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The Intake of High-Fat Diets Induces the Acquisition of Brown Adipocyte Gene Expression Features in White Adipose Tissue

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The Intake of High-Fat Diets Induces the Acquisition of Brown Adipocyte Gene Expression Features in White Adipose Tissue International Journal of Obesity (2015) 39, 1619–1629 © 2015 Macmillan Publishers Limited All rights reserved 0307-0565/15 www.nature.com/ijo ORIGINAL ARTICLE The intake of high-fat diets induces the acquisition of brown adipocyte gene expression features in white adipose tissue E García-Ruiz, B Reynés, R Díaz-Rúa, E Ceresi, P Oliver and A Palou BACKGROUND/OBJECTIVE: White-to-brown adipose tissue remodeling (browning) in response to different stimuli constitutes an active research area for obesity treatment. The emergence in traditional white adipose tissue (WAT) depots of multilocular adipocytes that express uncoupling protein 1 (UCP1) and resemble brown adipocytes, the so called 'brite' adipocytes, could contribute to increased energy expenditure. In rodents, obesogenic stimuli such as the intake of hyperlipidic diets can increase brown adipose tissue (BAT) thermogenic capacity and contribute to maintaining body weight. The aim of this study was to investigate the potential of two different hyperlipidic diets, a commercial high-fat (HF) diet and a highly palatable cafeteria (CAF) diet, to induce WAT browning. METHODS: We analyzed gene expression of a wide number of brown/brite adipocyte markers in different WAT depots, in BAT and in peripheral blood mononuclear cells (PBMCs) increasingly being used in nutrition studies as a potential source of biomarkers of physiological effects. We also performed morphological analysis of adipose tissue. RESULTS: Both HF diets studied were able to increase the expression of the markers studied in WAT in a depot-specific manner, as well as in BAT; some of these changes were also reflected in PBMCs. This increased browning capacity was translated into the appearance of UCP1- and CIDE-A (cell death-inducing DFFA-like effector A)-positive brite adipocytes in retroperitoneal WAT. Administration of the CAF diet, associated with higher adiposity, produced the strongest impact on the parameters studied while its withdrawal restored basal conditions. CONCLUSIONS: Acquisition of brown adipocyte features in WAT could evidence an adaptation to try to counteract increased adiposity due to the intake of HF diets. Additionally, PBMCs could constitute an interesting easily obtainable material to assess the effect of nutritional interventions on browning capacity. International Journal of Obesity (2015) 39, 1619–1629; doi:10.1038/ijo.2015.112 INTRODUCTION which can turn on in these cells an energy expenditure capacity 11 Adipose tissue has an important role in energy homeostasis.1 similar to that of classic brown adipocytes. Thus, in addition Excessive energy intake is stored as fat in white adipose tissue to the induction and activation of BAT thermogenesis, the (WAT).2 On the other hand, brown adipose tissue (BAT) has the induction of WAT into BAT remodeling could be the basis for a remarkable ability to dissipate excess energy as heat in a process powerful strategy to combat obesity and related complications.9,14 known as adaptive thermogenesis, activated in response to stimuli Stimulatingly, results based on cell gene expression signatures such as hyperlipidic diets or cold.3 Uncoupling protein 1 (UCP1), reported that human BAT depots would be composed mainly of expressed in the inner mitochondrial membrane of brown brite cells, and thus BAT activation in humans could in fact adipocytes, is the molecular responsible for thermogenesis.4 represent WAT browning.10,14 Because of its energy-dissipating role, BAT has an interest for Apart from adrenergic activators, diet appears as an interesting 9 body weight maintenance which has re-emerged due to the tool to induce browning. The intake of high-fat (HF) diets is discovery of inducible BAT in adult humans.5–7 associated with increased adiposity and with the development of Interestingly, brown-like adipocytes can appear in WAT depots disorders related to the metabolic syndrome.15,16 In rodents, in response to specific stimuli such as cold exposure or beta- hyperlipidic diets are known to increase thermogenic capacity adrenergic stimulation, in a process known as browning.8,9 These (BAT recruitment and activation) in an attempt to dissipate excess cells have also been called 'brite' (from brown-in-white) or 'beige' energy intake and maintain body weight.17,18 However, the ability adipocytes.10 Brite cells present a distinct transcriptional signature of HF diets to induce browning in rodents and its persistence is in comparison to classical brown adipocytes, suggesting that controversial.19 Our objective was to analyze, in normal ad libitum- they are derived from a different pool of precursor cells.10,11 fed Wistar rats, the effect of two different hyperlipidic diets An alternative idea indicates that brite cells could derive from (a commercial HF diet and a highly palatable cafeteria (CAF) diet) transdifferentiation of preexisting white adipocytes.12,13 Similar to on gene expression of a wide number of brown/brite adipocyte brown adipocytes, brite cells store fat in multiple vacuoles in the markers in different depots of WAT, BAT and peripheral blood cytoplasm (multilocular cells). Moreover, they express low levels of mononuclear cells (PBMCs) used in nutrition/obesity studies as UCP1, but this is inducible in response to appropriate stimulation, they can reflect to some extent gene expression profiles of Laboratory of Molecular Biology, Nutrition and Biotechnology, Universitat de les Illes Balears and CIBER de Fisiopatología de la Obesidad y Nutrición (CIBERobn), Palma de Mallorca, Spain. Correspondence: Dr P Oliver, Laboratory of Molecular Biology, Nutrition and Biotechnology, Universitat de les Illes Balears. Cra. Valldemossa Km 7.5, Palma de Mallorca E-07122, Spain. E-mail: [email protected] Received 20 December 2014; revised 2 June 2015; accepted 7 June 2015; accepted article preview online 11 June 2015; advance online publication, 7 July 2015 High-fat diets and adipose tissue browning E García-Ruiz et al 1620 internal tissues, such as adipose tissue.20,21 We also analyzed the Primers for the different genes analyzed are provided in Supplementary effect of the reversion of a CAF diet to a control balanced diet Table S1. All primers were obtained from Sigma Genosys (Sigma Aldrich (post-CAF model) on browning capacity. As WAT browning could Química SA, Madrid, Spain). Analysis of quantitative PCR data was 25 be occurring in humans, and because there is no clear conducted using StepOnePlus software and LinRegPCR. The relative confirmation of the potential of HF diets to induce browning in expression of each mRNA was calculated as a percentage of control rats, using Ptaffl's method.26 Data were normalized against the reference gene rats, understanding the effect of hyperlipidic feeding on white to guanosine diphosphate dissociation inhibitor 1 (Gdi1). Gdi1 was chosen brown remodeling could be of importance to better understand based on microarray data, which show its stability in control and diet- the implication of this process in body weight control. induced obese animals.27 MATERIALS AND METHODS Western blotting analysis of UCP1 and CIDE-A (cell death-inducing DFFA-like effector A) in BAT and WAT Ethics statement UCP1 and CIDE-A protein levels were determined by western blotting in All animal experimental procedures followed in this study were reviewed BAT and in selected WAT depots (inguinal and retroperitoneal). In all, 20 μg and approved by the Bioethical Committee of the University of the Balearic (for BAT) and 60 μg (for WAT) of RIPA protein extracts were separated by Islands, and guidelines for the use and care of laboratory animals of the sodium dodecyl sulfate-polyacrylamide gel electrophoresis and transferred University were followed. to nitrocellulose membranes by conventional procedures. Membranes were immunoblotted with primary rabbit UCP1 (Catalog number: Animals GTX10983, GeneTex International Corporation, Irvine, CA, USA) and CIDE- We analyzed browning capacity in male Wistar rats (Charles River A (Catalog number: C7977, Sigma, St Louis, MO, USA) polyclonal antibodies 22 diluted 1:2000 in TBS-T for UCP1 and 1:1000 for CIDE-A. Membranes were Laboratories España, SA, Barcelona, Spain) from a previous study. Before β dietary treatments, 2-month-old animals were stratified by body weight also incubated with anti- -actin antibody to ensure equal loading (Catalog and randomly assigned to four groups, fed for 4 months with a control number: 37005, from Cell Signaling, Inc., Danvers, MA, USA). Afterwards, (C; n = 6), commercial HF (n = 7) or CAF diet (n = 6) or with a CAF diet for membranes were incubated for 30 min with IRDye800CW-conjugated goat anti-rabbit IgG (LI-COR Biosciences, Lincoln, NE, USA) diluted 1:10000 in 2 months followed by a control diet for another 2 months (PCAF; n = 6). Odyssey Blocking Buffer (LI-COR Biosciences). Membranes were scanned Sample size was selected based on similar experimental designs, which and bands were quantified using the Odyssey Infrared Imaging System show that this size is adequate to detect statistical differences. Control and (LI-COR Biosciences) with 800- and 700-nm channel. HF diets contained 10% and 60% calories from fat, respectively (D12450B and D12492, Research Diets, Brogaarden, Denmark). CAF diet composition has been previously described23 and, based on the foodstuffs ingested by Histological analysis 24 the animals, provides 62% calories from fat. Animals were killed by Adipose tissue samples were fixed by immersion in 4% paraformaldehyde decapitation in the fed state and different WAT depots, both visceral in 0.1 M sodium phosphate buffer, pH 7.4, overnight at 4 °C, washed in (retroperitoneal, mesenteric and epididymal) and subcutaneous (inguinal), phosphate buffer, dehydrated in a graded series of ethanol, cleared in and interscapular BAT were rapidly removed, weighed and stored at xylene and embedded in paraffin blocks for light microscopy. Five- − 70 °C until analysis. Truncal blood was collected from the neck to collect micrometer-thick sections of tissues were cut with a microtome and serum. One week prior to killing, animals were submitted to nocturnal 14-h mounted on slides.
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