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Small-molecule inhibitors of FABP4/5 ameliorate dyslipidemia but not insulin resistance in mice with diet-induced obesity.

ABSTRACT: Fatty acid binding protein-4 (FABP4) and FABP5 are two closely related FA binding proteins expressed primarily in adipose tissue and/or macrophages. The small-molecule FABP4 inhibitor BMS309403 was previously reported to improve insulin sensitivity in leptin-deficient Lep(ob)/Lep(ob) (ob/ob) mice. However, this compound was not extensively characterized in the more physiologically relevant animal model of mice with diet-induced obesity (DIO). Here, we report the discovery and characterization of a novel series of FABP4/5 dual inhibitors represented by Compounds 1-3. Compared with BMS309403, the compounds had significant in vitro potency toward both FABP4 and FABP5. In cell-based assays, Compounds 2 and 3 were more potent than BMS309403 to inhibit lipolysis in 3T3-L1 adipocytes and in primary human adipocytes. They also inhibited MCP-1 release from THP-1 macrophages as well as from primary human macrophages. When chronically administered to DIO mice, BMS309403 and Compound 3 reduced plasma triglyceride and free FA levels. Compound 3 reduced plasma free FAs at a lower dose level than BMS309403. However, no significant change was observed in insulin, glucose, or glucose tolerance. Our results indicate that the FABP4/5 inhibitors ameliorate dyslipidemia but not insulin resistance in DIO mice.

SUBMITTER: Lan H

PROVIDER: S-EPMC3284158 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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Small-molecule inhibitors of FABP4/5 ameliorate dyslipidemia but not insulin resistance in mice with diet-induced obesity.

Lan Hong H Cheng Cliff C CC Kowalski Timothy J TJ Pang Ling L Shan Lixin L Chuang Cheng-Chi CC Jackson James J Rojas-Triana Alberto A Bober Loretta L Liu Li L Voigt Johannes J Orth Peter P Yang Xianshu X Shipps Gerald W GW Hedrick Joseph A JA

Journal of lipid research 20110204 4

Fatty acid binding protein-4 (FABP4) and FABP5 are two closely related FA binding proteins expressed primarily in adipose tissue and/or macrophages. The small-molecule FABP4 inhibitor BMS309403 was previously reported to improve insulin sensitivity in leptin-deficient Lep(ob)/Lep(ob) (ob/ob) mice. However, this compound was not extensively characterized in the more physiologically relevant animal model of mice with diet-induced obesity (DIO). Here, we report the discovery and characterization of ...[more]

PMID: 21296956

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Project description:Objectives: Diet quality may be a key modifiable factor for the prevention of non-communicable disease. We aimed to investigate the association between diet quality and prevalence of obesity, dyslipidemia, and insulin resistance among Filipino immigrant women in Korea. Methods: A total of 413 participants from the 2014-2016 baseline population of the Filipino Women's Diet and Health Study (FiLWHEL) were examined. Individual dietary intakes were evaluated through 24-h recalls and then converted into two dietary quality assessments: Minimum Dietary Diversity for Women (MDD-W) developed by the Food and Agriculture Organization (FAO) and the Data Derived Inflammation Index (DDII) originally developed by our group. Fasting blood levels of triglycerides, high-density lipoprotein cholesterols, glucose, and insulin were measured. We used logistic regression models for odds ratios (ORs) with 95% confidence intervals (CIs). Results: We found a statistically significant association between MDD-W scores and decreased prevalence of abdominal obesity; ORs (95% CIs) of the 3rd vs. 1st tertiles were 0.58 (0.36-0.94; p for trend = 0.029). Increased DDII was associated with elevated prevalence of dyslipidemia and insulin resistance; ORs (95% CIs) of the 5th vs. 1-3rd quintiles were 6.44 (2.56-16.20) for triglycerides (TG), 3.90 (1.92-7.90) for low-density lipoprotein (LDL) cholesterol, 3.36 (1.81-6.24) for total cholesterol (TC), 6.25 (2.53-15.41) for abnormal TG/HDL ratios, 3.59 (1.96-6.59) for HbA1c, 2.61 (1.11-6.17) for fasting blood glucose levels, 9.67 (4.16-22.48) for insulin levels, and 9.73 (4.46-21.25) for homeostasis model assessment of insulin resistance (HOMA-IR) (p for trend <0.001 for all, except 0.033 for fasting blood glucose). Conclusions: Greater dietary diversity was inversely associated with the prevalence of abdominal obesity in Filipino immigrant women. Proinflammatory scores based on diet and lifestyle factors were associated with an increased prevalence of dyslipidemia and insulin resistance. Further, epidemiological studies on the relationship between dietary acculturation and chronic disease are warranted.

Project description:ObjectiveIncreased plasma concentrations of apolipoprotein B100 often present in patients with insulin resistance and confer increased risk for the development of atherosclerosis. Naturally occurring polyphenolic compounds including flavonoids have antiatherogenic properties. The aim of the current study was to evaluate the effect of the polymethoxylated flavonoid nobiletin on lipoprotein secretion in cultured human hepatoma cells (HepG2) and in a mouse model of insulin resistance and atherosclerosis.Research design and methodsLipoprotein secretion was determined in HepG2 cells incubated with nobiletin or insulin. mRNA abundance was evaluated by quantitative real-time PCR, and Western blotting was used to demonstrate activation of cell signaling pathways. In LDL receptor-deficient mice (Ldlr(-/-)) fed a Western diet supplemented with nobiletin, metabolic parameters, gene expression, fatty acid oxidation, glucose homeostasis, and energy expenditure were documented. Atherosclerosis was quantitated by histological analysis.ResultsIn HepG2 cells, activation of mitogen-activated protein kinase-extracellular signal-related kinase signaling by nobiletin or insulin increased LDLR and decreased MTP and DGAT1/2 mRNA, resulting in marked inhibition of apoB100 secretion. Nobiletin, unlike insulin, did not induce phosphorylation of the insulin receptor or insulin receptor substrate-1 and did not stimulate lipogenesis. In fat-fed Ldlr(-/-) mice, nobiletin attenuated dyslipidemia through a reduction in VLDL-triglyceride (TG) secretion. Nobiletin prevented hepatic TG accumulation, increased expression of Pgc1? and Cpt1?, and enhanced fatty acid ?-oxidation. Nobiletin did not activate any peroxisome proliferator-activated receptor (PPAR), indicating that the metabolic effects were PPAR independent. Nobiletin increased hepatic and peripheral insulin sensitivity and glucose tolerance and dramatically attenuated atherosclerosis in the aortic sinus.ConclusionsNobiletin provides insight into treatments for dyslipidemia and atherosclerosis associated with insulin-resistant states.

Dataset Information

Small-molecule inhibitors of FABP4/5 ameliorate dyslipidemia but not insulin resistance in mice with diet-induced obesity.

Publications

Small-molecule inhibitors of FABP4/5 ameliorate dyslipidemia but not insulin resistance in mice with diet-induced obesity.

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