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. 2003 Feb;52(2):300-7.
doi: 10.2337/diabetes.52.2.300.

Role of the fatty acid binding protein mal1 in obesity and insulin resistance

Kazuhisa Maeda  1 , K Teoman Uysal, Liza Makowski, Cem Z Görgün, Genichi Atsumi, Rex A Parker, Jens Brüning, Ann Vogel Hertzel, David A Bernlohr, Gökhan S Hotamisligil
Affiliations

Role of the fatty acid binding protein mal1 in obesity and insulin resistance

Kazuhisa Maeda et al. Diabetes. 2003 Feb.

Abstract

The metabolic syndrome is a cluster of metabolic and inflammatory abnormalities including obesity, insulin resistance, type 2 diabetes, hypertension, dyslipidemia, and atherosclerosis. The fatty acid binding proteins aP2 (fatty acid binding protein [FABP]-4) and mal1 (FABP5) are closely related and both are expressed in adipocytes. Previous studies in aP2-deficient mice have indicated a significant role for aP2 in obesity-related insulin resistance, type 2 diabetes, and atherosclerosis. However, the biological functions of mal1 are not known. Here, we report the generation of mice with targeted null mutations in the mal1 gene as well as transgenic mice overexpressing mal1 from the aP2 promoter/enhancer to address the role of this FABP in metabolic regulation in the presence or absence of obesity. To address the role of the second adipocyte FABP in metabolic regulation in the presence and deficiency of obesity, absence of mal1 resulted in increased systemic insulin sensitivity in two models of obesity and insulin resistance. Adipocytes isolated from mal1-deficient mice also exhibited enhanced insulin-stimulated glucose transport capacity. In contrast, mice expressing high levels of mal1 in adipose tissue display reduced systemic insulin sensitivity. Hence, our results demonstrate that mal1 modulates adipose tissue function and contributes to systemic glucose metabolism and constitutes a potential therapeutic target in insulin resistance.

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Figures

FIG. 1
FIG. 1
The genomic structure around the mal1 loci and generation of a targeted null mutation in the mal1 gene. A: The genomic map around mal1 loci and construction of the targeting vector. B: Confirmation of the presence of the allele by Southern and PCR analysis in mice. Primers P1 and P2 amplify the wild-type allele; primers P3 and P4 amplify the targeted allele. Genomic DNA is digested with BamHI for use in Southern blot analysis. C: mRNA expression of mal1 in epididymal (EPI) and subcutaneous (SC) adipose tissue from mal1+/+ and mal1–/– mice. The expression of aP2 and 36B4 as well as the ethidium bromide staining of the RNA (EtBr) are shown as controls. D: Protein expression of mal1 in tongue, testis, white adipose tissue (WAT), and brown adipose tissue (BAT) from mal1–/– and mal1+/+ mice. Recombinant aP2 and mal1 proteins used as positive controls are shown on the left.
FIG. 2
FIG. 2
Expression of FABP isoforms and developmental characteristics of mal1–/– and control mice. A: Expression of fatty acid binding protein iso-forms in tissues from mal1–/– (–) and mal1+/+ (+) mice by Northern blot analyses. BAT, brown adi-pose tissue; EtBr, ethidium bromide staining of the RNA; WAT, white adipose tissue. B: Body weight measurements of mal1–/– and mal1+/+ mice on both a standard diet (RD) and a high-fat diet (HF). C: The weight of liver and adipose tissue at different depots. EPI, epididymal adipose depot; SC, subcutaneous adipose depot; VIS visceral (mesenteric) adipose depot. D: Total daily food intake (FI) and food intake per gram body weight (BW) in lean mal1–/– and mal1+/+ mice. ■, mal1+/+; □, mal1–/–. Statistical significance is indicated: *P < 0.05.
FIG. 3
FIG. 3
Glucose metabolism in mal1-deficient mice. Steady-state plasma glucose (A) and insulin (B) levels in lean and obese mal1–/– and mal1+/+ mice. Intraperitoneal insulin (C) and glucose (D) tolerance test in lean and obese mal1–/– and mal1+/+ mice. Statistical significance is indicated: *P < 0.05.
FIG. 4
FIG. 4
Adipose-derived hormones in mal1–/– mice. A: Expression of leptin, adiponectin, resistin, and tumor necrosis factor-α (TNF-α) mRNAs in the adipose tissue of lean (regular diet) and obese (high-fat diet) mice. Pooled total RNA (20 μg) from four to five mice was loaded in each lane. B: Plasma levels of leptin in lean and obese mal1–/– and mal1+/+ animals. C: Levels of glucose transporters GLUT1 and GLUT4 protein in white adipose tissue (WAT) and muscle tissues of obese mal1–/– and mal1+/+ animals. Pooled protein (25 μg) from four to five mice was loaded in each lane. D: Baseline and insulin-stimulated glucose transport in adipocytes isolated from obese mal1–/– and mal1+/+ mice. *P < 0.05.
FIG. 5
FIG. 5
Glucose metabolism in OB/OB- and ob/ob-mal1–deficient mice. Steady-state plasma insulin (A) and glucose (B) levels in lean (OB/OB) and obese (ob/ob) mal1–/– and mal1+/+ mice. Intraperitoneal insulin (C) and glucose (D) tolerance tests in OB/OB and ob/ob mal1–/– and mal1+/+ mice. Statistical significance is indicated: *P < 0.05.
FIG. 6
FIG. 6
Characteristics of the mal1 transgenic mice. A: Quantification of aP2 and mal1 protein levels in control and transgenic mice adipocytes. B: Total body and epididymal fat pad weight. C: Plasma glucose and insulin levels. D: Intraperitoneal glucose tolerance tests in control and transgenic mice. All mice were on a high-fat diet.
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