Epidemiological studies report that overweight or obese asthmatic subjects have more severe disease than those of a healthy weight. We postulated that accumulation of adipose tissue within the airway wall may occur in overweight patients and contribute to airway pathology. Our aim was to determine the relationship between adipose tissue within the airway wall and body mass index (BMI) in individuals with and without asthma.Transverse airway sections were sampled in a stratified manner frompost mortemlungs of control subjects (n=15) and cases of nonfatal (n=21) and fatal (n=16) asthma. The relationship between airway adipose tissue, remodelling and inflammation was assessed. The areas of the airway wall and adipose tissue were estimated by point count and expressed as area per mm of basement membrane perimeter (Pbm). The number of eosinophils and neutrophils were expressed as area densities.BMI ranged from 15 to 45 kg·m⁻²and was greater in nonfatal asthma cases (p6 mm), but was rarely seen in small airways (Pbm 12 mm, p6 mm, p=0.04).These data show that adipose tissue is present within the airway wall and is related to BMI, wall thickness and the number of inflammatory cells. Therefore, the accumulation of airway adipose tissue in overweight individuals may contribute to airway pathophysiology.

Non‐Technical Summary  Cardiovascular disease is responsible for 30% of deaths worldwide and epidemiological data demonstrate that poor growth before birth is associated with an increased risk of heart disease in adult life. We show that in response to reduced placental substrate supply there is an increase in cardiac insulin‐like growth factor‐2 (IGF‐2) and the IGF‐2 receptor (IGF‐2R) in the fetus. Importantly, this effect is programmed because it is also present after birth in the lamb at 21 days of age. We also show that the increase in IGF‐2 and IGF‐2R gene expression is not epigenetically regulated through the IGF‐2/H19 or IGF‐2R methylation process. This study places the IGF‐2 receptor signalling pathway as a prime candidate for mediating cardiac hypertrophy in fetal growth restriction before and after birth.

Key points: This study investigates the impact that insulin‐like growth factor 2 receptor (IGF‐2R) activation has on the fetal heart, by infusing Leu²⁷IGF‐2 into the left circumflex coronary artery of the sheep fetus, to specifically activate IGF‐2R and it's downstream signalling pathway. Activation of cardiac IGF‐2R resulted in cardiomyocyte hypertrophy, but with no changes in heart weight, cardiomyocyte proliferation, binucleation or apoptosis. This hypertrophy was mediated via protein kinase A activation. Infusion of Leu²⁷IGF‐2 increases atrial natriuretic peptide abundance, a marker of cardiac pathological hypertrophy. Cardiac IGF‐2R activation may alter important regulators of cardiac contractility and relaxation by decreasing sarcoplasmic reticulum Ca²⁺‐ATPase and phospho‐troponin I abundance. This study places the interaction between the IGF‐2R and Gαs signalling pathway as a potential mechanism that can contribute to cardiomyocyte growth in fetal life, but which may result in pathological cardiac hypertrophy in postnatal life. Abstract In vitro studies using rat and fetal sheep cardiomyocytes indicate that, in addition to its role as a clearance receptor, the insulin‐like growth factor 2 receptor (IGF‐2R) can induce cardiomyocyte hypertrophy. In the present study, we have determined the effect of specific activation of the IGF‐2R in the heart of the late gestation fetus on cardiomyocyte development. Leu²⁷IGF‐2, an IGF‐2R agonist, was infused into the fetal left circumflex coronary artery for 4 days beginning at 128.1 ± 0.4 days gestation. Ewes were humanely killed at 132.2 ± 1.2 days gestation (term, 150 days). Fetuses were delivered and hearts dissected to isolate the cardiomyocytes and to collect and snap‐freeze tissue. Leu²⁷IGF‐2 infusion into the left circumflex coronary artery of fetal sheep increased the area of binucleated cardiomyocytes in the left, but not the right, ventricle. However, this infusion of Leu²⁷IGF‐2 did not change fetal weight, heart weight, blood pressure, blood gases or cardiomyocyte proliferation/binucleation. The increase in cardiomyocyte size in the Leu²⁷IGF‐2‐infused group was associated with increased expression of proteins in the Gαs, but not the Gαq, signalling pathway. We concluded that infusion of Leu²⁷IGF‐2 into the left circumflex coronary artery causes cardiac IGF‐2R activation in the left ventricle of the heart, and this stimulates cardiomyocyte hypertrophy in a Gαs‐dependent manner.

The cardiac insulin-like growth factor 2 receptor (IGF-2R) can induce cardiomyocyte hypertrophy in a heterotrimeric G protein receptor-coupled manner involving αq (G_αq) or αs (G_αs). We have previously shown increased left ventricular weight and cardiac IGF-2 and IGF-2R gene expression in low-birth-weight (LBW) compared with average-birth-weight (ABW) lambs. Here, we have investigated the cardiac expression of IGF-2 gene variants, the degree of histone acetylation, and the abundance of proteins in the IGF-2R downstream signaling pathway in ABW and LBW lambs. Samples from the left ventricle of ABW and LBW lambs were collected at 21 days of age. There was increased phospho-CaMKII protein with decreased HDAC 4 abundance in the LBW compared with ABW lambs. There was increased GATA 4 and decreased phospho-troponin I abundance in LBW compared with ABW lambs, which are markers of pathological cardiac hypertrophy and impaired or reduced contractility, respectively. There was increased histone acetylation of H3K9 at IGF-2R promoter and IGF-2R intron 2 differentially methylated region in the LBW lamb. In conclusion, histone acetylation of IGF-2R may lead to increased IGF-2R mRNA expression and subsequently mediate G_αqsignaling early in life via CaMKII, resulting in an increased risk of left ventricular hypertrophy and cardiovascular disease in adult life.