Genetic and Pharmacological Inhibition of PAPP-A Protects Against Visceral Obesity in Mice.

Abstract

Pathogenicity of visceral adipose tissue (VAT) has been linked to the metabolic stress of enlarging mature adipocytes and a limited ability to recruit new adipocytes. One of the major distinguishing features of VAT preadipocytes is the high expression of the zinc metalloprotease, pregnancy-associated plasma protein-A (PAPP-A), when compared to subcutaneous adipose tissue (SAT). In this study we used 2 different approaches to investigate the effect of PAPP-A inhibition on different fat depots in mice on a high-fat diet (HFD) for 15 weeks. Conditional knockdown of PAPP-A gene expression in female adult mice resulted in significant decreases of 30% to 40% in adipocyte size in VAT (mesenteric and pericardial depots) compared to control mice. There was no effect on SAT (inguinal) or intra-abdominal perigonadal fat. Liver lipid was also significantly decreased without any effect on heart and skeletal muscle lipid. We found similar effects when using a pharmacological approach. Weekly injections of a specific immunoneutralizing monoclonal antibody (mAb-PA 1/41) or isotype control were given to male and female wild-type mice on HFD for 15 weeks. Adipocyte size was significantly decreased (30%-50%) only in VAT with mAb-PA 1/41 treatment. In this model, cell number was significantly increased in mesenteric fat in mice treated with mAb-PA 1/41, suggesting hyperplasia along with reduced hypertrophy in this VAT depot. Gene expression data indicated a significant decrease in F4/80 (macrophage marker) and interleukin-6 (proinflammatory cytokine) and a significant increase in adiponectin (anti-inflammatory adipokine with beneficial metabolic effects) in mesenteric fat compared to inguinal fat in mice treated with mAb-PA 1/41. Furthermore, there was significantly decreased liver lipid content with mAb-PA 1/41 treatment. Thus, using 2 different models systems we provide proof of principle that PAPP-A inhibition is a potential therapeutic target to prevent visceral obesity and its metabolic sequelae, such as fatty liver.

• Authors: Akhila Ramakrishna, Laurie K Bale, Sally A West, Cheryl A Conover
• Journal: Endocrinology (Endocrinology) Vol. 161 Issue 10 (10 01 2020) ISSN: 1945-7170 [Electronic] United States
• PMID: 32888014 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © Endocrine Society 2020. All rights reserved. For permissions, please e-mail: [email protected].

Chemical References

• Anti-Obesity Agents
• Antibodies, Monoclonal
• Pregnancy-Associated Plasma Protein-A

Topics

• Adipose Tissue (drug effects, metabolism, pathology)
• Animals
• Anti-Obesity Agents (pharmacology)
• Antibodies, Monoclonal (pharmacology)
• Diet, High-Fat (adverse effects)
• Female
• Gene Knockout Techniques
• Intra-Abdominal Fat (drug effects, metabolism)
• Lipid Metabolism (drug effects)
• Liver (drug effects, metabolism)
• Mice
• Mice, 129 Strain
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Obese
• Obesity, Abdominal (genetics, prevention & control)
• Pregnancy-Associated Plasma Protein-A (antagonists & inhibitors, genetics, immunology)
• Subcutaneous Fat (metabolism)