RNAi-mediated Germline Knockdown of FABP4 Increases Body Weight but Does Not Improve the Deranged Nutrient Metabolism of Diet-induced Obese Mice

Overview

Journal Int J Obes (Lond)

Specialty Endocrinology

Date 2010 Jul 7

PMID 20603627

Citations 28

Authors

R Yang

G Castriota

Y Chen

M A Cleary

K Ellsworth

M K Shin

J-Lv Tran

T F Vogt

M Wu

S Xu

X Yang

B B Zhang

J P Berger

S A Qureshi

Affiliations

Soon will be listed here.

Abstract

Objective: To investigate the impact of reduced adipocyte fatty acid-binding protein 4 (FABP4) in control of body weight, glucose and lipid homeostasis in diet-induced obese (DIO) mice.

Methods: We applied RNA interference (RNAi) technology to generate FABP4 germline knockdown mice to investigate their metabolic phenotype.

Results: RNAi-mediated knockdown reduced FABP4 mRNA expression and protein levels by almost 90% in adipocytes of standard chow-fed mice. In adipocytes of DIO mice, RNAi reduced FABP4 expression and protein levels by 70 and 80%, respectively. There was no increase in adipocyte FABP5 expression in FABP4 knockdown mice. The knockdown of FABP4 significantly increased body weight and fat mass in DIO mice. However, FABP4 knockdown did not affect plasma glucose and lipid homeostasis in DIO mice; nor did it improve their insulin sensitivity.

Conclusion: Our data indicate that robust knockdown of FABP4 increases body weight and fat mass without improving glucose and lipid homeostasis in DIO mice.

Citing Articles

NLRC5 affects diet-induced adiposity in female mice and co-regulates peroxisome proliferator-activated receptor PPARγ target genes.

Bauer S, Aeissen V, Bubeck A, Kienes I, Ellwanger K, Scheurenbrand M iScience. 2023; 26(4):106313.

PMID: 36968073 PMC: 10034470. DOI: 10.1016/j.isci.2023.106313.

FABP4 Expression in Subcutaneous Adipose Tissue Is Independently Associated with Circulating Triglycerides in Obesity.

Osorio-Conles O, Ibarzabal A, Balibrea J, Vidal J, Ortega E, de Hollanda A J Clin Med. 2023; 12(3).

PMID: 36769659 PMC: 9917808. DOI: 10.3390/jcm12031013.

A human liver organoid screening platform for DILI risk prediction.

Zhang C, Meyer S, OMeara M, Huang S, Capeling M, Ferrer-Torres D J Hepatol. 2023; 78(5):998-1006.

PMID: 36738840 PMC: 11268729. DOI: 10.1016/j.jhep.2023.01.019.

FABP4 Controls Fat Mass Expandability (Adipocyte Size and Number) through Inhibition of CD36/SR-B2 Signalling.

Berger E, Geloen A Int J Mol Sci. 2023; 24(2).

PMID: 36674544 PMC: 9867004. DOI: 10.3390/ijms24021032.

siRNA-based nanotherapeutics as emerging modalities for immune-mediated diseases: A preliminary review.

Sargazi S, Arshad R, Ghamari R, Rahdar A, Bakhshi A, Karkan S Cell Biol Int. 2022; 46(9):1320-1344.

PMID: 35830711 PMC: 9543380. DOI: 10.1002/cbin.11841.

References

Furuhashi M, Hotamisligil G . Fatty acid-binding proteins: role in metabolic diseases and potential as drug targets. Nat Rev Drug Discov. 2008; 7(6):489-503. PMC: 2821027. DOI: 10.1038/nrd2589. View

Seibler J, Kuter-Luks B, Kern H, Streu S, Plum L, Mauer J . Single copy shRNA configuration for ubiquitous gene knockdown in mice. Nucleic Acids Res. 2005; 33(7):e67. PMC: 1079974. DOI: 10.1093/nar/gni065. View

Jiang G, Li Z, Liu F, Ellsworth K, Dallas-Yang Q, Wu M . Prevention of obesity in mice by antisense oligonucleotide inhibitors of stearoyl-CoA desaturase-1. J Clin Invest. 2005; 115(4):1030-8. PMC: 1062893. DOI: 10.1172/JCI23962. View

Furuhashi M, Tuncman G, Gorgun C, Makowski L, Atsumi G, Vaillancourt E . Treatment of diabetes and atherosclerosis by inhibiting fatty-acid-binding protein aP2. Nature. 2007; 447(7147):959-65. PMC: 4076119. DOI: 10.1038/nature05844. View

Hotamisligil G, Johnson R, Distel R, Ellis R, Papaioannou V, Spiegelman B . Uncoupling of obesity from insulin resistance through a targeted mutation in aP2, the adipocyte fatty acid binding protein. Science. 1996; 274(5291):1377-9. DOI: 10.1126/science.274.5291.1377. View

Simpson M, Licata V, Ribarik Coe N, Bernlohr D . Biochemical and biophysical analysis of the intracellular lipid binding proteins of adipocytes. Mol Cell Biochem. 1999; 192(1-2):33-40. View

Maeda K, Uysal K, Makowski L, Gorgun C, Atsumi G, Parker R . Role of the fatty acid binding protein mal1 in obesity and insulin resistance. Diabetes. 2003; 52(2):300-7. PMC: 4027060. DOI: 10.2337/diabetes.52.2.300. View

Yang R, Wilcox D, Haasch D, Jung P, Nguyen P, Voorbach M . Liver-specific knockdown of JNK1 up-regulates proliferator-activated receptor gamma coactivator 1 beta and increases plasma triglyceride despite reduced glucose and insulin levels in diet-induced obese mice. J Biol Chem. 2007; 282(31):22765-74. DOI: 10.1074/jbc.M700790200. View

Xu H, Barnes G, Yang Q, Tan G, Yang D, Chou C . Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest. 2003; 112(12):1821-30. PMC: 296998. DOI: 10.1172/JCI19451. View

10.

Hertzel A, Bernlohr D . The mammalian fatty acid-binding protein multigene family: molecular and genetic insights into function. Trends Endocrinol Metab. 2000; 11(5):175-80. DOI: 10.1016/s1043-2760(00)00257-5. View

11.

Haunerland N, Spener F . Fatty acid-binding proteins--insights from genetic manipulations. Prog Lipid Res. 2004; 43(4):328-49. DOI: 10.1016/j.plipres.2004.05.001. View

12.

Makowski L, Boord J, Maeda K, Babaev V, Uysal K, Morgan M . Lack of macrophage fatty-acid-binding protein aP2 protects mice deficient in apolipoprotein E against atherosclerosis. Nat Med. 2001; 7(6):699-705. PMC: 4027052. DOI: 10.1038/89076. View

13.

Tuncman G, Erbay E, Hom X, De Vivo I, Campos H, Rimm E . A genetic variant at the fatty acid-binding protein aP2 locus reduces the risk for hypertriglyceridemia, type 2 diabetes, and cardiovascular disease. Proc Natl Acad Sci U S A. 2006; 103(18):6970-5. PMC: 1447594. DOI: 10.1073/pnas.0602178103. View

14.

Coe N, Simpson M, Bernlohr D . Targeted disruption of the adipocyte lipid-binding protein (aP2 protein) gene impairs fat cell lipolysis and increases cellular fatty acid levels. J Lipid Res. 1999; 40(5):967-72. View

15.

Furuhashi M, Fucho R, Gorgun C, Tuncman G, Cao H, Hotamisligil G . Adipocyte/macrophage fatty acid-binding proteins contribute to metabolic deterioration through actions in both macrophages and adipocytes in mice. J Clin Invest. 2008; 118(7):2640-50. PMC: 2423863. DOI: 10.1172/JCI34750. View

16.

Aigner A . Cellular delivery in vivo of siRNA-based therapeutics. Curr Pharm Des. 2008; 14(34):3603-19. DOI: 10.2174/138161208786898815. View

17.

Hotamisligil G . Inflammation and metabolic disorders. Nature. 2006; 444(7121):860-7. DOI: 10.1038/nature05485. View

18.

Uysal K, Scheja L, Wiesbrock S, Bonner-Weir S, Hotamisligil G . Improved glucose and lipid metabolism in genetically obese mice lacking aP2. Endocrinology. 2000; 141(9):3388-96. DOI: 10.1210/endo.141.9.7637. View

19.

Maeda K, Cao H, Kono K, Gorgun C, Furuhashi M, Uysal K . Adipocyte/macrophage fatty acid binding proteins control integrated metabolic responses in obesity and diabetes. Cell Metab. 2005; 1(2):107-19. DOI: 10.1016/j.cmet.2004.12.008. View

20.

Cao H, Maeda K, Gorgun C, Kim H, Park S, Shulman G . Regulation of metabolic responses by adipocyte/macrophage Fatty Acid-binding proteins in leptin-deficient mice. Diabetes. 2006; 55(7):1915-22. DOI: 10.2337/db05-1496. View