1 Scientific RepoRts | 5:13717 | DOi: 10.1038/srep13717 www.nature.com/scientificreports Fibroblast growth factor 21 in breast milk controls neonatal intestine function Aleix Gavaldà-Navarro 1,2 , elayne Hondares 1,2 , Marta Giralt 1,2 , teresa Mampel 1,2 , Roser Iglesias 1,2 & Francesc Villarroya 1,2 FGF21 is a hormonal factor with important functions in the control of metabolism. FGF21 is found in rodent and human milk. Radiolabeled FGF21 administered to lactating dams accumulates in milk and is transferred to neonatal gut. the small intestine of neonatal (but not adult) mice highly expresses β-Klotho in the luminal area. FGF21-Ko pups fed by FGF21-Ko dams showed decreased expression and circulating levels of incretins (GIp and GLp-1), reduced gene expression of intestinal lactase and maltase-glucoamylase, and low levels of galactose in plasma, all associated with a mild decrease in body weight. When FGF21-Ko pups were nursed by wild-type dams (expressing FGF21 in milk), intestinal peptides and digestive enzymes were up-regulated, lactase enzymatic activity was induced, and galactose levels and body weight were normalized. Neonatal intestine explants were sensitive to FGF21, as evidenced by enhanced eRK1/2 phosphorylation. oral infusion of FGF21 into neonatal pups induced expression of intestinal hormone factors and digestive enzymes, lactase activity and lactose absorption. These fndings reveal a novel role of FGF21 as a hormonal factor contributing to neonatal intestinal function via its presence in maternal milk. Appropriate signaling of FGF21 to neonate is necessary to ensure optimal digestive and endocrine function in developing intestine. Milk, which is the essential source of nutrition for mammalian neonates provides major nutrients, vita- mins, minerals and water, as well as numerous biologically active molecules, including growth factors, hormones and adipokines 1–3 . Tese biological active factors play important roles in maintaining neonatal homeostasis and supporting proper neonatal development. Some of these factors, such as leptin and adiponectin, are absorbed from the lumen of the gut into the neonatal circulation 4 . Leptin in breast milk is known to be involved in the control of energy balance during the post-natal period 5 . Other fac- tors present in milk are believed to function in protecting the gut; for example epidermal growth factor present in milk facilitates the development of essential digestive functions and regulates the maturation of the gastrointestinal tract 2,6 . Te identifcation of the biologically active factors in milk should help improve our understanding and management of optimal nutrition strategies for childhood development. Te enteral nutrition of intestinally immature neonates relies on breast milk because of unique properties and composition of milk 7 . Nutrition in early childhood has been implicated in the long-term tendencies towards obesity and metabolic syndrome, and epidemiological data indicate that breastfeeding protects against such met- abolic alterations in later life 3 . It is considered that these protective efects may involve the efects of bioactive compounds found in breast milk. Fibroblast growth factor 21 (FGF21) is a hormonal factor that plays important roles in controlling glu- cose homeostasis and energy metabolism 8 . In adults, FGF21 is produced mainly in the liver; it favors glu- cose uptake by peripheral tissues, and thus possesses anti-diabetic properties 9 . FGF21 is also expressed in 1 Departament de Bioquimica i Biologia Molecular, institute of Biomedicine (iBUB), University of Barcelona, Av Diagonal 643, 08028 Barcelona, catalonia, Spain. 2 ciBeR fisiopatologia de la Obesidad y nutrición, Av Diagonal 643, 08028 Barcelona, catalonia, Spain. correspondence and requests for materials should be addressed to f.V. (email: fvillarroya@ub.edu) Received: 08 february 2015 Accepted: 21 July 2015 Published: 02 September 2015 opeN