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Milk Fat Globular Membrane comprises less than 1% of the total milk lipids, but the technological significance and health benefits of MFGM are immeasurable. MFGM as a bioactive compound present in milk, constitutes the majority of indigenous enzymes and plays vital role in stability of fat globules while processing. Due to its benefits, MFGM and its fractions became a hot topic in functional food especially in the infant food formula category. MFGM contributes several health benefits such as anticancer, anticholesterolemic and improves physical and dermal health. Food application of the MFGM can be highlighted as an emulsifier and stabilizer with excellent water holding capacity in dairy products. Beyond its technological significance, MFGM is also used in food emulsion and lactic acid bacteria encapsulation techniques. MFGM is considered to be a nutraceutical ingredient which gives more opportunity for exploration of milk lipids.
Department of Dairy Chemistry, College of Food and Dairy Technology, Tamilnadu Veterinary and Animal Sciences University, Chennai, Tamilnadu, India
*Address all correspondence to: dharanimuthusamy98@gmail.com
1. Introduction
Milk is a wholesome food that contains several health providing nutrients ranging from carbohydrates, fat, protein, minerals and up to some bioactive substance. In recent years, active research has been done on the underlying or unrevealed part of milk components such as oligosaccharides, metal binding proteins, fatty acids, lactoferrin and milk fat globular membrane (MFGM). Several studies were carried out in the finding the bioactive components. Due to its favorable outcomes, milk bioactive substances were being commercialized and consumed in day to day life for short term benefits to treating ailments. Milk is an emulsified solution that comprises fat as dispersed phase, protein as colloidal particle, and minerals as the true solution. The average size of fat globule present in the milk ranges from 0.1–15 μm and 95% of micro fat globules are concealed into 8-10 nm thick globular membrane which is the Milk Fat Globular Membrane [1]. In the 17th century, Van Leeuwenhoek discovered the fat globules with the aid of a light microscope through a thin glass capillary tube. Later in the 19th century, Ascherson revealed that fat globules had a membrane that was the structure comprising condensed form of protein and accumulation of small fat globules at the surface. Followed by several studies were carried out in finding the structure and composition of MFGM along with their properties in stabilizing milk fat.
In this chapter, structure, composition, technological significance and health benefits of MFGM will be discussed.
Understanding the origin and mechanism of membrane formation is crucial for the better knowledge in case of MFGM, since its complex structure has effect on stabilizing and sensory application on dairy products. The origin of MFGM was found during lipid secretion along with formation of fat globules in the mammary gland. MFGM has three different origins, primarily from apical plasma membrane, endoplasmic reticulum (ER) and certain post- golgi apparatus of mammary gland cells. Fat globules of diameter < 0.5 μm accumulates and reaches ER at centre and gets trapped between the outer and inner lipid bilayer of ER, which is later expelled into cytosol as cytoplasmic covered lipid droplets. The monolayer protein present in ER is responsible for the growth and fusion of lipid droplets before reaching the apical plasma membrane.
In budding stages of lipid droplets, there occurs a static distance of 10–20 nm between lipid globules and apical plasma membrane, that gap gets covered with electron clouded inner face of apical plasma membrane and phospholipids (PLs) that forms as primary lipid bilayer of MFGM (pathway A in Figure 1). Few micro lipids resist the change in the size that constitutes microlipid pathway (pathway B in Figure 1). Milk plasma components like casein, whey protein, lactose and other substances condense in the golgi apparatus and get compacted within the secretory vesicles membrane through a process called exocytosis (pathway C in Figure 1). Similar patterns of micro lipid fusion have been reported in cell free systems with the aid of gangliosides in the presence of calcium [2, 3].
Figure 1.
A = cytoplasmic lipid droplet pathway; B = microlipid droplet pathway; C = secretory pathway for milk plasma constituents.
Understanding the fusion mechanism in the growth of micro lipids and sealing into MFGM would be useful in separation of milk, based on the size of fat globules that help to avoid the use of centrifugation. Manipulation of expression level of fat from the mammary cell by means of genetic engineering would be able to produce low fat milk naturally from udder. Since MFGM anchors several lipolytic enzymes this manipulation will be useful in the elongation of storage stability of the fat rich dairy products. Historical review of MFGM with their physico-chemical properties was reviewed briefly by Leroy S. Palmer, refer [4].
2.1 Composition of MFGM
2.1.1 Protein fraction of MFGM
On isolation and characterization of MFGM from fresh cream of jersey cow, it was concluded that the membrane is mostly protein in nature [5]. The composition of MFGM itself can be divided into lipid rich MFGM and protein rich MFGM [6] since, protein and lipid constitute 90% of MFGM. Protein content of MFGM ranges from 26 to 60% as its concentration is greatly affected by the method of isolation. The highly sialylated part of MFGM is mucins, it can be further classified into MUC 1 and MUC 15 with molecular weight of 160–200. MFGM also consists of Butyrophilin (BTN), Adipophilin (ADPH), lactadherin, Proteose peptone 3, some fatty acid binding protein [7] and RNA [3]. Molecular weight of native proteins present in MFGM was tabulated in Table 1.
Protein name
Molecular weight
Breast cancer protein (BRCA1 and BRCA2)
210
Mucin I (MUC1)
160–200
Xanthine oxidase (XO)
146–155
PAS III
94–100
CD36
76–78
Butyrophilin (BTN)
52
Adipophilin (ADPH)
47–59
PAS 6/7 (lactadherin)
47–59
Proteose peptone 3
18–34
Fatty Acid Binding Protein.
13–15
Table 1.
Protein fractions of naturally extracted MFGM isolates, from [7].
2.1.2 Lipid fraction of MFGM
MFGM contains 35% of high melting point unsaturated fatty acids constituting 3% of total triglyceride composition [5], but these fatty acids was not originated from MFGM, rather it comes from fat globules attached to the membrane during processing operation [6]. The major lipid present in the MFGM was found to be PLs (26–31% of total lipids) in the form of protein –phospholipid complex [8] that exhibits emulsion stabilizing property along with other phosphatides proteins lecithin, cephalin and sphingomyelin. Among these phosphatides lecithin was notably prominent in creaming stability and emulsion of cow milk [9]. Triacylglycerols constitutes 62% of total lipids and other minor constitutes are mono, di-acylglycerols (responsible for the lipolysis in dairy products), sterols and their esters, non-esterified fatty acids and hydrocarbons [5, 10]. Next to protein and lipids, enzymes are highly concentrated in MFGM that are significantly crucible for lipolytic activity in dairy products. About 28 enzymes have been found in MFGM, but their physiological activities are undiscovered. The major enzyme is xanthine oxidase (XDH), responsible for the development of fat globules in plasma membrane and purine metabolism. The origins of these enzymes are predominantly from plasma membrane [11, 12] and cytosol. Composition and their proportions are detailed by Keenan and Mather [3].
Several isolation studies on MFGM have been done due to the presence of nutraceutical proteins and their nourishing effect towards the infant. In spite of its uses, these isolates are produced on commercial scale and it have been supplemented in various nutritive formula and functional foods. Since casein and MFGM are same in size and share almost similar isoelectric points, it is a tedious isolation process. The separation techniques used for MFGM, involve many physical processing methods with repeated washings using chemicals to remove milk proteins, lactose and salts which is suitable for lab purposes, but not optimal for commercial production [13]. The molecular size of milk protein casein and MFGM are same, this makes it even more difficult to isolate during membrane separation [14].
The natural extraction of MFGM can be obtained from the by-products such as buttermilk, cream serum and cheese whey while processing butter, cream and cheese respectively (Figure 2). These by-products are the raw materials for the production of MFGM. Processing conditions like cooling, heating and physical separation techniques such as churning and phase inversion affects the migration and association of MFGM fragments in dairy products. Chilling or cooling shifts MFGM towards whey and heating causes complex association between whey protein and exterior layer of MFGM. Same pattern takes place in cream serum that MFGM gets concentrated at water-in-oil emulsion (AMF) during cooling. In cheese preparation, the disruption of MFGM during processing of cheese curd results in migration towards the milk serum portion. Condensation of defatted fluid whey into whey protein concentrates and isolates (WPC and WPI) is used for MFGM extraction. Among the by-products, cream serum and buttermilk provides a great source of MFGM. Dehydration and membrane separation of the above described final ingredients are used to produce MFGM enriched powder [7, 15].
Figure 2.
Production of MFGM enriched powdered product from various processing methods. Adapted from [7].
During manufacturing of butter, phase inversion occurs by churning that involves in conversion of oil-in-water to water-in-oil, MFGM associated with TG gets drifted into buttermilk due to coalescence. MFGM isolates from buttermilk at lab scale was studied by [16], commercialized buttermilk powders was used to characterize lipids present in the MFGM isolates. The study showed that MFGM fractions had high cholesterol and PUFA content and serves as the best source of bioactive lipids. The lipid profile proved that MFGM had higher concentration of medium molecular weight TGs mainly due to linoleic acid.
Most successfully used method for production of MFGM from buttermilk was reported [13], using microfiltration and multiple diafiltration. Each batch contains 8 to 16 liters of reconstituted buttermilk with total solids content of 8% w/v in water was used. 2% sodium citrate at 1.4%w/w was added to reconstituted buttermilk to disrupt the casein micelles and to increase the PLs content in the buttermilk whey (pH 7.2), then stored for overnight at 6°C. The first step in separation involved in membrane filtration polyvinyl-dilfluoride (PVDF) membrane with 250,000 and 500,000 Da cut-off at 50°C. Then retentate was feed into 2-HP centrifugal pump with the pressure of 1.2 MPa at 50°C by circulating in shell and tube heat exchanger until favorable concentration is reached. Again the retentate goes to multiple diafiltration at 50°C, followed by high speed centrifugation to isolate MFGM fragments.
The authors noticed that, intact of small amount of β- lactoglobulin (30%) in MFGM even after 2 steps of diafiltration, this is due to the complex formation of whey protein and kappa casein with MFGM during heat processing [17]. Absence of sodium citrate resulted in increased level of skim milk proteins in the retentate and caused contamination of non- MFGM material in final retentate. To obtain MFGM isolate in powdered form, the retentate was freeze dried. During SDS-PAGE electrophoresis analysis, the final isolate contained 60% and 35% of protein and lipid (w/w) respectively, among the protein composition was 70%, 24% and 6% of MFGM, whey protein and casein respectively.
Another method of isolation was studied by [18], coagulation of native casein protein to obtain specific MFGM isolate cannot be obtained through membrane separation due to skim milk protein contaminants. 40% raw cream was cream separated and skim milk was subjected to continuous butter making process and the resulted buttermilk was coagulated by addition of rennet at 0.03% to hydrolyse the casein micelles at 45°C for 30 min to reach pH of 6.8. The obtained buttermilk whey was passed through microfiltration with average pore size of 80 nm at the constant pressure of 0.1 MPa at 50°C to remove whey protein. To remove further residues of whey protein, the retentate was diafiltered with deionized water (6 diafiltration steps). Interestingly, after 6 diafiltration steps complete absence of whey protein was detected during SDS-PAGE protein analysis.
High amount of protein loss was encountered in this isolation method, however the loss was considerably lesser when compared to the cream washing method [19]. The final isolate contained 70%, 30% and 20% of peripheral protein – periodic Schiff acid (PAS 6/7), XO and butyrophilin (BTN) respectively. Compared to the previously mentioned method of isolation [18], the coagulation method [19] showed neither whey protein nor casein in the final isolate and this method can be used industrially.
Effect of addition of cationic salts like calcium acetate and zinc acetate on selective isolation of MFGM in cheese whey was studied by [20, 21, 22, 23]. The studies showed that removal of Ca2+/Mg2+ from cheese whey through diafiltration and addition of 25 mm of zinc acetate at pH 4.2 at 30–35°C causes the maximum precipitation of MFGM.
Ethanolic extraction method (90% ethanol at 70°C) was used to solubilize the calcium chloride and acetate in dairy by-products to maximize the extraction of MFGM and phospholipids to produce dairy lecithin [22]. Composition and physico-chemical properties of spray-dried and freeze- dried MFGM isolate from cheese whey showed that freeze dried MFGM has higher retention of bioactive components and better oxidative stability than spray dried MFGM [24]. This study supports the findings of [25], concentrated buttermilks from raw milk (RCB) and pasteurized creams from buttermilk (PCB) were produced by condensing cheese buttermilk in falling film evaporator to reach 20% total solids, and then the spray-dried concentrate was used in the study. Unexpectedly, the amount of lipids was higher in PCB at the level of 19.7% vs. RCB 8.29% under the same skimming level. Double the amount of lipid concentration in PCB was stated due to attachment of milk protein to the exterior of MFGM, inhibiting the coalescence of fat globules [26].
Spray drying of buttermilk resulted in major loss of all classes of phospholipids and found that the inner portion of MFGM was exposed to interaction with other components. As already discussed in previous studies, serum protein contaminants were higher in PCB due to interaction with β- lactoglobulin and formation of complex systems. The color of RCB was reddish brown and PCB was yellowish white due to the presence of iron in RCB. Micrographs of MFGM in RCB and PCB revealed that casein is entrapped in the MFGM rather than its attachment to the exterior layer of MFGM. The study does not explain the storage stability and loss of phospholipids after spray drying.
From above stated studies of MFGM, it was clear that membrane separation techniques like microfiltration, diafiltration and ultrafiltration, addition of sodium citrate and cationic salts plays a major role in isolation of MFGM. Heat treatments like pasteurization of cream and spray drying mainly affected the phospholipids concentration and increased the serum protein contaminants in final MFGM isolates. Optimization of separation techniques and processing conditions should focus on minimal damage on functional bioactive components in MFGM fragments to ensure the delivery of clinical benefits to the consumers. Most of the studies were conducted only on the characterization of bovine MFGM isolates rather than other species. Characterization of other species’s MFGM uncovers the underlying potential health benefits and commercialization of novel MFGM fractions especially in the neonatal nutrition.
4. MFGM as key strategy in infant food (IF) formulation
In recent decades, formulations of infant and neonatal foods have introduced several new components and modifications to enhance its functional health performance to mimic human milk. Major changes in the IF that has been successfully introduced are supplementation of prebiotics (FOS and GOS) [27, 28], probiotics [29, 30, 31], docosahexaenoic acid (DHA) and arachidonic acid (ARA) [32], meat protein [33], plant protein (pea and soy protein) [34], taurine [35], MFGM [7, 36], polyamines [37, 38], folates [39] and osteopontin [40]. Even though many of these modifications are being carried out, very little knowledge is known to us on human milk’s minor bioactive compounds that are essential for the neonatal development on long and short term studies.
Sometimes, supplementation of IF with bioactive compounds as same in human milk can cause adverse effects on infant growth and nutrition. Example, addition of opioid protein (beta-casomorphin) in IF can cause life threatening events due to its exogenous nature. Adaptation of infants and biosimulation of metabolic activities in infant digestion can be responsible for this condition [41]. Still now the regulation on fortification or supplementation of bioactive compounds in IF and nutrition was not standardized globally. However, fortification of MFGM was profitably done and studied for their effect on health benefits in many infants. Animal and human studies of commercially available MFGM formula and their outcomes are tabulated in Table 2.
Source
Formulation
Model
Brand
Dosage
Experimental finding
Reference
Whey
MFGM-10 Lacprodan® with phospholipids and sialic acid
Rat pups
Arla Food ingredients
100 mg/kg of body weight
Improved cognition and object recognition performance
Anticancerous activity of bovine MFGM was well detailed by Spitsberg and Gorewit, especially they play an important role in prevention of breast and ovarian cancer. A notable protein called Fatty Acid Binding Protein (FABP 1) present in bovine MFGM has effect on cancer cell proliferation on the epithelial part of mammary gland during lactation period [60, 61]. The presence of genes like BRCA1 and BRCA2 that have a capability to suppress breast cancer was also found in human milk. The origin of these genes was through exocytosis from the epithelial cells and usually covered by plasma membrane similar to the origin of milk fat globules in bovine milk. The study also addressed that presence of BRCA1 and BRCA2 in human milk fat globule (HMFG) has a vital role in neonatal nutrition [62].
The structure of bovine and human milk BRCA1 was quietly identical (72.5% similarity rate) and also had the same type of reaction towards DNA repairment and cell nuclear expression pattern in vitro study [63]. The major functions of BRCA1 and BRCA2 are repairing the damaged DNA and regulation of cytokinesis [64]. The principle behind the suppression process of cancerous cells involves, after MFGM is ingested, the protein would be degraded into several inhibitory peptides in the stomach and reaches the bloodstream and starts its action on cancerous cells in particular tissue or organ.
The role of MFGM against intestinal cancer was studied [65] that 0.88 g/day of trysin derivatives of MFGM significantly reduced 90% of β- Glucuronidase activity and kappa casein reduced 35% of activity in the mice. β- Glucuronidase acts as a catalyst in conversion of onco-precursors to carcinogens. Less than 20% of MFGM such as 5% and 10% had only 15–20% inhibitory effect on β- Glucuronidase activity. The possible science behind the scene was due to release of inhibitory peptidase of ingested MFGM. However, the exact mechanism was not clarified by the authors, these studies proved that supplementation of MFGM particularly in solubilized state has potent effect on intestinal cancer, which can be effectively used in geriatric functional foods. The action of MFGM-PLs and sphingolipids towards colon tumors was reported by several authors [66, 67, 68, 69, 70, 71].
5.2 Anticholesterolemic effect
The positive impact of MFGM on serum cholesterol was studied [71], the study involved in supplementation of cream and butter into the diet of subjects. The results revealed that volunteers who had butter showed increased levels of serum cholesterol than those who were fed with cream. The obvious reason behind the relation is that MFGM is the principle compound responsible for reducing the level of serum cholesterol by its association with cholesterol binding in the intestine.
Similarly, consumption of 4 liters of whole milk per day reduced the uptake of cholesterol in the body [72]. A study [73] compared egg sphingomyelin (SM) and milk SM for their effective control on cholesterol absorption. Undoubtedly, the milk SM inhibited the absorption of cholesterol due to the presence of long chain and saturated fatty acids in their complex structure which makes them difficult to solubilize and unfold.
Cohort study by direct supplementation of milk fat 40 g/day showed markedly decreased level of total cholesterol and LDL lipoprotein in adults during 8 week observation [74]. Micellar insolubilization and transfer of cholesterol molecule in micellar cells to enterocytes are the major roleplay of MFGM in anticholesterolemic effect.
5.3 MFGM in physical health
Muscle strength, mass and function are important factors in physical performance of sports nutrition. Milk products especially whey protein plays a major role in muscle protein function and became an undeniable product in sports nutrition. Nutritional significance of milk on muscle function was mainly due to its nutrient rich constituents and its ability for specific gene expression [75]. In that way, the effect of uptake of milk during leg resistance exercise was studied in 3 groups of young volunteers who were fed with free-fat milk, whole milk and free-fat milk isocaloric with whole milk. The results showed increased levels of two aminoacids such as phenylalanine and threonine which indicates net muscle protein synthesis in the group fed with whole milk. The balance of net muscle protein shifted from negative to positive in same group. Hence the study concluded that intake of milk serves a reservoir for amino acids (phenylalanine and threonine) for muscle protein synthesis [76]. In an animal study with senescence-accelerated mice, intake of MFGM along with regular exercise improved the muscle contractile force and lipid fraction of MFGM (PL and SM) had a beneficial effect on mechanical strength of muscle (quadriceps muscle) [77]. Long term effect on supplementation of MFGM diet on endurance capacity on swimmers was studied [78]. The MFGM regulated the gene expression for energy metabolism, increased oxygen intake, lipid oxidation, energy recharge and fat catabolism in 12 a week study. Similar studies on physical performance in human were studied [79, 80, 81]. Most of the studies are focused only on the supplemented MFGM fraction, study shall also be focused on natural MFGM rich dairy products intake and their effect on weight gain and loss in athletes.
As supplementation of MFGM is popularized in IFs, it also gained interest in incorporating dairy products like yoghurt, cheese and dairy beverages. Incorporation of MFGM in skim milk yoghurt from 1 to 4% (w/w) total solids concentration increased the firmness, water holding capacity and adhesiveness. Addition of MFGM also improved the concentration of polar lipids and protein content (including casein) (5.3% MFGM yoghurt vs 4.08% control). Below 3% of MFGM solids the gel strength was slightly weaker but increased when added above 3%. Similarly, firmness also decreased when yoghurt has 1% MFGM solid due to prevention of contraction of casein during curd formation.
Overall quality of the MFGM supplemented yoghurt was superior and shows the technological applications like water holding capacity [82]. Cohort study in yoghurt was done by [83], homogenized and unhomogenized set yoghurt were prepared with 4% Lacprodan®PL-20 with addition 0f 0.5% yoghurt culture with final total solids content of 15%. During homogenization, the surface area of the MFGM gets decreased and due to its polarity the affinity between PL and milk protein increases resulting in improved body and texture of the set yoghurt. The authors commented that addition of MFGM in yoghurt prevents the physical defects and improves the health benefits of the product.
Since MFGM is an amphiphilic molecule, it can be used as a stabilizer in dairy products to avoid the usage of artificial stabilizers to improve the quality of the product. Beyond the use of MFGM as a technological ingredient, MFGM was also used to encapsulate the lactic acid bacteria (LAB). Study on interaction between MFGM and LAB revealed that most of the bacteria are located at whey protein-fat interface or trapped in MFGM in the food matrix. Even after ripening, the bacteria are found to be trapped in MFGM [84, 85, 86]. This interaction was probably due to the reaction between bacteria and mucin factor of MFGM [87]. These studies clearly depict the encapsulation efficacy of natural ingredient MFGM as an emulsifier for LAB culture, especially in the location of bacteria on the surface of the cheese matrix. Further investigation on microstructure of MFGM material in cheese could be advantageous in improving flavor and color (in blue veined cheese) in cheese for the higher consumer preference.
Most recently, development of oil-in-water food emulsions are being prevalent due to their emulsion stability and protection against the oxidation of lipids. Likewise, MFGM coated lipid systems are studied to mimic the human fat globule to deliver the health benefits notably in IFs. The process involved in coating of MFGM around the triacylglycerol (TAG) through higher pressure homogenization methods [88]. Not only in IFs, these types of emulsions can be used in various products ranging from cheese, cream and dairy beverages irrespective of the consumer age. This concept of emulsion leads to the production of commercial MFGM –PL (from beta serum or butter serum) coated vegetable oil in IMF called Nuturis®. This novel formula was prepared by mixing bovine PL (0.5 g PL in one liter) from beta serum in the aqueous phase of formula containing other ingredients and heating for 85°C/6 min, followed by homogenization with lipid phase (vegetable oil mixture) in inline mixer to form larger fat droplets coated with phospholipid. The microscopic examination showed that the fat droplet size and the location of cholesterol exposure were more or less similar to the human milk. This regulates the uptake of cholesterol in early childhood that maintains the weight gain and loss similar to the human milk intake [89]. This proves that MFGM and its fractions are important in emulsion formation because of their emulsifying capacity and physical stability due to their complex formation while processing.
In conclusion, deeper knowledge on human milk morphology and characterization of distribution of lipid will lead to develop novel and more innovative technologically significant functional food for the infant nutrition to reduce the incidence of overweight and obesity in early stages of childhood which was considered to be most prominent problem encountered while ingestion of other infant formula with imbalanced concept of nutrition.
In this chapter, we can summarize that MFGM prepared from dairy by-products such as buttermilk, a major by-product in butter processing and whey by-products in cheese and paneer processing, can be effectively used rather than discarded. However, almost all the minor components in MFGM were well established. But still some of the minor proteins present in MFGM resulting from processing were not well defined. Several studies on health benefits in infants and adults are mannered in various populations with excellent outcomes. Still now no adverse effect on intake of MFGM was reported even when taken at a higher level than the recommended level. Promising effect of MFGM on tumor inhibiting, altering gene expression and modulation of cholesterol absorption will have a positive impact on weight management and obesity control while consumption of fat rich dairy products. MFGM has excellent bioactive compounds, production of MFGM on larger scale and supplementing in commercially available foods will be upgrading the dairy foods and industry to the next level.
I would like to thank Professor Dr. Manoharan for proofreading the manuscript. I also wish to extend my thanks to P. Ameena Benazir, M.K. Gayathri Devi and M. Ramya, College of Food and Dairy Technology for their help in revising the manuscript.
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Written By
Dharani Muthusamy
Submitted: 04 June 2022Reviewed: 03 August 2022Published: 16 December 2022
Open access peer-reviewed chapter
