Effects of fetal exposure to high-fat diet or maternal hyperglycemia on L-arginine and nitric oxide metabolism in lung

H Grasemann,J Starschinova,R Herrmann,C Grasemann,M Gertsen,M R Palmert

doi:10.1038/nutd.2016.56

Abstract

Background/Objectives:Alterations in the L-arginine/nitric oxide (NO) metabolism contribute to diseases such as obesity, metabolic syndrome and airway dysfunction. The impact of early-life exposures on the L-arginine/NO metabolism in lung later in life is not well understood. The objective of this work was to study the effects of intrauterine exposures to maternal hyperglycemia and high-fat diet (HFD) on pulmonary L-arginine/NO metabolism in mice.Methods:We used two murine models of intrauterine exposures to maternal (a) hyperglycemia and (b) HFD to study the effects of these exposures on the L-arginine/NO metabolism in lung in normal chow-fed offspring.Results:Both intrauterine exposures resulted in NO deficiency in the lung of the offspring at 6 weeks of age. However, each of the exposures leading to different metabolic phenotypes caused a distinct alteration in the L-arginine/NO metabolism. Maternal hyperglycemia leading to impaired glucose tolerance but no obesity in the offspring resulted in increased levels of asymmetric dimethylarginine and impairment of NO synthases. Although maternal HFD led to obesity without impairment in glucose tolerance in the offspring, it resulted in increased expression and activity of arginase in the lung of the normal chow-fed offspring.Conclusions:These data suggest that maternal hyperglycemia and HFD can cause alterations in the pulmonary L-arginine/NO metabolism in offspring.

Highlights

Nitric oxide (NO) and NO metabolites are messenger molecules that are involved in a number of physiological and pathophysiological conditions, including obesity and metabolic syndrome.[1]
While nitrate plus nitrite was significantly reduced in the lungs of both high-fat diet (HFD) and Akita offspring at 6 weeks of age, the two intrauterine exposures resulted in distinct effects on the pulmonary L-arginine and asymmetric dimethylarginine (ADMA) metabolism in the offspring
There was a 1.6-fold increase in the lung expression of arginase 1 (P = 0.03) but not arginase 2, as measured by rtPCR, and increased (P = 0.0337, n = 5 vs 5/group) total arginase activity, as measured by an in vitro assay,[14] in the lungs of 6-weeks-old HFD offspring compared with control (Figure 2b)

Summary

Introduction

Nitric oxide (NO) and NO metabolites are messenger molecules that are involved in a number of physiological and pathophysiological conditions, including obesity and metabolic syndrome.[1] NO is the product of NO synthases (NOSs), which form NO and L-citrulline from the semi-essential amino acid L-arginine. All three isoforms of NOS are expressed in the human lung, but differ in their regulation and NO production. The availability of L-arginine for NOS is in part regulated by the enzyme arginase, which catalyzes the hydrolysis of L-arginine to urea and L-ornithine. Arginase exists in two isoforms, arginase 1 and arginase 2. Both are expressed in multiple tissues, including the lung.[2] NO production from NOS can be limited by presence of asymmetric dimethylarginine (ADMA), a product of protein degradation that acts as an NOS inhibitor. Increased ADMA was recently found in obesity, insulin resistance and Type 2 diabetes[3,4] and in asthma.[5,6,7,8]

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