Insulin resistance and dyslipidemia are both considered to be risk factors for metabolic syndrome. Low levels of IGF1 are associated with insulin resistance. Elevation of low-density lipoprotein cholesterol (LDL-C) concomitant with depression of high-density lipoprotein cholesterol (HDL-C) increase the risk of obesity and type 2 diabetes mellitus (T2DM). Liver secretes IGF1 and catabolizes cholesterol regulated by the rate-limiting enzyme of bile acid synthesis from cholesterol 7α-hydroxylase (CYP7A1). NO-1886, a chemically synthesized lipoprotein lipase activator, suppresses diet-induced insulin resistance with the improvement of HDL-C. The goal of the present study is to evaluate whether NO-1886 upregulates IGF1 and CYP7A1 to benefit glucose and cholesterol metabolism. By using human hepatoma cell lines (HepG2 cells) as an in vitro model, we found that NO-1886 promoted IGF1 secretion and CYP7A1 expression through the activation of signal transducer and activator of transcription 5 (STAT5). Pretreatment of cells with AG 490, the inhibitor of STAT pathway, completely abolished NO-1886-induced IGF1 secretion and CYP7A1 expression. Studies performed in Chinese Bama minipigs pointed out an augmentation of plasma IGF1 elicited by a single dose administration of NO-1886. Long-term supplementation with NO-1886 recovered hyperinsulinemia and low plasma levels of IGF1 suppressed LDL-C and facilitated reverse cholesterol transport by decreasing hepatic cholesterol accumulation through increasing CYP7A1 expression in high-fat/high-sucrose/high-cholesterol diet minipigs. These findings indicate that NO-1886 upregulates IGF1 secretion and CYP7A1 expression to improve insulin resistance and hepatic cholesterol accumulation, which may represent an alternative therapeutic avenue of NO-1886 for T2DM and metabolic syndrome.

Two prolactin receptors (PRLRs) encoded by two different genes were identified in the fugu and zebrafish genomes but not in the genomes of other vertebrates. Subsequently, two cDNA sequences corresponding to two PRLRs were identified in black seabream and Nile tilapia. Phylogenetic analysis of PRLR sequences in various vertebrates indicated that the coexistence of two PRLRs in a single species is a unique phenomenon in teleosts. Both PRLRs in teleosts (the classical one named as PRLR1, the newly identified one as PRLR2) resemble the long-form mammalian PRLRs. However, despite their overall structural similarities, the two PRLR subtypes in fish share very low amino acid similarities (about 30%), mainly due to differences in the intracellular domain. In particular, the Box 2 region and some intracellular tyrosine residues are missing in PRLR2. Tissue distribution study by real-time PCR in black seabream (sb) revealed that both receptors (sbPRLR1 and sbPRLR2) are widely expressed in different tissues. In gill, the expression level of sbPRLR2 is much higher than that of sbPRLR1. In the intestine, the expression of sbPRLR1 is higher than that of sbPRLR2. The expression levels of both receptors are relatively low in most other tissues, with sbPRLR1 generally higher than sbPRLR2. The sbPRLR1 and sbPRLR2 were functionally expressed in cultured human embryonic kidney 293 cells. Both receptors can activate the β-casein and c-fos promoters; however, only sbPRLR1 but not sbPRLR2 can activate the Spi promoter upon receptor stimulation in a ligand-specific manner. These results indicate that both receptors share some common functions but are distinctly different from each other in mobilizing post-receptor events. When challenged with different steroid hormones, the two PRLRs exhibited very different gene expression patterns in the seabream kidney. The sbPRLR1 expression was up-regulated by estradiol and cortisol, whereas testosterone had no significant effect. For sbPRLR2, its expression was down-regulated by estradiol and testosterone, while cortisol exerted no significant effect. The 5′-flanking regions of the sbPRLR1 and sbPRLR2 genes were cloned and the promoter activities were studied in transfected GAKS cells in the absence or presence of different steroid hormones. The results of the promoter studies were in general agreement with the in vivo hormonal regulation of gene expression results. The sbPRLR1 gene promoter activity was activated by estradiol and cortisol, but not by testosterone. In contrast, the sbPRLR2 gene promoter activity was inhibited by estradiol, cortisol, and testosterone.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are an ideal therapy for type 2 diabetes and, as of recently, for obesity. In contrast to visceral fat, subcutaneous fat appears to be protective against metabolic diseases. Here, we aimed to explore whether liraglutide, a GLP-1RA, could redistribute body fat via regulating lipid metabolism in different fat depots. After being fed a high-fat diet for 8 weeks, 50 male Wistar and Goto-Kakizaki rats were randomly divided into a normal control group, a diabetic control group, low- and high-dose liraglutide-treated groups and a diet-control group. Different doses of liraglutide (400 μg/kg/day or 1200 μg/kg/day) or an equal volume of normal saline were administered to the rats subcutaneously once a day for 12 weeks. Body composition and body fat deposition were measured by dual-energy X-ray absorptiometry and MRI. Isotope tracers were infused to explore lipid metabolism in different fat depots. Quantitative real-time PCR and Western blot analyses were conducted to evaluate the expression of adipose-related genes. The results showed that liraglutide decreased visceral fat and relatively increased subcutaneous fat. Lipogenesis was reduced in visceral white adipose tissue (WAT) but was elevated in subcutaneous WAT. Lipolysis was also attenuated, and fatty acid oxidation was enhanced. The mRNA expression levels of adipose-related genes in different tissues displayed similar trends after liraglutide treatment. In addition, the expression of browning-related genes was upregulated in subcutaneous WAT. Taken together, the results suggested that liraglutide potentially redistributes body fat and promotes browning remodeling in subcutaneous WAT to improve metabolic disorders.