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

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.

Patterns of amiodarone-induced thyroid dysfunction in infants and children.

BACKGROUND: Heart Rhythm Society guidelines recommend obtaining thyroid function tests (TFTs) at amiodarone initiation and every 6 months thereafter in adults, with no specific pediatric recommendations. Untreated hypothyroidism in young children negatively affects brain development and somatic growth, yet the optimal screening frequency for pediatric patients remains unclear, and limited data exist on pediatric amiodarone-induced thyroid dysfunction. OBJECTIVE: The purpose of this study was to describe the patterns of amiodarone-induced thyroid dysfunction in pediatric patients. METHODS: We established a retrospective cohort of 527 pediatric patients who received amiodarone between 1997 and 2017. We defined amiodarone therapy lasting 3-30 days as "short term" and >30 days as "long term." RESULTS: The final cohort (n = 150) consisted of 27 neonates (18%), 25 infants (16%), 27 young children (18%), and 71 children (47%). Of the children in whom TFTs were checked, half (50.8%) developed a thyroid-stimulating hormone (TSH) value above the reference for age. Neonates had the highest median peak TSH values in both short- and long-term groups: 23.5 mIU/L (interquartile range 11.4-63.1) and 28.8 mIU/L (interquartile range 11.4-34.4), respectively. Although concurrent use of inotropic support was significantly associated with lower initial TSH values, no variable related to cardiac illness or type of heart disease was associated with peak TSH values. CONCLUSION: Neonates and infants receiving amiodarone had more thyroid dysfunction with greater degrees of TSH elevation than older children. TSH elevations occurred early, even with short-term exposure. Given the concern for brain development and growth in hypothyroid children, our results suggest the need for more rigorous pediatric-specific thyroid monitoring guidelines.