*Article* **Slower Growth during Lactation Rescues Early Cardiovascular and Adipose Tissue Hypertrophy Induced by Fetal Undernutrition in Rats**

**Pilar Rodríguez-Rodríguez 1,2, Ignacio Monedero-Cobeta 1,2, David Ramiro-Cortijo 1,2, Sophida Puthong 3, Begoña Quintana-Villamandos 4, Alicia Gil-Ramírez 2,5, Silvia Cañas 2,5, Santiago Ruvira 1,2 and Silvia M. Arribas 1,2,\***

	- Madrid, Ciudad Universitaria de Cantoblanco, 28049 Madrid, Spain

**Citation:** Rodríguez-Rodríguez, P.; Monedero-Cobeta, I.; Ramiro-Cortijo, D.; Puthong, S.; Quintana-Villamandos, B.; Gil-Ramírez, A.; Cañas, S.; Ruvira, S.; Arribas, S.M. Slower Growth during Lactation Rescues Early Cardiovascular and Adipose Tissue Hypertrophy Induced by Fetal Undernutrition in Rats. *Biomedicines* **2022**, *10*, 2504. https://doi.org/10.3390/ biomedicines10102504

Academic Editors: Josef Zicha and Ivana Vanˇeˇcková

Received: 11 August 2022 Accepted: 5 October 2022 Published: 7 October 2022

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**Abstract:** Low birth weight (LBW) and accelerated growth during lactation are associated with cardiometabolic disease development. LBW offspring from rats exposed to undernutrition during gestation (MUN) develops hypertension. In this rat model, we tested if slower postnatal growth improves early cardiometabolic alterations. MUN dams were fed *ad libitum* during gestation days 1–10, with 50% of the daily intake during days 11–21 and *ad libitum* during lactation. Control dams were always fed *ad libitum.* Pups were maintained with their own mother or cross-fostered. Body weight and length were recorded weekly, and breastmilk was obtained. At weaning, the heart was evaluated by echocardiography, and aorta structure and adipocytes in white perivascular fat were studied by confocal microscopy (size, % beige-adipocytes by Mitotracker staining). Breastmilk protein and fat content were not significantly different between groups. Compared to controls, MUN males significantly accelerated body weight gain during the exclusive lactation period (days 1–14) while females accelerated during the last week; length growth was slower in MUN rats from both sexes. By weaning, MUN males, but not females, showed reduced diastolic function and hypertrophy in the heart, aorta, and adipocytes; the percentage of beige-type adipocytes was smaller in MUN males and females. Fostering MUN offspring on control dams significantly reduced weight gain rate, cardiovascular, and fat hypertrophy, increasing beige-adipocyte proportion. Control offspring nursed by MUN mothers reduced body growth gain, without cardiovascular modifications. In conclusion, slower growth during lactation can rescue early cardiovascular alterations induced by fetal undernutrition. Exclusive lactation was a key period, despite no modifications in breastmilk macronutrients, suggesting the role of bioactive components. Our data support that lactation is a key period to counteract cardiometabolic disease programming in LBW and a potential intervention window for the mother.

**Keywords:** fetal undernutrition programming; cross-fostering; lactation period; cardiovascular hypertrophy; adipose tissue browning
