Catch-up growth in juvenile rats, fat expansion, and dysregulation of visceral adipose tissue

Abstract

A prime concern of young patients with Polycystic Ovary Syndrome (PCOS) is the control of body adiposity, given their tendency to gain weight and/or their difficulty to lose weight. Circulating growth-and-differentiation factor-15 (GDF15) facilitates the control of body weight via receptors in the brainstem. C-reactive protein (CRP) and insulin are endogenous GDF15 secretagogues. We hypothesised that PCOS in non-obese adolescents is characterised by low concentrations of circulating GDF15, when judged by the degree of CRP and insulin drive. GDF15 was added as a posthoc endpoint of two previously reported, randomised studies in non-obese adolescent girls with PCOS (N = 58; 60% normal weight; 40% overweight) who received either an oral oestroprogestogen contraceptive (OC), or a low-dose combination of spironolactone-pioglitazone-metformin (SPIOMET) for 1 year; subsequently, all girls remained untreated for 1 year. Adolescent girls with regular menses (N = 20) served as healthy controls. Circulating GDF15, CRP and fasting insulin were assessed prior to treatment, and halfway the on-and post-treatment years. Pre-treatment, the absolute GDF15 concentrations were normal in PCOS girls, but their relative levels were markedly low, in view of the augmented CRP and insulin drives. OC treatment was accompanied by a near-doubling of circulating GDF15 (on average, from 296 to 507 pg/mL) and CRP, so that the relative GDF15 levels remained low. SPIOMET treatment was accompanied by a 3.4-fold rise of circulating GDF15 (on average, from 308 to 1045 pg/mL) and by a concomitant lowering of CRP and insulin concentrations towards normal, so that the relative GDF15 levels became markedly abundant. Post-OC, the relatively low GDF15 levels persisted; post-SPIOMET, the circulating concentrations of GDF15, CRP and insulin were all normal. BMI remained stable in both treatment groups. Only SPIOMET was accompanied by a reduction of hepato-visceral fat (by MRI) towards normal. In conclusion, early PCOS was found to be characterised by a relative GDF15 deficit that may partly explain the difficulties that young patients experience to control their body adiposity. This relative GDF15 deficit persisted during and after OC treatment. In contrast, SPIOMET treatment was accompanied by an absolute and a relative abundance of GDF15, and followed by normal GDF15, CRP and insulin concentrations. The present findings strengthen the rationale to raise the concentrations of circulating GDF15 in early PCOS, for example with a SPIOMETlike intervention that attenuates low-grade inflammation, insulin resistance and ectopic adiposity, without necessarily lowering body weight. Clinical trial registries: ISRCTN29234515 and ISRCTN11062950.

Implication of RAS in Postnatal Cardiac Remodeling, Fibrosis and Dysfunction Induced by Fetal Undernutrition

“…In addition to the classical axis formed by ACE, accumulating evidence has revealed a new axis, implicating ACE type 2 (ACE2). ACE produces several peptides such as Ang- (1)(2)(3)(4)(5)(6)(7)(8)(9), derived from Ang I, alamandine, derived from Ang A and Ang 1(1-7), derived from Ang II or from Ang- (1)(2)(3)(4)(5)(6)(7)(8)(9), the latter through the enzymatic activity of ACE or neutral endopeptidase (NEP). In turn, Ang-(1-7) can interact with MasR and Alamandine with MrgD receptors, exerting vasorelaxant, antiproliferative and antifibrotic actions [14], but also exerting a pivotal role in balancing the vasoconstrictor, proliferative and fibrotic actions of Ang II through AT1 receptors [15,16].…”

“…Studies in LBW children have demonstrated that catch-up growth increases the risk of developing cardio-metabolic diseases later in life [ 5 , 6 , 7 ]. In experimental animal models, there is also evidence that catch-up growth during lactation has deleterious consequences, leading to adipose tissue accumulation [ 8 , 9 ]. In a rat model of fetal programming induced by undernutrition (MUN rat), we have observed that catch-up growth also affects cardiovascular organs; male rats exposed to undernutrition are born with a smaller aorta, which is enlarged during lactation [ 10 ].…”

Effect of transgenerational diabetes via maternal lineage in female rats

“…The present study demonstrated that F2_D rats showed abnormal body weight in adulthood. Regardless of whether the newborn is classified as small (SGA) or large (LGA) for gestational age, consequences occur in adult life due to abnormal growth to compensate for the birth weight [ 19 ]. Sinzato et al [ 11 ] showed that female F2_D rats were born SGA.…”

“…The short-term benefits of rapid and accelerated growth are resistance to infections and childhood survival [ 21 ]. However, intrauterine restriction-induced catch-up growth in rats increases the adipocyte size in the retroperitoneal muscle, which increases the levels of circulating triglycerides and HOMA-IR, indicating the effect of catch-up growth on fat accumulation and abnormal metabolism [ 19 , 22 ].…”

Comparative Analysis of Gene Expression Profiles in the Adipose Tissue of Obese Adult Mice With Rapid Infantile Growth After Undernourishment In Utero

“…the NN-Veh, NN-TU, UN-RG-Veh, and UN-RG-TU groups, but not a NN-RG-Veh or NN-RG-TU group because of the restrictions of our animal facility accommodation. It is noted that Lizarraga-Mollinedo reported that different growth speed in the pups with undernourishment in utero showed conflicting levels of gene expression patterns in adipose tissue compared to normally nourished pups by using rat animal model ( 44 ). We did not investigate a condition without HFD due to the same animal facility limitation.…”