

“…For instance, abnormal secretion and action of RBP4 (retinol-binding protein 4) and lipocalin 2 contribute to insulin resistance in type 2 diabetes (12, 14 -16, 19). MUP1 (major urinary protein 1), a lipocalin family member expressed primarily in hepatocytes, improves insulin sensitivity and glucose metabolism; MUP1 deficiency may contribute to insulin resistance and hyperglycemia in obese mice (17,18). We reported recently that LCN13 is produced by multiple cell types and secreted into the bloodstream in mice (6).…”