Elisa Principi1,2, Ambra Buschiazzo2,3, Andrea Papait1,2, Patrizio Castagnola2, Delfina Costa2, Roberta Pece1,2, Irena Maric1, Mara Scussolini4, Cecilia Marini5, Gianmario Sambuceti2,3, Felice Strollo6, Sara Tavella7,8. 1. Dipartimento di Medicina Sperimentale, Università degli Studi di Genova, Genova, Italy. 2. IRCCS Ospedale Policlinico San Martino, Genova, Italy. 3. Dipartimento di Scienze della Salute, Università degli Studi di Genova, Genova, Italy. 4. Dipartimento di Matematica, Università degli Studi di Genova, Genova, Italy. 5. CNR Istituto di Bioimmagini e Fisiologia Molecolare, Milano, Italy. 6. Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy. 7. Dipartimento di Medicina Sperimentale, Università degli Studi di Genova, Genova, Italy. sara.tavella@unige.it. 8. IRCCS Ospedale Policlinico San Martino, Genova, Italy. sara.tavella@unige.it.
Abstract
BACKGROUND: Lipocalin-2 (LCN2) is widely expressed in the organism with pleiotropic roles. In particular, its overexpression correlates with tissue stress conditions including inflammation, metabolic disorders, chronic diseases and cancer. OBJECTIVES: To assess the effects of systemic LCN2 overexpression on adipose tissue and glucose metabolism. SUBJECTS: Eighteen-month-old transgenic mice with systemic LCN2 overexpression (LCN2-Tg) and age/sex-matched wild-type mice. METHODS: Metabolic cages; histology and real-time PCR analysis; glucose and insulin tolerance tests; ELISA; flow cytometry; microPET and serum analysis. RESULTS: LCN2-Tg mice were smaller compared to controls but they ate (P = 0.0156) and drank (P = 0.0057) more and displayed a higher amount of visceral adipose tissue. Furthermore, LCN2-Tg mice with body weight ≥20 g showed adipocytes with a higher cell area (P < 0.0001) and altered expression of genes involved in adipocyte differentiation and inflammation. In particular, mRNA levels of adipocyte-derived Pparg (P ≤ 0.0001), Srebf1 (P < 0.0001), Fabp4 (P = 0.056), Tnfa (P = 0.0391), Il6 (P = 0.0198), and Lep (P = 0.0003) were all increased. Furthermore, LCN2-Tg mice displayed a decreased amount of basal serum insulin (P = 0.0122) and a statistically significant impaired glucose tolerance and insulin sensitivity consistent with Slc2a2 mRNA (P ≤ 0.0001) downregulated expression. On the other hand, Insr mRNA (P ≤ 0.0001) was upregulated and correlated with microPET analysis that demonstrated a trend in reduced whole-body glucose consumption and MRGlu in the muscles and a significantly reduced MRGlu in brown adipose tissue (P = 0.0247). Nevertheless, an almost nine-fold acceleration of hexokinase activity was observed in the LCN2-Tg mice liver compared to controls (P = 0.0027). Moreover, AST and ALT were increased (P = 0.0421 and P = 0.0403, respectively), which indicated liver involvement also demonstrated by histological staining. CONCLUSIONS: We show that LCN2 profoundly impacts adipose tissue size and function and glucose metabolism, suggesting that LCN2 should be considered as a risk factor in ageing for metabolic disorders leading to obesity.
BACKGROUND:Lipocalin-2 (LCN2) is widely expressed in the organism with pleiotropic roles. In particular, its overexpression correlates with tissue stress conditions including inflammation, metabolic disorders, chronic diseases and cancer. OBJECTIVES: To assess the effects of systemic LCN2 overexpression on adipose tissue and glucose metabolism. SUBJECTS: Eighteen-month-old transgenic mice with systemic LCN2 overexpression (LCN2-Tg) and age/sex-matched wild-type mice. METHODS: Metabolic cages; histology and real-time PCR analysis; glucose and insulin tolerance tests; ELISA; flow cytometry; microPET and serum analysis. RESULTS:LCN2-Tg mice were smaller compared to controls but they ate (P = 0.0156) and drank (P = 0.0057) more and displayed a higher amount of visceral adipose tissue. Furthermore, LCN2-Tg mice with body weight ≥20 g showed adipocytes with a higher cell area (P < 0.0001) and altered expression of genes involved in adipocyte differentiation and inflammation. In particular, mRNA levels of adipocyte-derived Pparg (P ≤ 0.0001), Srebf1 (P < 0.0001), Fabp4 (P = 0.056), Tnfa (P = 0.0391), Il6 (P = 0.0198), and Lep (P = 0.0003) were all increased. Furthermore, LCN2-Tg mice displayed a decreased amount of basal serum insulin (P = 0.0122) and a statistically significant impaired glucose tolerance and insulin sensitivity consistent with Slc2a2 mRNA (P ≤ 0.0001) downregulated expression. On the other hand, Insr mRNA (P ≤ 0.0001) was upregulated and correlated with microPET analysis that demonstrated a trend in reduced whole-body glucose consumption and MRGlu in the muscles and a significantly reduced MRGlu in brown adipose tissue (P = 0.0247). Nevertheless, an almost nine-fold acceleration of hexokinase activity was observed in the LCN2-Tg mice liver compared to controls (P = 0.0027). Moreover, AST and ALT were increased (P = 0.0421 and P = 0.0403, respectively), which indicated liver involvement also demonstrated by histological staining. CONCLUSIONS: We show that LCN2 profoundly impacts adipose tissue size and function and glucose metabolism, suggesting that LCN2 should be considered as a risk factor in ageing for metabolic disorders leading to obesity.
Authors: Daniel Ferguson; Irina Hutson; Eric Tycksen; Terri A Pietka; Kevin Bauerle; Charles A Harris Journal: Endocrinology Date: 2020-02-01 Impact factor: 4.736