# Molecular Determinants of Lactation Success

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2020 · $388,750

## Abstract

Milk is a complex fluid capable of sustaining the total nutrition of the human infant for 6 months or longer, as
well as providing protection against infection and common childhood illnesses during the critical early postnatal
period. Milk lipids provide the majority of the calories required for neonatal growth, in addition to being the
primary mechanism for transferring fat-soluble vitamins to infants and the source of essential fatty acids
needed for neonatal membrane synthesis and the synthesis of eicosanoids and other bioactive lipid signalling
molecules. To meet caloric and nutritional demands of newborns, a unique apocrine mechanism evolved in
mammals to efficiently secrete large quantities of lipid into milk. Evidence from humans and animal models
suggest that apocrine lipid secretion is also important for initiating and sustaining lactation, and that
interference with this process increases the risk of lactation failure. Work from our laboratories indicates that
apocrine lipid secretion involves three mechanistically distinct steps: (1) formation of specialized “docking”
contacts between CLD and the apical plasma membrane (APM); (2) membrane envelopment of docked CLD,
driven in part by Golgi derived secretory vesicles; and (3) release of membrane enveloped CLD into the
luminal space as trilaminar membrane coated structures, referred to as milk fat globules (MFG), by an apocrine
scission process. We previously identified interactions between butyrophilin (Btn), a mammary gland specific
transmembrane protein, the cytoplasmic redox enzyme, xanthine oxidoreductase (XOR), and the CLD coat
protein, perilipin-2 (Plin2) as important for apocrine lipid secretion in mice. Importantly, we have demonstrated
that genetic deletion of either of these proteins interferes with CLD secretion, and impairs or prevents lactation.
The goals of this proposal are: (1) to investigate the mechanism of apocrine lipid secretion and test the
hypothesis that prolactin and oxytocin independently regulate discrete steps of this process; (2) define how
apocrine lipid secretion affects apical membrane properties, secretory vesicle trafficking, lactogenesis and
lactation success; and (3) to define critical molecular determinants of interactions between XOR, Btn and Plin2
that mediate apocrine lipid secretion. The proposed studies take advantage of novel XOR, Btn and Plin2
knockout mouse models developed in our laboratories, quantitative high resolution imaging, and innovative
physiological and biochemical analyses and cell culture models of apocrine lipid secretion to accomplish these
goals.

## Key facts

- **NIH application ID:** 9952391
- **Project number:** 5R01HD093729-03
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** James Lewis McManaman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $388,750
- **Award type:** 5
- **Project period:** 2018-09-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9952391

## Citation

> US National Institutes of Health, RePORTER application 9952391, Molecular Determinants of Lactation Success (5R01HD093729-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9952391. Licensed CC0.

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