RESEARCH ARTICLES Divergent effects of a CLA-enriched beef diet on metabolic health in ApoE -/- and ob/ob mice☆ , ☆☆ Clare M. Reynolds a,1 , Sinead Toomey a,1 , Rachael McBride a , Jolene McMonagle a , Melissa J. Morine a,b , Orina Belton c , Aidan P. Moloney d , Helen M. Roche a, ⁎ a Nutrigenomics Research Group, School of Public Health, Physiotherapy and Population Science, UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland b The Microsoft Research - University of Trento Centre for Computational Systems Biology, Rovereto, Italy c School of Biomolecular and Biomedical Science, UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland d Teagasc, Animal and Grassland Research and Innovation Centre, Grange, Dunsany, Co. Meath, Ireland Received 12 August 2011; received in revised form 1 December 2011; accepted 21 December 2011 Abstract Conjugated linoleic acid (CLA) is found naturally in meat and dairy products, and represents a potential therapeutic functional nutrient. However, given the discrepancies in isomer composition and concentration, controversy surrounds its proposed antidiabetic, antiobesity effects. This study focused on the effects of CLA-enriched beef (composed predominantly of c9, t11-CLA) in two separate models of metabolic disease: proatherosclerotic ApoE -/- mice and diabetic, leptin- deficient ob/ob mice. Animals were fed CLA-enriched beef for 28 days, and markers of the metabolic syndrome and atherosclerosis were assessed. Comprehensive hepatic transcriptomic analysis was completed to understand divergent metabolic effects of CLA. CLA-enriched beef significantly reduced plasma glucose, insulin, nonesterified fatty acid and triacylglycerol and increased adiponectin levels in ob/ob mice. In contrast, plasma lipid profiles and glucose homeostasis deteriorated and promoted atherosclerosis following the CLA-enriched beef diet in ApoE -/- mice. Hepatic transcriptomic profiling revealed divergent effects of CLA-enriched beef on insulin signaling and lipogenic pathways, which were adversely affected in ApoE -/- mice. This study demonstrated clear divergence in the effects of CLA. CLA-enriched beef improved metabolic flexibility in ob/ob mice, resulting in enhanced insulin sensitivity. However, CLA- enriched diet increased expression of lipogenic genes, resulting in inefficient fatty acid storage which increases lipotoxicity in peripheral organs, and led to profound metabolic dysfunction in ApoE -/- mice. While CLA may have potential health effects, in some circumstances, caution must be exercised in presenting this bioactive lipid as a potential functional food for the treatment of metabolic disease. © 2013 Elsevier Inc. All rights reserved. Keywords: Conjugated linoleic acid; ApoE; ob/ob; Atherosclerosis; Metabolic syndrome 1. Introduction Conjugated linoleic acid (CLA) represents the positional and geometric isomers of linoleic acid. Found in meat and dairy produce of ruminant animals, up to 28 isomers have been identified [1]. The two most abundant isomers, cis9, trans11-CLA (c9,t11-CLA) and trans10, cis12 (t10,c12)-CLA, have focused attention on the role of CLA in human health. C9,t11-CLA accounts for up to 90% of total CLA and is reported to have anti-inflammatory properties demonstrating potential for treatment of proinflammatory conditions such as rheumatoid arthritis, inflammatory bowel disease and insulin resistance [2-4]. T10,c12-CLA is less abundant, representing 1%–10% of total CLA, and has received considerable attention as an antiobesity agent [5]. However, use in human subjects remains a controversial issue, as its prolonged use has been associated with dysfunctional glucose homeostasis and increased risk of developing type 2 diabetes [6–8]. The anti-inflammatory, antiobesity effects of CLA make it a prime candidate for the treatment of metabolic syndrome. This syndrome includes an array of metabolic complications, such as dyslipidemia, hypertension, low-grade inflammation and insulin resistance, which predispose to type 2 diabetes and atherosclerosis [9–11]. Reports indicate divergent metabolic mechanisms for both c9,t11-CLA and t10,c12-CLA in animal feeding studies [12]. C9,t11-CLA has potent anti-inflammatory effects leading to a reduction in adipose tissue macrophage infiltration and to improved insulin and lipid profiles, thus ameliorating the progression of insulin resistance and athero- sclerosis [4,13,14]. T10,c12-CLA is associated with a reduction in fat mass; however, subsequent increases in plasma lipids increase the risk of lipotoxic effects in peripheral insulin-sensitive organs [15]. It is important to note that these effects are observed in studies using high concentrations of synthetic CLA isomers rather than naturally occurring sources. Available online at www.sciencedirect.com Journal of Nutritional Biochemistry 24 (2013) 401 – 411 ☆ Funding support: This work was funded by the Food Institutional Research Measure, Department of Agriculture and Food, Ireland. ☆☆ All other authors have no financial conflict of interest. ⁎ Corresponding author. Tel.: +353 1 7166845; fax: +353 1 7166701. E-mail address: helen.roche@ucd.ie (H.M. Roche). 1 First authors C.M.R. and S.T. contributed equally to this work. 0955-2863/$ - see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jnutbio.2011.12.006