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Genetic and Pharmacological Inhibition of PAPP-A Protects Against Visceral Obesity in Mice
Journal article   Open access   Peer reviewed

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

Akhila Ramakrishna, Laurie K Bale, Sally A West and Cheryl A Conover
Endocrinology (Philadelphia), Vol.161(10), p.1
10/01/2020
DOI: 10.1210/endocr/bqaa160
PMCID: PMC7528556
PMID: 32888014
url
https://doi.org/10.1210/endocr/bqaa160View
Published (Version of record) Open Access

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

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