White Adipocyte Stem Cell Expansion Through Infant Formula Feeding: New Insights into Epigenetic Programming Explaining the Early Protein Hypothesis of Obesity

International Journal of Molecular Sciences, vol. 26, pp. 4493

Abstract

Prolonged breastfeeding (BF), as opposed to artificial infant formula feeding (FF), has been shown to prevent the development of obesity later in life. The aim of our narrative review is to investigate the missing molecular link between postnatal protein overfeeding—often referred to as the “early protein hypothesis”—and the subsequent transcriptional and epigenetic changes that accelerate the expansion of adipocyte stem cells (ASCs) in the adipose vascular niche during postnatal white adipose tissue (WAT) development. To achieve this, we conducted a search on the Web of Science, Google Scholar, and PubMed databases from 2000 to 2025 and reviewed 750 papers. Our findings revealed that the overactivation of mechanistic target of rapamycin complex 1 (mTORC1) and S6 kinase 1 (S6K1), which inhibits wingless (Wnt) signaling due to protein overfeeding, serves as the primary pathway promoting ASC commitment and increasing preadipocyte numbers. Moreover, excessive protein intake, combined with the upregulation of the fat mass and obesity-associated gene (FTO) and a deficiency of breast milk-derived microRNAs from lactation, disrupts the proper regulation of FTO and Wnt pathway components. This disruption enhances ASC expansion in WAT while inhibiting brown adipose tissue development. While BF has been shown to have protective effects against obesity, the postnatal transcriptional and epigenetic changes induced by excessive protein intake from FF may predispose infants to early and excessive ASC commitment in WAT, thereby increasing the risk of obesity later in life.

Authors 7

1. Bodo Clemens Melnik corresponding

   Osnabrück University

   Affiliation as printed

   Department of Dermatology, Environmental Medicine and Health Theory, University of Osnabrück, D-49076 Osnabrück, Germany

2. Ralf Weiskirchen corresponding Aachen Institute of Molecular Pathobiochemistry Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC)

   RWTH Aachen University · Universitätsklinikum Aachen

   Affiliation as printed

   Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH University Hospital Aachen, D-52074 Aachen, Germany

3. Swen Malte John

   Osnabrück University

   Affiliation as printed

   Department of Dermatology, Environmental Medicine and Health Theory, University of Osnabrück, D-49076 Osnabrück, Germany

   Institute for Interdisciplinary Dermatological Prevention and Rehabilitation (iDerm), University of Osnabrück, D-49076 Osnabrück, Germany

4. Wolfgang Stremmel
   Affiliation as printed

   Praxis for Internal Medicine, D-76530 Baden-Baden, Germany

5. Claus Leitzmann

   Justus-Liebig-Universität Gießen

   Affiliation as printed

   Institut für Ernährungswissenschaft, Universität Gießen, D-35392 Gießen, Germany

6. Sabine Weiskirchen Aachen Institute of Molecular Pathobiochemistry Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC)

   RWTH Aachen University · Universitätsklinikum Aachen

   Affiliation as printed

   Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH University Hospital Aachen, D-52074 Aachen, Germany

7. Gerd Schmitz

   University of Regensburg · University Hospital Regensburg

   Affiliation as printed

   Institute of Clinical Chemistry and Laboratory Medicine, University Hospital of Regensburg, D-93053 Regensburg, Germany