Human Milk Metabolic Hormones

Human milk (HM) contains a wide array of peptide hormones including leptin and adiponectin, which are involved in the regulation of infant growth and development. These essential hormones might play an important role in the regulation of metabolic reprogramming of the new-born infant. The protective activity of HM is thought to be due to the presence of bioactive molecules that are dynamic in response to maternal conditions and can positively modulate energy metabolism and inflammatory responses in infants and mothers. Hormones such as leptin, adiponectin, ghrelin, insulin, resistin, obestatin and apelin have been recently identified in HM.

leptin;adiponectin;ghrelin;insulin;obestatin;resistin;apelin;human milk;metabolic hormones

1. Leptin

Leptin, a polypeptide hormone with an average of 167 amino acids (16.2 kDa), is mainly synthesised and secreted by adipocytes of white adipose tissue as a product of the obese (Ob) gene expression [10][1]. Leptin signals the amount of fat stored in the body; thus, plasma leptin concentration is positively correlated with body fat mass in adults [11,12][2][3]. Leptin modulates energy homeostasis; it induces energy consumption and reduces food intake by initiating a signal cascade beginning with leptin binding to the Ob receptor in the hypothalamus [13,14][4][5]. At birth, cord blood leptin concentrations are reported to correlate positively with neonatal fat mass index [15][6]. Two mechanisms contribute to the presence of leptin in HM. First, it is suggested that maternal plasma leptin enters HM via diffusion or receptor-mediated transport [16,17,18][7][8][9]. Second, mammary epithelial cells can produce small amounts of leptin [19][10]. HM leptin is present in a relatively high and variable concentration (range: 0.2 to 1.47 ng/mL), which generally decreases as the duration of lactation increases (Table 1).
Table 1.
 Studies examining human milk leptin.
Author Year Sample Size (n) Sample Type Sampling Time of the Day (h) Time

Postpartum
Preparation Method Intra, Inter

Assay (%CV)
LOD

(ng/mL)
R (%) Concentration

(ng/mL)
Houseknecht et al. [20][11] 1997 14 - 12 h fast 08:00 - SM and Wm RIA 3.0, 12.6 0.3 SM: 90

WM: 82
WM, 10.1 ± 2.6;

SM, 1.5 ± 0.87
Uçar et al. [21][12] 2000 18 C, M pre- and post-feed 9:00–12:00 3–120 d SM RIA - 0.5 - (0.8–15)

(range)
Lönnerdal and Havel [22][13] 2000 - M - - 2–4 mo SM and WM RIA - - - WM, 32.7 ± 14.1

SM, 0.2 ± 0.1
Resto et al. [23][14] 2001 29 M - - 1–4 wk M, added pancreatic

lipase,

NaHCO3
RIA - - - 5.28 (24.79)
Uysal et al. [24][15] 2002 50 M 2 h after last feed 8:00–10:00 1,2, 3 mo SM RIA <6, - 0.1 - Non-Ob, 0.37 ± 0.4

Ob, 0.27 ± 0.2
Bielicki et al. [25][16] 2004 33 C, M 1–3 h after breakfast - 2–3, 4–5 d

4–6 wk
WM RIA <10, 9.7 0.25 97 Preterm, 0.63 ± 0.18

Term, 1.34 ± 0.14
Dundar et al. [26][17] 2005 47 M pre-feed 10:00–11:00 15 d, 1, 2, 3 mo WM RIA 6.2, - 0.5 83 ± 4 15 d, AGA, 18.4 ± 2;

LGA, 28.5 ± 4.4;

SGA, 13.4 ± 2.2
Ilcol et al. [27][18] 2006 160 C, M pre-feed, 3 h after breakfast morning 2, 8, 25 d WM IRMA <5, 7 0.1 - 2 d, 3.35 ± 0.25;

8 d, 2.65 ± 0.21;

25 d, 1.63 ± 0.18
Bronsky et al. [28][19] 2006 59 C collected on EDTA and aprotinin after 7:00 1–2 d SM ELISA 7.6, 9.1 0.05 - 0.50 (0.05)

mean (SEM)
Miralles et al. [29][20] 2006 28 M post-feed morning 1, 3, 6, 9 mo WM ELISA - 0.008 103.1 ± 1.4 1 mo, 0.156 ± 0.039
Weyermann et al. [17][8] 2006 766 M pre-feed - 6 wk,

6 mo
SM ELISA <7 - - 12.8 ± 10.1
Weyermann et al. [30][21] 2007 767 M - - 6 wk SM ELISA <7, - - - 0.175 (0–4.1)

median (range)
Aydin et al. [31][22] 2008 31 C, M pre-feed, collected on aprotinin 9:00 2, 25 d SM ELISA - - - C, 2.01 ± 0.34;

M, 2.04 ± 0.67
Savino et al. [32][23] 2010 36 - - - <6 mo SM RIA <5, 8 0.04 - 0.51 (0.34)
Bronsky et al. [33][24] 2011 72 C, M collected on EDTA + protease inhibitor - 1 d; 1, 3, 6, 12 mo SM ELISA 6, 9 0.5 - 1 d, 0.3 ± 0.04;

1 mo, 0.2 ± 0.03;

3 mo, 0.1 ± 0.01;

6 mo, 0.1 ± 0.02;

12 mo, 0.2 ± 0.04
Schuster et al. [34][25] 2011 23 C, M - - 1, 2, 3, 4 wk

2, 3, 4, 5, 6 mo
SM RIA - 0.01 70.2 ± 8.7 1 wk, 0.21 ± 0.19

6 mo, 0.18 ± 0.15
Eilers et al. [35][26] 2011 77 C, M fasting 2 h prior sampling 16:00–20:00 3 d, 28 d SM RIA 5, 6 - ~94 Preterm,

3 d, 0.7 ± 0.79;

28 d, 0.5 ± 0.4;

Term,

3 d, 0.65 ± 0.67;

28 d, 0.5 ± 0.4
Fields and Demerath [36][27] 2012 19 M complete breast

expression
8:00–10:00 ~1 mo SM - - - - 0.95 ± 0.73
Savino et al. [37][28] 2012 23 - - - <6 mo SM ELISA <5, 6.8 6 - 2.34 (5.73)
Schueler et al. [38][29] 2013 13 M overnight fast,

pre- and post-feed
7:00–10:00 29–38 d. SM RIA 9.4, - - - pre, 0.9 ± 0.7

post, 1.0 ± 0.8
Chang et al. [39][30] 2013 - - - - 3–4 mo SM ELISA <5, 6 0.5 - -
Ojeda et al. [40][31] 2013 - - - - 2 mo - ECIs, & ELISA     + ECIs, 2.6 ± 0.1

ELISA, 2.9 ± 0.5
Kon et al. [41][32] 2014 103 M - Morning 1, 2, 3 mo SM ELISA 3.7, - 0.42 - LWG, 1 mo, 1.63 (0.27);

3 mo, 1.35 (0.31);

NWG, 1 mo, 1.55 (0.17);

2 mo, 1.83 (0.23);

3 mo, 3.29 (0.70)

HWG,1 mo: 1.53 (0.29);

2 mo, 2.20 (0.28);

3 mo, 3.57 (1.37)

mean (SEM)
Brunner et al. [42][33] 2014 6 wk, 152

6 mo, 120
M overnight fast Morning 6 wk,

6 mo
SM RIA - - - 6 wk, 0.11 (0.19);

6 mo, 0.09 (0.18)
Khodabakhshi et al. [43][34] 2015 Ob, 40

NW, 40
M overnight fast, 2 h after last breast feed 8:00–10:00 2–5 mo SM ELISA - - - NW, 1.81 (1.65–1.94)

Ob, 1.78 (1.67–1.94)
Cannon et al. [44][35] 2015 19 M pre- and post-feed 24 h milk collection 3–21 wk SM RIA -, 9.9 0.017 98.4 ± 6.8 pre, 0.43 ± 0.10,

post, 0.42 ± 0.11
Quinn et al. [45][36] 2015 113   mid-feed sampling 6:00–10:00 10 d–36 mo SM ELISA - - - 0.3 ± 0.29
Andreas et al. [46][37] 2016 120 - 1 h fast prior sampling, pre- and post-feed, on protease inhibitors 10:00–13:00 1 wk,

3 mo
SM Multiplex

assay
3, - 3.1 - 1 wk, pre 541.7 (161.2);

post 614.4 (172.1)

3 mo, pre 684.8 (117.4);

post 464.3 (125.1)

mean (SEM)
Gridneva et al. [47][38] 2016 27 M pre- and post-feed 09:30–11:30 2–5 mo SM and WM ELISA -, <7.2 - 97.7 ± 9.7 WM, 0.51 ± 0.18 [0.23–1.10]

SM, 0.28 ± 0.12 [0.20–0.84]
Kugananthan et al. [48][39] 2016 61 M pre- and post-feed 11:00 2, 5, 9, 12 mo SM and WM ELISA <5, 7.2 - 97.7 ± 9.7 WM, 2 mo, 0.50 ± 0.16;

5 mo, 0.48 ± 0.16;

9 mo, 0.56 ± 0.11;

12 mo, 0.54 ± 0.14

SM, 2 mo, 0.32 ± 0.16;

5 mo, 0.26 ± 0.07;

9 mo, 0.22 ± 0.03;

12 mo, 0.21 ± 0.02
De Luca et al. [49][40] 2016 100 M over-feed 9:00–11:00 1 mo SM RIA <10, - 0.5 + Non-Ob, 2.5 [2.1–3.0]

Ob, 4.8 [4.1–5.6]

mean (95% CI)
Savino et al. [50][41] 2016 58 - collected on

protease inhibitor
7:00–9:00 - SM RIA - 0.04 - 0.89 (1.32)
Fields et al. [51][42] 2017 37 M complete breast

expression
8:00–10:00 1, 6 mo SM - - - - 1 mo (n = 37),

0.589 (0.353–1.45)

6 mo (n = 30),

0.426 (0.145–940)
Meyer et al. [52][43] 2017 147 M overnight fast - 6 wk, 4 mo - RIA - - - -
Quinn and Childs [53][44] 2017 116 - mid-feed 6:00–10:00 - SM ELISA 17.8, - - - 0.27 ± 0.25
Nunes et al. [54][45] 2017 69 C, M - - 1, 2, 30 d SM ELISA - - - SGA, M, 0.377 (0.36–0.41)

GDM, M, 0.460 (0.45–0.70)

CTL, M, 0.715 (0.48–0.9)
Cannon et al. [55][46] 2017 20 - pre- and post-feed 24 h milk collection 6–32 wk SM ELISA -, 9.9 0.017 98.4 ± 6.8 0.51 ± 0.16

(0.42–1.15)
Kugananthan et al. [18][9] 2017 59 M pre- and post-feed 9:30–11:30 2, 5, 9, 12 mo SM and WM ELISA -, <7.2 0.05 SM,

96.3 ± 1.2

WM,

97.1 ± 9.1
WM, 0.53 ± 0.19 (0.20–2.24)

2 mo, 0.55 ± 0.29;

5 mo, 050 ± 0.17;

9 mo, 0.53 ± 0.15;

12 mo, 0.54 ± 0.13

SM, 0.28 ± 0.12 (0.19–1.46)

2 mo, 0.34 ± 0.21;

5 mo, 0.27 ± 0.07;

9 mo, 0.26 ± 0.09;

12 mo, 0.26 ± 0.08
Gridneva et al. [7][47] 2018 20 M pre- and post-fed 24 h milk collection 2, 5, 9, 12 mo SM and WM ELISA -, <7.2 0.05 97.1 ± 9.1 WM, 2 mo, 0.50 ± 0.18;

5 mo, 0.49 ± 0.17;

9 mo, 0.56 ± 0.11;

12 mo, 0.50 ± 0.11

SM, 2 mo, 0.34 ± 0.20;

5 mo, 0.26 ± 0.08;

9 mo, 0.21 ± 0.02;

12 mo, 0.21 ± 0.03
Chan et al. [56][48] 2018 430 M pooled 24 h

milk collection
24 h milk collection 4 mo SM ELISA - 0.137 _ 349 (186–689)
Yu et al. [57][49] 2018 96 C, M pre- and post-feed for mature milk 3 d, 8:00–9:00

42, 90 d, 14:00–16:00
3, 42,

90 d
SM ELISA <7.4, 9.3 - - GDM (n = 48),

3 d, 1.28 (0.87–2.63);

Healthy (n = 48),

3 d, 1.49 (0.56–3.25)
Sadr Dadres et al. [58][50] 2019 135 M 2 h after feeding 10:00–12:00 1, 3 mo SM ELISA <6, 6 0.008 90–94 1 mo, 0.640 ± 0.606

3 mo, 0.484 ± 0.672
Zamanillo et al. [59][51] 2019 59 M - 9:00–14:00 30, 60, 90 d WM ELISA - - - 1 mo, 0.376 ± 0.353;

2 mo, 0.341 ± 0.314;

3 mo, 0.346 ± 0.333
Logan et al. [60][52] 2019 SPATZ, 1090

UBCS, 1006
M 1 h after last feed 9:00–12:00 6 wk,

6 mo
SM ELISA <7.0, - - - SPATZ, 6 wk,

266.5 (152.0–498.0);

UBCS, 6 wk,

175.0 (79.8–350.0)
Larrosa Haro et al. [61][53] 2019 131 M pre- and post-feed - 8, 16 wk SM ELISA - 0.01 - 8 wk, pre, 0.316 (0.50);

post, 0.317 (0.57);

16 wk, pre, 0.447 (0.48);

post, 0.411 (0.64)
Logan et al. [62][54] 2019 694 M 1 h after last feed 9:00–12:00 6 wk,

6 mo,

12 mo
SM ELISA -, 5.8 - - 6 wk (n = 668), 388.8 ± 398.1;

6 mo (n = 445), 269.6 ± 305.3;

12 mo (n = 69), 320.4 ± 345.2
Kocaadam et al. [63][55] 2019 65 M pre-feed, ~2 h fast prior, ~2 h after last feed, on EDTA and aprotinin 8:00–11:00 15–30 d SM ELISA - - - preterm, (n = 31), 2.0 (2.5)

term, (n = 34), 0.0 (2.3)
Schneider-Worthington et al. [64][56] 2020 25 M - - 1 mo SM ELISA 4.48, 13.56 - - 0.47 (0.94)
Dal Bello et al. [65][57] 2020 - - - - - - nano-HPLC-HRMS - 27 - 6.70
Galante et al. [66][58] 2020 501 - pre-feed 10:00–24:00 2–3 mo SM ELISA 4, 8 - - 0.116 ± 0.112, ng/mg

(raw values corrected per mg of

protein per mL)
Joung et al. [67][59] 2021 50 C, M post-feed, 24 h pooled - 7, 14, 21 and 28 d WM ELISA 10 0.01 - -
Data reported as mean ± SD or median (IQR) unless specified. AGA, appropriate age for gestational age; C, colostrum milk; CTL, control group; CI, confidence interval; CV, coefficient variation; d, day; ECIs, electrochemical immunosensor; EDTA, ethylenediaminetetraacetic acid; ELISA, enzyme-linked immunosorbent assay; GDM, gestational diabetes mellitus; IRMA, immunoradiometric assay; LGA, large for gestational age; LOD, limit of detection; M, mature milk; mo, month; Non-Ob, without obesity; Ob, with obesity; R, recovery of analyte; RIA, radioimmunoassay; SGA, small for gestational age; SM, skim milk; SPATZ, Ulm SPARTZ health study; UBCS, Ulm birth cohort study; wk, week; WM, whole milk; y, year.

2. Adiponectin

Adiponectin, the most abundant adipokine, consists of 247-amino acids (27 kDa). Three circulating oligomers of adiponectin have been identified in the blood (low-, medium- and high- molecular weight), each with discrete biological activities. The high molecular weight oligomer is the more active and prevalent form of adiponectin in intracellular spaces, whereas low-molecular-weight adiponectin dominates the blood circulation [72][60]. Adiponectin is involved in the regulation of lipid and glucose metabolism and the stimulation of food intake, as well as the reduction of energy expenditure and regulation of the inflammatory response [3,73][61][62]. Although adiponectin is mainly synthesised by adipocytes, some evidence suggests that it also may be synthesised by the mammary epithelial cells [71][63]. Adiponectin is also the most abundant adipokine in HM, with a concentration range of ~4.2–78.9 ng/mL [7,74,75][47][64][65]. HM is dominated by the more biologically active high-molecular-weight adiponectin [76][66] that may enhance insulin sensitivity and metabolic control and suppresses inflammation [74][64].

3. Ghrelin

Ghrelin is a small polypeptide hormone comprising 28-amino acids (33.7 kDa) and is predominantly synthesised by the stomach, with smaller amounts produced by other organs, including the pancreas, kidneys and placenta [94][67]. Two different isoforms of ghrelin exist in the circulation: acetylated ghrelin (active) and deacylated ghrelin (restricted activity). Ghrelin is an appetite-stimulant hormone; it acts in a positive feedback loop that signals feeding behaviour to the hypothalamus, inducing food intake and controlling energy homeostasis. Further, in humans active ghrelin induces growth hormone (GH) secretion through binding and activation of GH secretagogue receptor 1a (GHS-R 1a) [95][68]. Ghrelin is present in HM, and there are two potential sources, maternal circulating ghrelin [31,81,96][22][69][70] and mammary epithelial cell expression [97,98][71][72].

4. Insulin

The β cells of the pancreas synthesise insulin, a glucose controlling hormone that consists of 51 amino acids (5.8 kDa) [110][73]. Insulin is present in HM, with the primary source being maternal blood. The detection of artificial insulin in HM of women with type 1 diabetes suggests an active transport mechanism of HM insulin from the maternal circulation [111][74]. However, some evidence suggests that mammary epithelial cells can also produce insulin [112][75]. Colostrum concentrations of insulin are substantial (114–306 mU/L) and rapidly decrease so HM concentrations match that of maternal blood by day 5 postpartum [111][74].

5. Resistin

Resistin is a 12.5 kDa cysteine-rich polypeptide hormones consisting of 114 amino acids. First discovered in rodents as an adipose-secreted hormone, resistin plays a physiological role as a subclinical inflammatory mediator between obesity and diabetes. Serum resistin concentrations are higher in obese and diabetic mice, and mouse models with diet-induced obesity [117][76]. Resistin antagonises insulin action and induces glucose intolerance in vivo [117][76]. In humans, the primary source of resistin is macrophages, therefore it is strongly related to inflammatory conditions [118][77]. Resistin gene expression has been reported in human placental tissue with its prominence in the chorionic villi during the first trimester suggesting a role in modulating insulin sensitivity during pregnancy [119][78]. Concentrations of resistin in HM are lower than that of maternal and infant serum, and decrease throughout the lactation period [120][79].

6. Obestatin

Obestatin is a 23 amino acid peptide, discovered in 2003 as a carboxyl-terminal fragment of pro-ghrelin (C-ghrelin) [121][80]. Obestatin is encoded by the ghrelin gene and is derived from the carboxy-terminal part of proghrelin; ghrelin is derived from the N-terminal part of the same precursor preproghrelin. Obestatin is considered an antagonist to ghrelin as it inhibits feeding and digestive motility by binding to the orphan G protein-coupled receptor GPR39 [121,122][80][81]. Gronberg et al. [97][71] reported the subcellular localisation of obestatin and that obestatin immunoreactive cells were present in the gastrointestinal tract, pancreatic islets and mammary glands. Obestatin appears to be involved in many physiological functions, cell proliferation, decreasing food intake, reducing body weight gain, increasing the secretion of pancreatic enzymes, and inhibiting glucose-induced insulin secretion [123][82]. HM obestatin concentrations are 538.90 ± 46.21 pg/mL and 528.5 ± 39.00 pg/mL in HM colostrum and mature milk, respectively [31][22]. HM obestatin concentrations are almost twice higher than in maternal serum; indicating it is an important component for the infant that may be synthesised by the mammary gland.

7. Apelin

Apelin is a small peptide that results from a cleavage of pre-proprotein of 77 amino acids into a signal peptide from the N-terminal region and 55 amino acids apelin precursor called proprotein. The proprotein precursor produces a group of active peptides that includes apelin-36, apelin-17, apelin-13 and apelin-12 [124,125][83][84]. Apelin peptides are endogenous ligands of the apelin receptor (APJ), this APJ is a class A G-protein-coupled receptor that is widely distributed in several tissues such as the heart, lung, brain, kidney, adipose tissue, vascular epithelium, gastrointestinal tract and mammary gland [126][85]. Habata et al. [127][86] reported the highest expression of apelin mRNA in the mammary gland of pregnant rats, and this biologically active apelin and its mRNA increased substantially during pregnancy and lactation [127][86]. Immunohistochemistry techniques have detected apelin immunoreactivity in the ductal and lobular epithelial cells and vascular endothelial cells of human mammary gland [128][87]. Apelin has been demonstrated to be involved in the regulation of cardiovascular and fluid homeostasis, food intake, cell proliferation, angiogenesis and most importantly, glucose and lipid metabolism. Apelin also appears to possess anti-obesity and anti-diabetic properties [129][88].

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