Rikke Hjortebjerg1, Darlene E Berryman2, Ross Comisford3, Edward O List4, Claus Oxvig5, Mette Bjerre6, Jan Frystyk7, John J Kopchick8. 1. Medical Research Laboratory, Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark; Danish Diabetes Academy, Odense, Denmark; Edison Biotechnology Institute, Ohio University, Athens, OH 45701, USA. Electronic address: rikke.hjortebjerg@clin.au.dk. 2. Edison Biotechnology Institute, Ohio University, Athens, OH 45701, USA; Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA; The Diabetes Institute, Ohio University, Athens, OH 45701, USA. Electronic address: berrymad@ohio.edu. 3. Edison Biotechnology Institute, Ohio University, Athens, OH 45701, USA; The Diabetes Institute, Ohio University, Athens, OH 45701, USA. Electronic address: ross.comisford@osumc.edu. 4. Edison Biotechnology Institute, Ohio University, Athens, OH 45701, USA; The Diabetes Institute, Ohio University, Athens, OH 45701, USA. Electronic address: list@ohio.edu. 5. Department of Molecular Biology and Genetics, Faculty of Science and Technology, Aarhus University, Aarhus, Denmark. Electronic address: co@mbg.au.dk. 6. Medical Research Laboratory, Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark. Electronic address: mette.bjerre@clin.au.dk. 7. Medical Research Laboratory, Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark; Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark. Electronic address: frystyk@clin.au.dk. 8. Edison Biotechnology Institute, Ohio University, Athens, OH 45701, USA; Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA; The Diabetes Institute, Ohio University, Athens, OH 45701, USA. Electronic address: kopchick@ohio.edu.
Abstract
INTRODUCTION: Pregnancy-associated plasma protein-A (PAPP-A) stimulates insulin-like growth factor (IGF)-I action through proteolytic cleavage of IGF binding protein-4 (IGFBP-4). Recently, stanniocalcin-2 (STC2) was discovered as an inhibitor of PAPP-A. Most members of the IGF system are expressed in adipose tissue (AT), but there is a relative paucity of information on the distribution of IGFBP-4, PAPP-A, and STC2 in different AT depots. Since IGF-I expression in AT is highly GH-dependent, we used bovine GH transgenic (bGH) and GH receptor knockout (GHR-/-) mice to investigate AT depot-specific expression patterns of IGFBP-4, PAPP-A, and STC2, and whether the regulation is GH-dependent. METHODS: Seven-month-old male bGH, GHR-/- and wild type (WT) control mice were used. Body composition was determined, and subcutaneous, epididymal, retroperitoneal, mesenteric and brown adipose tissue (BAT) depots were collected. RNA expression of Igfbp4, Pappa, and Stc2 was assessed by reverse transcription quantitative PCR and IGFBP-4 protein by Western blotting. RESULTS: Igfbp4, Pappa, and Stc2 RNA levels were differentially expressed in an AT depot-dependent manner in WT mice. Igfbp4 RNA levels were significantly higher in all white AT depots than in BAT. Pappa was most highly expressed in the mesenteric depot: levels were 7.5-fold higher in mesenteric than in subcutaneous AT (p < .001). Although intraabdominal in origin, epididymal and retroperitoneal Pappa expression levels were 69% and 68% lower, respectively, as compared to mesenteric levels (p < .001). Stc2 RNA expression was significantly higher in all intraabdominal white AT as compared to subcutaneous AT and BAT; levels in epididymal, retroperitoneal, and mesenteric were all more than three-fold higher than in subcutaneous AT (p < .001) and 12-fold higher than in BAT (p < .001). Gene expression patterns in bGH and GHR-/- mice mimicked those in WT mice, suggesting that GH does not affect the transcription of the STC2-PAPP-A-IGFBP-4-axis in AT. However, proteins levels of intact IGFBP-4 were significantly increased in bGH mice and decreased in GHR-/- mice, whereas the PAPP-A-generated IGFBP-4 fragment level was unaltered. CONCLUSION: Expression of Igfbp4, Pappa, and Stc2 differ between AT depots and is generally higher in white AT than in BAT. The transcription appears to occur in a GH-independent manner, whereas IGFBP-4 protein levels are highly influenced by altered GH activity.
INTRODUCTION:Pregnancy-associated plasma protein-A (PAPP-A) stimulates insulin-like growth factor (IGF)-I action through proteolytic cleavage of IGF binding protein-4 (IGFBP-4). Recently, stanniocalcin-2 (STC2) was discovered as an inhibitor of PAPP-A. Most members of the IGF system are expressed in adipose tissue (AT), but there is a relative paucity of information on the distribution of IGFBP-4, PAPP-A, and STC2 in different AT depots. Since IGF-I expression in AT is highly GH-dependent, we used bovine GH transgenic (bGH) and GH receptor knockout (GHR-/-) mice to investigate AT depot-specific expression patterns of IGFBP-4, PAPP-A, and STC2, and whether the regulation is GH-dependent. METHODS: Seven-month-old male bGH, GHR-/- and wild type (WT) control mice were used. Body composition was determined, and subcutaneous, epididymal, retroperitoneal, mesenteric and brown adipose tissue (BAT) depots were collected. RNA expression of Igfbp4, Pappa, and Stc2 was assessed by reverse transcription quantitative PCR and IGFBP-4 protein by Western blotting. RESULTS:Igfbp4, Pappa, and Stc2 RNA levels were differentially expressed in an AT depot-dependent manner in WT mice. Igfbp4 RNA levels were significantly higher in all white AT depots than in BAT. Pappa was most highly expressed in the mesenteric depot: levels were 7.5-fold higher in mesenteric than in subcutaneous AT (p < .001). Although intraabdominal in origin, epididymal and retroperitoneal Pappa expression levels were 69% and 68% lower, respectively, as compared to mesenteric levels (p < .001). Stc2 RNA expression was significantly higher in all intraabdominal white AT as compared to subcutaneous AT and BAT; levels in epididymal, retroperitoneal, and mesenteric were all more than three-fold higher than in subcutaneous AT (p < .001) and 12-fold higher than in BAT (p < .001). Gene expression patterns in bGH and GHR-/- mice mimicked those in WT mice, suggesting that GH does not affect the transcription of the STC2-PAPP-A-IGFBP-4-axis in AT. However, proteins levels of intact IGFBP-4 were significantly increased in bGH mice and decreased in GHR-/- mice, whereas the PAPP-A-generated IGFBP-4 fragment level was unaltered. CONCLUSION: Expression of Igfbp4, Pappa, and Stc2 differ between AT depots and is generally higher in white AT than in BAT. The transcription appears to occur in a GH-independent manner, whereas IGFBP-4 protein levels are highly influenced by altered GH activity.
Authors: Yanrong Qian; Darlene E Berryman; Reetobrata Basu; Edward O List; Shigeru Okada; Jonathan A Young; Elizabeth A Jensen; Stephen R C Bell; Prateek Kulkarni; Silvana Duran-Ortiz; Patricia Mora-Criollo; Samuel C Mathes; Alison L Brittain; Mat Buchman; Emily Davis; Kevin R Funk; Jolie Bogart; Diego Ibarra; Isaac Mendez-Gibson; Julie Slyby; Joseph Terry; John J Kopchick Journal: Pituitary Date: 2021-11-19 Impact factor: 4.107
Authors: Raziel Rojas-Rodriguez; Rachel Ziegler; Tiffany DeSouza; Sana Majid; Aylin S Madore; Nili Amir; Veronica A Pace; Daniel Nachreiner; David Alfego; Jomol Mathew; Katherine Leung; Tiffany A Moore Simas; Silvia Corvera Journal: Sci Transl Med Date: 2020-11-25 Impact factor: 17.956
Authors: Marisol Castillo-Castrejon; Ivana V Yang; Elizabeth J Davidson; Sarah J Borengasser; Purevsuren Jambal; Jamie Westcott; Jennifer F Kemp; Ana Garces; Sumera A Ali; Sarah Saleem; Robert L Goldenberg; Lester Figueroa; K Michael Hambidge; Nancy F Krebs; Theresa L Powell Journal: J Nutr Date: 2021-03-11 Impact factor: 4.798
Authors: Daniela Ohde; Michael Walz; Christina Walz; Antonia Noce; Julia Brenmoehl; Martina Langhammer; Andreas Hoeflich Journal: Cells Date: 2020-09-26 Impact factor: 6.600
Authors: Vicente Barrios; Julie A Chowen; Álvaro Martín-Rivada; Santiago Guerra-Cantera; Jesús Pozo; Shoshana Yakar; Ron G Rosenfeld; Luis A Pérez-Jurado; Juan Suárez; Jesús Argente Journal: Cells Date: 2021-12-18 Impact factor: 6.600