BackgroundFrequent consumption of a diet high in fat and sucrose contributes to lifestyle-related diseases. However, limited information is available regarding the short-term effects of such a diet on the onset of obesity-associated metabolic abnormalities.MethodsMale C57BL/6 J mice were divided into two groups and fed a standard chow diet (control group) or a high fat–high sucrose diet containing 21% fat and 34% sucrose (HF–HS diet group) for 2 or 4 weeks.ResultsThe HF–HS diet significantly induced body weight gain beginning at week 1 and similarly increased mesenteric white adipose tissue weight and plasma insulin levels at weeks 2 and 4. Plasma resistin levels were notably elevated after feeding with the HF–HS diet for 4 weeks. Measurement of hepatic triglycerides and Oil Red O staining clearly indicated increased hepatic lipid accumulation in response to the HF–HS diet as early as 2 weeks. Quantitative PCR analysis of liver and white adipose tissue indicated that, starting at week 2, the HF–HS diet upregulated mRNA expression from genes involved in lipid metabolism and inflammation and downregulated genes involved in insulin signalling. Although plasma cholesterol levels were also rapidly increased by the HF–HS diet, no differences were found between the control and HF–HS diet–fed animals in the expression of key genes involved in cholesterol biosynthesis.ConclusionsOur study demonstrates that the rapid onset of hepatosteatosis, adipose tissue hypertrophy and hyperinsulinemia by ingestion of a diet high in fat and sucrose may possibly be due to the rapid response of lipogenic, insulin signalling and inflammatory genes.
We report that a novel sulfonylamino compound, 4-[2-(phenylsulfonylamino)ethylthio]-2,6-difluoro-phenoxyacetamide (PEPA), selectively potentiates glutamate receptors of the AMPA subtype. PEPA (1-200 M) dose dependently potentiated glutamateevoked currents in Xenopus oocytes expressing AMPA (GluRAGluRD), but not kainate (GluR6 and GluR6ϩKA2) or NMDA (1 ϩ ⑀1-⑀4), receptor subunits. PEPA was effective at micromolar concentrations and, in contrast to the action of cyclothiazide, preferentially modulated AMPA receptor flop isoforms. At 200 M, PEPA potentiated glutamate responses by 50-fold in oocytes expressing GluRC flop (EC 50 ϳ50 M) versus only threefold for GluRC flip ; a similar preference for flop isoforms was observed for other AMPA receptor subunits. Dose-response analysis for GluRC flop revealed that 100 M PEPA produced a sevenfold increase in AMPA receptor affinity for glutamate. PEPA produced considerably weaker potentiation of kainate-evoked than glutamate-evoked currents, suggesting modulation of the process of receptor desensitization. In human embryonic kidney 293 cells transfected with AMPA receptor subunits, PEPA either abolished or markedly slowed the rate of onset of desensitization and potentiated steady-state equilibrium currents evoked by glutamate with subunit (GluRC Ն GluRD Ͼ GluRA) and splice-variant (flop Ͼ flip) selectivity similar to that observed in oocytes. Our results show that PEPA is a novel, flop-preferring allosteric modulator of AMPA receptor desensitization at least 100 times more potent than aniracetam. Key words: glutamate receptors; AMPA; desensitization; alternative splicing; flip and flop; allosteric modulationAllosteric modulation of the three subtypes of ionotropic glutamate receptors-AM PA, kainate, and NMDA receptors-is produced by a diverse spectrum of agents, including lectins, a variety of drugs, polyamines, and divalent cations. The unusually strong modulation of AM PA receptors by the benzothiadiazine and pyrrolidinone compounds cyclothiazide, aniracetam, and their derivatives (Ito et al
Androgens play an important role in male sexual differentiation and development. The activity of androgens is mediated by an androgen receptor (AR), which binds to specific DNA recognition sites and regulates transcription. We describe here the isolation of two distinct rainbow trout cDNA clones, designated rtAR-␣ and rtAR-, which contain the entire androgen receptor coding region. Comparison of the predicted amino acid sequence of rtAR-␣ to that of rtAR- revealed 85% identity. Interestingly, despite this high homology, rtAR-␣ activated transcription of an androgen-responsive reporter gene in co-transfection assays, but rtAR- did not. These results suggest that rainbow trout contains two distinct isoforms of androgen receptors whose functions differ. The region of rtAR- responsible for its inactivity was mapped to its ligand binding domain by analyzing chimeras of the rtAR-␣, rtAR-, and rtGR-I (glucocorticoid) receptors. Alteration of any one of three out of four segments within this domain restored activity.Extracts made from COS-1 cells transfected with an rtAR-␣ expression plasmid produced a high level of [ 3 H]mibolerone binding, whereas no binding was observed by extracts of cells transfected with an rtAR- expression plasmid. These data demonstrate that the lack of transactivation activity of rtAR- is due to its inability to bind hormone.In contrast to mammals, fish can undergo gonadal sex inversion in either direction by treatment with exogenous sex steroid if it is applied early enough during development (1, 2). These observations led to the postulate that androgens and estrogens are the substances responsible for sex differentiation of male and female fish, respectively (3), and has resulted in the development of protocols for the masculinization and feminization of large numbers of fish for experimental or economic purposes (1, 4, 5). The androgen receptor (AR) 1 is a critical mediator of male sexual differentiation and development in both fish and mammals. Structurally and functionally, the AR belongs to the superfamily of ligand-responsive transcription modifiers, which encompasses the receptors for the steroid and thyroid hormones. Like other nuclear receptors, steroid receptors are composed of three major functional domains: an NH 2 -terminal hypervariable transcriptional activation domain (TAD), a central highly conserved DNA binding domain (DBD) consisting of two Cys-Cys zinc finger motifs, and a COOH-terminal ligand binding domain (LBD) (6 -9). It has been reported that the AR regulates androgen target genes by binding to a specific DNA sequence, the androgen-responsive element (ARE; consensus ϭ 5Ј-GGTACANNNTGTTCT), which is similar to the glucocorticoid response element (12)(13)(14). The AR can either up-or downregulate the expression of androgen target genes, the outcome probably depending on interactions with specific adapters or co-activators (10, 11).At present, complete AR cDNAs have been cloned only from mammalian species (human, rat, and mouse) (6, 15). We have undertaken the isola...
The objective of present study was to examine the effect of long-chain monounsaturated fatty acids (LC-MUFAs) with chain lengths longer than 18 (i.e., C20:1 and C22:1 isomers combined) on obesity-related metabolic dysfunction and its molecular mechanisms. Type-2 diabetic KK-Ay mice (n = 20) were randomly assigned to the 7% soybean oil-diet group (control group) and 4% LC-MUFA concentrate-supplemented-diet group (LC-MUFA group). At 8 weeks on the diet, the results showed that plasma, liver and adipose tissue levels of C20:1 and C22:1 isomers increased significantly with LC-MUFA treatment. Supplementation with LC-MUFAs markedly reduced white fat pad weight as well as adipocyte size in the mice. The levels of plasma free fatty acids, insulin, and leptin concentration in the obese diabetic mice of the LC-MUFA group were also decreased as compared with the mice in the soybean oil-diet control group. Dietary LC-MUFAs significantly increased the mRNA expression of peroxisome proliferator-activated receptor gamma (Pparg), lipoprotein lipase (Lpl), fatty acid transport protein (Fatp), fatty acid translocase/CD36 (Cd36), as well as mRNA expression of genes involved in lipid oxidation such as carnitine palmitoyltransferase-1A (Cpt1a) and citrate synthase (Cs), and decreased the mRNA expression of inflammatory marker serum amyloid A 3 (Saa3) in the adipose tissues of diabetic mice. The results suggest that LC-MUFAs may ameliorate obesity-related metabolic dysfunction partly through increased expression of Pparg as well as its target genes, and decreased inflammatory marker expression in white adipose tissue.
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