While low levels of unesterified long chain fatty acids (LCFAs) are normal metabolic intermediates of dietary and endogenous fat, LCFAs are also potent regulators of key receptors/enzymes and at high levels become toxic detergents within the cell. Elevated levels of LCFAs are associated with diabetes, obesity and metabolic syndrome. Consequently, mammals evolved fatty acid-binding proteins (FABPs) that bind/sequester these potentially toxic free fatty acids in the cytosol and present them for rapid removal in oxidative (mitochondria, peroxisomes) or storage (endoplasmic reticulum, lipid droplets) organelles. Mammals have a large (15-member) family of FABPs with multiple members occurring within a single cell type. The first described FABP, liver-FABP (L-FABP or FABP1), is expressed in very high levels (2-5% of cytosolic protein) in liver as well as in intestine and kidney. Since L-FABP facilitates uptake and metabolism of LCFAs in vitro and in cultured cells, it was expected that abnormal function or loss of L-FABP would reduce hepatic LCFA uptake/oxidation and thereby increase LCFAs available for oxidation in muscle and/or storage in adipose. This prediction was confirmed in vitro with isolated liver slices and cultured primary hepatocytes from L-FABP gene-ablated mice. Despite unaltered food consumption when fed a control diet ad libitum, the L-FABP null mice exhibited age- and sex-dependent weight gain and increased fat tissue mass. The obese phenotype was exacerbated in L-FABP null mice pair fed a high-fat diet. Taken together with other findings, these data suggest that L-FABP could have an important role in preventing age- or diet-induced obesity.

/pdf/liver-fatty-acid-binding-protein-and-obesity-19sktiwkqr.pdf

Liver fatty acid-binding protein and obesity

Following fertilization, a number of molecular events are triggered in the mammalian zygote. As biochemical studies using mammalian gametes and zygotes have inherent difficulties, the molecular nature of these processes is currently unclear. We have developed a method to visualize these events. In vitro transcribed mRNAs encoding for proteins fused with green fluorescent protein were microinjected into oocytes or embryos and fluorescence signals were observed. Using this technique we succeeded in obtaining images of the DNA methylation status in living mouse and rabbit embryos. Moreover, time-lapse images were acquired of spindle and nuclear formation during second meiosis and first mitosis. Importantly, the microinjected embryos developed to the normal offspring even after observation, suggesting that the technique is relatively noninvasive. Thus, our method may help elucidate the molecular aspects of fertilization and preimplantation development and, based on the real-time genetic and epigenetic status, could become a tool to select “good quality” embryos before implantation. genesis 43:71–79, 2005. © 2005 Wiley-Liss, Inc.

Noninvasive visualization of molecular events in the mammalian zygote.

Transgenic animals have become a key tool in functional genomics to generate models for human diseases and validate new drugs. Transgenesis includes the addition of foreign genetic information to animals and specific inhibition of endogenous gene expression. Recently, animal models provided novel insight and significantly improved our understanding of the initiation and perpetuation of human diseases. Moreover, they are an invaluable tool for target discovery, validation, and production of therapeutic proteins. However, despite the generation of several transgenic and knockout models, obtaining relevant models still faces several theoretical and technical challenges. Indeed, genes of interest are not always available and gene addition or inactivation sometimes does not allow clear conclusions because of the intrinsic complexity of living organisms or the redundancy of some metabolic pathways. In addition to homologous recombination, endogenous gene expression can be specifically inhibited using several mechanisms such as RNA interference. Here, some animal models are described to illustrate their importance in biomedical research. Moreover, guidelines for generation of these animals are presented.

Transgenic Animal Models in Biomedical Research

To investigate a possible mechanism for inducing epigenetic defects in the preimplantation embryo, a human embryonic stem cell model was developed, and gene expression of the key methyl cycle enzymes, MAT2A, MAT2B, GNMT, SAHH, CBS, CGL, MTR, MTRR, BHMT, BHMT2, mSHMT, cSHMT and MTHFR was demonstrated, while MAT1 was barely detectable. Several potential acceptors of cycle-generated methyl groups, the DNA methyltransferases (DNMT1, DNMT3A, DNMT3B and DNMT3L), glycine methyltransferase and the polyamine biosynthetic enzymes, SAM decarboxylase and ornithine decarboxylase, were also expressed. Expression of folate receptor α suggests a propensity for folate metabolism. Methotrexate-induced depletion of folate resulted in elevated intracellular homocysteine concentration after 7 days in culture and a concomitant increase in cysteine and glutathione, indicating clearance of homocysteine through the transulphuration pathway. These studies indicate that altered methyl group metabolism provides a potential mechanism for inducing epigenetic changes in the preimplantation embryo.

https://www.rbmojournal.com/article/S1472-6483(10)61120-0/pdf

Human embryonic stem cell methyl cycle enzyme expression: modelling epigenetic programming in assisted reproduction?

Although the function of liver fatty acid binding protein in hepatic fatty acid metabolism has been extensively studied, its potential role in hepatic cholesterol homeostasis is less clear. Althoug...

Hepatic phenotype of liver fatty acid binding protein gene-ablated mice.

Impact of embryonic expression of enhanced green fluorescent protein on early mouse development.

To improve efficiency of trans- genesis, we compared M16 and CZB embryo culture media, supporting development to blastocysts of FVB/ N mouse pronuclear-eggs, microinjected with enhanc- ed green fluorescent protein (EGFP) transgene. When EGFP-injected-eggs were cultured (120 hr), blastocyst development was significantly (P < 0.03) higher in M16 medium (72.5 � 2.4%) than that in CZB (13.2 � 4.3%) or CZBG (CZB with 5.6 mM glucose at 48 hr culture) (62.1 � 3.7%) media. Blastocyst development of noninjected embryos was higher in M16 (92.0 � 2.6%) and CZBG (83.9 � 3.9%) media than in CZB (31.9 � 2.8%) medium (P < 0.0001). However, percentages of morulae at 72 hr were comparable in all treatments. Developed blastocysts were better in M16 than in CZB or CZBG media. Consistent with this, mean cell number per blastocyst, developed from injected embryos, was significantly (P < 0.002) higher in M16 medium (79.6), than those in CZB (31.3) or CZBG media (60.7); similar with noninjected embryos. Cell allocation to trophectoderm (TE) and inner cell mass (ICM), i.e., TE:ICM ratio, for injected blastocysts in M16 (3.0) was less than (P < 0.05) those in CZB (4.2) and CZBG (4.4) media; similar with noninjected blastocysts. Moreover, blas- tocysts, developed in M16 and CZBG media, hatched, attached, and exhibited trophoblast outgrowth; 18% of them showed EGFP-expression. Importantly, blasto- cysts from M16 medium produced live transgenic ''green'' pups (11%) following embryo transfer. Taken together, our results indicate that supplementation of glucose, at 48 hr of culture (CZBG), is required for morula to blastocyst transition; M16 medium, containing glucose from the beginning of culture, is superior to CZB or CZBG for supporting devel- opment of biologically viable blastocysts from EGFP- transgene-injected mouse embryos. Mol. Reprod. Dev. 65: 269-277, 2003. 2003 Wiley-Liss, Inc.

/pdf/successful-development-of-viable-blastocysts-from-enhanced-23olh9758b.pdf

Successful development of viable blastocysts from enhanced green fluorescent protein transgene‐microinjected mouse embryos: Comparison of culture media

Embryo culture-based generation of enhanced green fluorescent protein-transgenic mice.

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Impact of embryonic expression of enhanced green fluorescent protein on early mouse development.

Successful development of viable blastocysts from enhanced green fluorescent protein transgene‐microinjected mouse embryos: Comparison of culture media

Embryo culture-based generation of enhanced green fluorescent protein-transgenic mice.