ORIGINAL ARTICLE Inflammation and insulin resistance exert dual effects on adipose tissue tumor protein 53 expression FJ Ortega 1,2 , JM Moreno-Navarrete 1,2 , D Mayas 1,3 , M Serino 4 , JI Rodriguez-Hermosa 5 , W Ricart 1,2 , E Luche 4 , R Burcelin 4 , FJ Tinahones 1,3 , G Fru ¨ hbeck 1,6 , G Mingrone 7 and JM Ferna ´ ndez-Real 1,2 OBJECTIVE: The purpose of this study was to investigate the expression of human adipose tissue protein 53 (p53) in subjects who varied widely in terms of obesity and insulin resistance. We also analyzed different in vivo and in vitro models to try to comprehend the associations found in humans. METHODS: p53 was analyzed in human adipose and isolated adipocytes, in high fat-fed and GLP-1R KO mice, during in vitro adipogenesis, and in adipocytes after high glucose, rosiglitazone and inflammatory conditions. The effects of surgery-induced weight loss and ex vivo metformin were also evaluated. RESULTS: Omental (OM) p53 gene expression ( þ 27%, P ¼ 0.001) and protein ( þ 11%, P ¼ 0.04) were increased in obese subjects and high fat diet-induced obese mice ( þ 86%, P ¼ 0.018). Although the obesity-associated inflammatory milieu was associated with increased OM p53, this was negatively related to insulin resistance and glycated hemoglobin, and positively with biomarkers for insulin sensitivity. Multiple linear regression analyses revealed that glycated hemoglobin (Po0.0001) and body mass index (P ¼ 0.048) contributed independently to explain 13.7% (Po0.0001) of the OM p53 variance. Accordingly, the improvement of insulin sensitivity with surgery-induced weight loss ( þ 51%, P ¼ 0.01) and metformin ( þ 42%, P ¼ 0.02) led to increased adipose p53. While the glucose-intolerant GLP-1R KO mice showed decreased mesenteric p53 ( À 45.4%, P ¼ 0.017), high glucose led to decreased p53 in pre-adipocytes ( À 27%, Po0.0001). Inflammatory treatments led to increased p53 ( þ 35%, Po0.0001), while Rs downregulated this expression ( À 40%, P ¼ 0.005) in mature adipocytes. CONCLUSION: Inflammation and insulin resistance exert dual effects on adipose p53, which seems to be the final result of these opposing forces. International Journal of Obesity (2014) 38, 737–745; doi:10.1038/ijo.2013.163 Keywords: tumor protein 53; adipocytes; adipose tissue; inflammation; insulin resistance; type 2 diabetes INTRODUCTION The tumor suppressor activity of the protein 53 (p53) has been clearly established in the last three decades (see Levine and Oren 1 for a review). Less attention has been given to its possible involvement in other biological processes such as cell metabolism and development. Notably, inflammatory stress triggers the p53 response, 2 and p53 itself is also emerging as an important regulator of metabolic homeostasis. 3 Both adipose tissue and systemic inflammation are up- regulated in obese subjects, having a crucial role in the progression of metabolic disturbances. 4,5 Omental (OM) adipose tissue dysfunction is known to act as a source of inflammatory- related factors in individuals with central obesity. 6 On the other hand, adipose tissue senescence has been recently recognized to be linked to inflammation in obese subjects with shortened telomeres. 5,7 Minamino et al. 8 recently reported that p53 in mice adipose tissue was closely associated with cellular aging, a new target for the treatment of diabetes. These authors used Ay mice, known to develop obesity and diabetes in the context of increased oxidative stress and pro-inflammatory cytokines. 8 They demonstrated the induction of senescence-like changes (for example, increased p53 and shortened telomeres) in adipose tissue from these mice. 8 Results from this study suggested that p53 in adipose tissue may lead to increased oxidative stress-induced nuclear transcription factor (NF)-kB activation and the induction of inflammatory cytokines, promoting at the end the development of insulin resistance in mice. Recent findings also demonstrate that p53 modulates the coordinated interplay between proliferation and differentiation in many cell lineages, 9–11 including adipocytes, 12 having unsuspected effects on cellular metabolism. 13,14 Molchadsky et al. 15 demonstrated that p53 has opposing roles in a cell fate-dependent manner, inhibiting adipogenesis but promoting muscle differentiation. In vitro and in vivo studies have also provided interesting insights into the association of p53 with adipocytes’ fate decisions (see Bazuine et al. 12 for a review), its involvement in adipose tissue dysfunction 8 and in metabolic homeostasis. 1 CIBER de la Fisiopatologı ´a de la Obesidad y Nutricio ´ n (CIBERobn, CB06/03/0010), and Instituto de Salud Carlos III (ISCIII), Santiago de Compostela, Spain; 2 Service of Diabetes, Endocrinology and Nutrition (UDEN), Institut d’Investigacio ´ Biome `dica de Girona (IdIBGi), Hospital ‘‘Dr Josep Trueta’’ of Girona, Girona, Spain; 3 Service of Endocrinology and Nutrition, Hospital Clı ´nico Universitario Virgen de Victoria de Ma ´laga, Ma ´ laga, Spain; 4 INSERM Unite ´ 858, Institut de Me ´decine Mole ´ culaire de Rangueil, Universite ´ Paul Sabatier, IFR31, Toulouse, France; 5 Department of Surgery, Institut d’Investigacio ´ Biome ` dica de Girona (IdIBGi), Girona, Spain; 6 Department of Endocrinology & Nutrition, Clı ´nica Universidad de Navarra–CIBERobn CBO6/03/1014, Pamplona, Spain and 7 Institute of Internal Medicine, Catholic University of Rome, Rome, Italy. Correspondence: Dr JM Ferna ´ndez-Real or Dr FJ Ortega, Service of Diabetes, Endocrinology and Nutrition (UDEN), Institut d’Investigacio ´ Biome ` dica de Girona (IdIBGi), Hospital ‘‘Dr Josep Trueta’’ of Girona, Carretera de Franc ¸a s/n, Girona 17007, Spain. E-mail: jmfreal@idibgi.org or fortega@idibgi.org Received 21 March 2013; revised 2 July 2013; accepted 5 August 2013; accepted article preview online 3 September 2013; advance online publication, 1 October 2013 International Journal of Obesity (2014) 38, 737–745 & 2014 Macmillan Publishers Limited All rights reserved 0307-0565/14 www.nature.com/ijo