lactoferrin and Obesity

Milk-derived bioactive proteins have increasingly gained attention and consideration throughout the world due to their high-quality amino acids and multiple health-promoting attributes. Apparently, being at the forefront of functional foods, these bioactive proteins are also suggested as potential alternatives for the management of various complex diseases. In this review, we will focus on lactoferrin (LF) and osteopontin (OPN), two multifunctional dairy proteins, as well as to their naturally occurring bioactive LF-OPN complex. While describing their wide variety of physiological, biochemical, and nutritional functionalities, we will emphasize their specific roles in the perinatal period. Afterwards, we will evaluate their ability to control oxidative stress, inflammation, gut mucosal barrier, and intestinal microbiota in link with cardiometabolic disorders (CMD) (obesity, insulin resistance, dyslipidemia, and hypertension) and associated complications (diabetes and atherosclerosis). This review will not only attempt to highlight the mechanisms of action, but it will critically discuss the potential therapeutic applications of the underlined bioactive proteins in CMD.

Topics: Cardiovascular Diseases; Female; Humans; Inflammation; Lactoferrin; Milk Proteins; Obesity; Osteopontin; Pregnancy

Many pathological conditions, including obesity, diabetes, hypertension, heart disease, and cancer, are associated with abnormal metabolic states. The progressive loss of metabolic control is commonly characterized by insulin resistance, atherogenic dyslipidemia, inflammation, central obesity, and hypertension, a cluster of metabolic dysregulations usually referred to as the "metabolic syndrome". Recently, nutraceuticals have gained attention for the generalized perception that natural substances may be synonymous with health and balance, thus becoming favorable candidates for the adjuvant treatment of metabolic dysregulations. Among nutraceutical proteins, lactoferrin (Lf), an iron-binding glycoprotein of the innate immune system, has been widely recognized for its multifaceted activities and high tolerance. As this review shows, Lf can exert a dual role in human metabolism, either boosting or resetting it under physiological and pathological conditions, respectively. Lf consumption is safe and is associated with several benefits for human health, including the promotion of oral and gastrointestinal homeostasis, control of glucose and lipid metabolism, reduction of systemic inflammation, and regulation of iron absorption and balance. Overall, Lf can be recommended as a promising natural, completely non-toxic adjuvant for application as a long-term prophylaxis in the therapy for metabolic disorders, such as insulin resistance/type II diabetes and the metabolic syndrome.

Topics: Adjuvants, Immunologic; Diabetes Mellitus, Type 2; Energy Metabolism; Humans; Hypertension; Inflammation; Insulin Resistance; Iron; Lactoferrin; Metabolic Syndrome; Obesity

Lactoferrin is a multipotent protein that belongs to the transferrin family. It was first isolated from cow's milk in 1939. In the 1960s, it was also found in breast milk. In the human body, lactoferrin can also be found in other body fluids, e.g., saliva, tears, and vaginal discharge. Its biological activity depends on receptors present on the membrane surface of many cells, such as neutrophils, hepatocytes, and intestinal epithelial cells. Lactoferrin can bind iron. Because of this property, it also has antibacterial, antiviral, and antifungal activity. Its antiinflammatory and anticancer activity has also been confirmed. Recent studies have demonstrated that lactoferrin might have a beneficial effect in the prevention and treatment of obesity-related metabolic abnormalities, such as type 2 diabetes, hypertension, and dyslipidaemia. It is also worth to notice the potential relationship between polymorphisms in lactoferrin gene, genes for lactoferrin receptors and metabolic abnormalities in obese subjects.

Topics: Animals; Cattle; Diabetes Mellitus, Type 2; Female; Humans; Lactoferrin; Obesity; Prevalence; Receptors, Cell Surface

Obesity is a strong predictive factor in the development of chronic disease and has now superseded undernutrition as a major public health issue. Chronic inflammation is one mechanism thought to link excess body weight with disease. Increasingly, the gut and its extensive population of commensal microflora are recognized as playing an important role in the development of obesity-related chronic inflammation. Obesity and a high fat diet are associated with altered commensal microbial communities and increased intestinal permeability which contributes to systemic inflammation as a result of the translocation of lipopolysaccharide into the circulation and metabolic endotoxemia. Various milk proteins are showing promise in the prevention and treatment of obesity and chronic low-grade inflammation via reductions in visceral fat, neutralization of bacteria at the mucosa and reduced intestinal permeability. In this review, we focus on evidence supporting the potential antiobesogenic and anti-inflammatory effects of bovine whey-derived lactoferrin and immunoglobulins.

Topics: Animals; Anti-Inflammatory Agents; Anti-Obesity Agents; Body Weight; Cattle; Chronic Disease; Disease Models, Animal; Endotoxemia; Functional Food; Gastrointestinal Microbiome; Gastrointestinal Tract; Humans; Immunoglobulins; Inflammation; Lactoferrin; Lipopolysaccharides; Obesity; Randomized Controlled Trials as Topic; Whey

Currently, obesity-associated metabolic disturbances are envisioned as chronic inflammatory processes, characterized by activation of both innate and adaptive immunity. Although the features of chronic inflammation in obese subjects are clearly defined, the signals and mechanisms that trigger chronic inflammation are not well understood. Recent studies suggest an imbalance in circulating antimicrobial proteins as a possible cause of obesity-associated metabolic disturbances and insulin resistance. This imbalance promotes a relative failure in the capacity of buffering external insults and might cause the onset of chronic inflammation and immunologic alterations in obesity. Here, we review the current literature on the possible role of circulating antimicrobial proteins in obesity-associated immunologic alterations.

Topics: Antimicrobial Cationic Peptides; Humans; Immune System Diseases; Inflammation; Lactoferrin; Lipocalins; Obesity

Obesity, dyslipidemia, hyperglycemia/type II diabetes and hypertension together constitute the so-called metabolic syndrome. Frequency of occurrence of these serious metabolic disturbances is associated with life style and is on the rise in prosperous industrialized countries. These diseases represent not only a serious health problem but also social and economic ones, and involve in prophylaxis and treatment various specialists (physicians, dieticians and psychologists). For about two decades research has been conducted on the possibility to apply milk-derived proteins in prevention and treatment of the above mentioned metabolic diseases. Lactoferrin (LF), a protein present in milk and excretory fluids of mammals, is one of the most intensively studied milk proteins for therapeutic application. Initial trials revealing an advantageous effect of LF on lipid metabolism and obesity enrolled only a few volunteers and were performed in Japan in 2003. Subsequent trials were conducted on animals as well as in clinics, and the positive results were supported by in vitro tests. After oral administration of LF, decreases of body weight, waist measurement, visceral fat tissue, plasma and liver fatty acid concentrations, triglycerides and cholesterol were registered. The mechanism of LF action may involve several processes, such as inhibition of adipogenesis, decrease of dietary triglyceride absorption, elevation of HDL cholesterol possessing anti-atherogenic properties, inhibition of accumulation of oxidized LDL cholesterol forms in macrophages and protection against formation of foam cells. LF also increases the susceptibility of cells to insulin action, including in conditions when the response to insulin is lowered (during inflammation). In addition, LF regulates activity of insulin-like growth factor (IGF). The data collected to date indicate that LF is a promising, completely nontoxic, natural remedy which (as for example a food supplement) may be applied in long-term prophylaxis and therapy of metabolic disturbances, such as dyslipidemia, obesity and insulin resistance/type II diabetes. 

Topics: Animals; Blood Glucose; Cholesterol, HDL; Humans; Hyperglycemia; Insulin Resistance; Japan; Lactoferrin; Lipid Metabolism; Metabolic Syndrome; Obesity; Somatomedins; Triglycerides

Obesity is a global epidemic, it can induce glucose and lipid metabolism disorder and non-alcoholic fatty liver disease (NAFLD). This study explored a new way to control weight and improve fatty liver, namely, living in hypoxia environment and supplement with lactoferrin (Lf). Sixty male C57BL/6J mice were divided into six groups, namely, control, hypoxia, high-fat diet, hypoxia + high-fat diet, hypoxia + high-fat diet + low dose Lf intervention, and hypoxia + high-fat diet + high-dose Lf intervention. Mice in the hypoxia treatment groups were treated with approximately 11.5 % oxygen for 6 h every day for 8 weeks. Results showed that interventions combining Lf and hypoxia treatments showed better effect against obesity and NAFLD than hypoxia treatment alone. The interventions controlled weight gain in mice, improved glucolipid metabolism in mice. The combination intervention reduced cholesterol absorption by reducing the level of hydrophobic bile acids, and elevating the level of hydrophilic bile acids. Gut microbiota analysis revealed that the combination intervention considerably elevated short chain fatty acids (SCFAs)-producing bacteria level, and reduced the Desulfovibrionaceae_unclassified level. Thus, Lf combined with hypoxia intervention effectively prevents obesity and NAFLD by restoring gut microbiota composition and bile acid profile.

Topics: Animals; Bile Acids and Salts; Diet, High-Fat; Hypoxia; Lactoferrin; Liver; Male; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Obesity

The secretory glycoprotein lactoferrin (LF) is suggested to ameliorate overweight regardless of non-genetic or genetic mechanisms. Although maternal overweight represents a key predictor of offspring growth, the efficacy of LF on fertility problems in overweight and obese mothers remains unknown. To address this issue, we examined the effect of LF ingestion by analyzing overweight mice (Institute of Cancer Research (ICR) mice with high-fat diets; HF mice) and obese mice (

Topics: Animals; Diabetes Mellitus, Type 2; Female; Fertility; Fertility Agents, Female; Infertility, Female; Lactoferrin; Mice; Obesity; Overweight; Up-Regulation

This study aimed to evaluate the association of genetic variants in lactoferrin (

Topics: Aged; Female; Genetic Predisposition to Disease; Genotype; Humans; Lactoferrin; Male; Middle Aged; Obesity; Polymorphism, Single Nucleotide; Receptors, Cell Surface

The aim of the study was to compare serum lactoferrin concentrations in metabolically healthy obese (MHO) and metabolically unhealthy obese (MUHO) women.. Three hundred (101 MHO and 199 MUHO) women were recruited to the study. Basic anthropometric parameters and blood pressure were measured. Body mass index (BMI) was calculated. Fat mass and visceral adipose tissue mass were assessed using dual X-ray absorptiometry scan. Fasting glucose, insulin, lipid profile, high sensitivity C-reactive protein (hs-CRP) and lactoferrin levels were determined.. Lactoferrin levels did not differ between MHO and MUHO subjects (median (interquartile range): 1639 (1055-2396) vs. 1622 (1009-23345) ng/mL). However, in the total population insulin (r = 0.131,. Lactoferrin levels did not differ between MHO and MUHO women. However, some mild correlations between lactoferrin concentrations and anthropometric and metabolic parameters were observed mostly in MHO subjects.

Topics: Adiposity; Biomarkers; Body Mass Index; Body Weight; Energy Metabolism; Female; Humans; Lactoferrin; Middle Aged; Obesity; Obesity, Metabolically Benign; Waist Circumference

To determine whether diets enriched with the whey protein components lactalbumin and lactoferrin interact additively with inulin to improve energy balance by decreasing food intake and body weight (BW).. In four experiments, diet-induced obese rats were randomized to diets containing either lactalbumin or lactoferrin at low (20% kcal) or high (40% kcal) doses, and inulin at low (7.5% w/w) or high (15% w/w) doses, alone or in combination. Energy intake (EI), energy expenditure (EE), respiratory quotient (RQ), BW, body composition, plasma insulin, and leptin concentrations were measured.. Lactalbumin and inulin at low doses were ineffective, whereas high doses additively decreased EI and RQ. Low doses of lactoferrin and inulin additively decreased EI, BW, fat and lean mass, and RQ. High doses of lactoferrin and inulin additively decreased EI, supra-additively decreased BW, fat, and lean mass, and also decreased RQ and plasma leptin concentrations.. High doses of lactalbumin and inulin additively decreased EI. Importantly, lactoferrin and inulin at both low and high dose combinations, additively or supra-additively, decreased EI, BW, and adiposity.

Topics: Animals; Diet; Disease Models, Animal; Energy Intake; Energy Metabolism; Inulin; Lactalbumin; Lactoferrin; Male; Obesity; Rats; Rats, Sprague-Dawley

Whey protein promotes weight loss and improves diabetic control, however, less is known of its bioactive components that produce such benefits. We compared the effects of normal protein (control) diet with high protein diets containing whey, or its fractions lactalbumin and lactoferrin, on energy balance and metabolism. Diet-induced obese rats were randomized to isocaloric diets: Control, Whey, Lactalbumin, Lactoferrin, or pair-fed to lactoferrin. Whey and lactalbumin produced transient hypophagia, whereas lactoferrin caused prolonged hypophagia; the hypophagia was likely due to decreased preference. Lactalbumin decreased weight and fat gain. Notably, lactoferrin produced sustained weight and fat loss, and attenuated the reduction in energy expenditure associated with calorie restriction. Lactalbumin and lactoferrin decreased plasma leptin and insulin, and lactalbumin increased peptide YY. Whey, lactalbumin and lactoferrin improved glucose clearance partly through differential upregulation of glucoregulatory transcripts in the liver and skeletal muscle. Interestingly, lactalbumin and lactoferrin decreased hepatic lipidosis partly through downregulation of lipogenic and/or upregulation of β-oxidation transcripts, and differentially modulated cecal bacterial populations. Our findings demonstrate that protein quantity and quality are important for improving energy balance. Dietary lactalbumin and lactoferrin improved energy balance and metabolism, and decreased adiposity, with the effects of lactoferrin being partly independent of caloric intake.

Topics: Adiposity; Animals; Body Weight; Diet; Energy Intake; Energy Metabolism; Insulin; Lactalbumin; Lactoferrin; Leptin; Male; Obesity; Peptide YY; Rats; Whey Proteins

Lactoferrin (Lf) is an important protein found on mucosal surfaces, within neutrophils and various cells, and in biological fluids. It displays multiple functions, including iron-binding as well as antimicrobial, immunomodulatory and anti-inflammatory activities. Although Lf ingestion has been suggested to cause adiposity reduction in murine models and humans, its relationship with insulin resistance (IR) has not been studied thoroughly.. To establish the association between circulating Lf levels, glucose status and blood lipid/lipoprotein profile.. Two independent cohorts were examined: lean to moderately obese women admitted for gynecological surgery (n = 53) and severely obese subjects undergoing biliopancreatic diversion (n = 62).. Although body mass index (BMI) and total body fat mass were negatively associated with Lf, IR (assessed by the HOMA-IR index) was positively and independently associated with plasma Lf concentrations of the first cohort of lean to moderately obese women. These observations were validated in the second cohort in view of the positive correlation between plasma Lf concentrations and the HOMA-IR index, but without a significant association with the body mass index (BMI) of severely obese subjects. In subsamples of severely obese subjects matched for sex, age and BMI, but with either relatively low (1.89 ± 0.73) or high (13.77 ± 8.81) IR states (according to HOMA-IR), higher plasma Lf levels were noted in insulin-resistant vs insulin-sensitive subjects (P<0.05). Finally, Lf levels were significantly higher in lean to moderately obese women than in severely obese subjects (P<0.05).. Our findings revealed that plasma Lf levels are strongly associated with IR independently of total adiposity, which suggests an intriguing Lf regulation mechanism in conditions of obesity and IR.

Topics: Adiposity; Adult; Biomarkers; Blood Glucose; Cohort Studies; Female; Humans; Insulin Resistance; Lactoferrin; Lipids; Lipoproteins; Male; Middle Aged; Obesity; Thinness

Metabolic disorders like diabetes mellitus and obesity may compromise the fertility of men and women. To unveil disease-associated proteomic changes potentially affecting male fertility, the proteomes of sperm cells from type-1 diabetic, type-2 diabetic, non-diabetic obese and clinically healthy individuals were comparatively analyzed by difference gel electrophoresis. The adaptation of a general protein extraction procedure to the solubilization of proteins from sperm cells allowed for the resolution of 3187 fluorescent spots in the difference gel electrophoresis image of the master gel, which contained the entirety of solubilized sperm proteins. Comparison of the pathological and reference proteomes by applying an average abundance ratio setting of 1.6 and a p ≤ 0.05 criterion resulted in the identification of 79 fluorescent spots containing proteins that were present at significantly changed levels in the sperm cells. Biometric evaluation of the fluorescence data followed by mass spectrometric protein identification revealed altered levels of 12, 71, and 13 protein species in the proteomes of the type-1 diabetic, type-2 diabetic, and non-diabetic obese patients, respectively, with considerably enhanced amounts of the same set of one molecular form of semenogelin-1, one form of clusterin, and two forms of lactotransferrin in each group of pathologic samples. Remarkably, β-galactosidase-1-like protein was the only protein that was detected at decreased levels in all three pathologic situations. The former three proteins are part of the eppin (epididymal proteinase inhibitor) protein complex, which is thought to fulfill fertilization-related functions, such as ejaculate sperm protection, motility regulation and gain of competence for acrosome reaction, whereas the putative role of the latter protein to function as a glycosyl hydrolase during sperm maturation remains to be explored at the protein/enzyme level. The strikingly similar differences detected in the three groups of pathological sperm proteomes reflect a disease-associated enhanced formation of predominantly proteolytically modified forms of three eppin protein complex components, possibly as a response to enduring hyperglycemia and enhanced oxidative stress.

Topics: Adult; Aged; Biomarkers; Case-Control Studies; Cell Shape; Clusterin; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Infertility, Male; Lactoferrin; Male; Middle Aged; Multiprotein Complexes; Obesity; Protein Isoforms; Proteinase Inhibitory Proteins, Secretory; Proteome; Reference Standards; Seminal Vesicle Secretory Proteins; Sperm Count; Sperm Motility; Spermatozoa; Two-Dimensional Difference Gel Electrophoresis; Young Adult

The aim of the study was to compare the effect of different whey protein-containing high-Ca diets on weight loss and weight regain in a model of diet-induced obesity. Obesity was induced in C57BL/6J mice with a high-fat (60 % of energy) diet. Weight loss by energy restriction was performed on four different high-Ca diets (1.8 % CaCO3) containing different whey proteins (18 % of energy): alpha-lactalbumin (ALA), beta-lactoglobulin (BLG), lactoferrin (LF) and whey protein isolate (WPI). After 7 weeks of energy restriction some of the mice were killed and the rest were fed with the same diets ad libitum for 7 weeks. The mice on the LF diet lost significantly more weight than mice on the WPI diet. The body fat content in the ALA and LF groups was significantly lower than in the WPI group (P < 0.05) and the LF group differed significantly even from the BLG group (P < 0.05). Ad libitum feeding after weight loss resulted in weight regain in all groups and only the ALA diet significantly reduced fat accumulation during weight regain. The weight regain was most pronounced in the LF group, but the adipocyte size was still significantly smaller than in the other groups. There were no differences in food intake or apparent fat digestibility between the groups. It can be concluded that a high-Ca diet with ALA significantly improves the outcome of weight loss and subsequent weight regain during the feeding of a high-fat diet in C57BL/6J mice, in comparison with WPI.

Topics: Adipocytes; Animals; Blood Glucose; Calcium; Calcium, Dietary; Cell Size; Dietary Fats; Energy Intake; Feces; Lactalbumin; Lactoferrin; Lactoglobulins; Male; Mice; Mice, Inbred C57BL; Milk Proteins; Models, Animal; Obesity; Treatment Outcome; Weight Loss; Whey Proteins

Lactoferrin, an innate immune protein with antiinflammatory properties, shows considerable antiatherosclerosis activity in animal studies. We investigated the relationship between circulating lactoferrin, lactoferrin gene (LTF, lactotransferrin) polymorphisms, dyslipidemia, and vascular reactivity in the context of glucose-tolerance status in men.. We evaluated 2 nonsynonymous LTF polymorphisms (rs1126477 and rs1126478) and measured circulating lactoferrin concentrations by ELISA under nonstressed conditions in healthy Caucasian men (n = 188) and male patients with an altered glucose tolerance (n = 202). We also studied the association of lactoferrin concentration with vascular reactivity via high-resolution ultrasound analysis of the brachial artery in a subsample of study participants.. Circulating lactoferrin concentration was inversely associated with fasting triglyceride concentration (r = -0.24; P = 0.001), body mass index (BMI) (r = -0.20; P = 0.007), waist-to-hip ratio (r = -0.35; P <0.001), and fasting glucose concentration (r = -0.18; P = 0.01), and directly correlated with HDL cholesterol concentration (r = 0.21; P = 0.004). Control AG heterozygotes for rs1126477 had significantly decreased fasting triglyceride concentrations (P = 0.001). Similarly, control individuals who were G carriers for rs1126478 had significantly lower fasting triglyceride concentrations (P = 0.044) and significantly higher HDL cholesterol concentrations (P = 0.028) than AA homozygotes. These associations remained significant after controlling for age, BMI, waist-to-hip ratio, fasting glucose concentration, smoking status, and alcohol intake. Circulating lactoferrin concentration was not significantly associated with endothelium-dependent vasodilatation (EDVD) in the individuals studied (n = 95); however, lactoferrin was positively associated with EDVD in obese participants with an altered glucose tolerance (r = 0.54; P = 0.04).. We have identified associations among LTF polymorphisms, circulating lactoferrin concentration, fasting triglyceride concentration, and vascular reactivity in humans.

Topics: Alcohol Drinking; Body Mass Index; Cholesterol, HDL; Cholesterol, LDL; Dyslipidemias; Endothelium, Vascular; Enzyme-Linked Immunosorbent Assay; Glucose Intolerance; Glucose Tolerance Test; Humans; Lactoferrin; Male; Middle Aged; Obesity; Polymorphism, Single Nucleotide; Reference Values; Smoking; Triglycerides; Vasodilation; Waist-Hip Ratio; White People

We have developed a novel platform for display and delivery of bioactive peptides that links the biological properties of the peptide to the pharmacokinetic properties of an antibody. Peptides engineered in the MIMETIBODY platform have improved biochemical and biophysical properties that are quite distinct from those of Fc-fusion proteins. CNTO736 is a glucagon-like peptide 1 (GLP-1) receptor agonist engineered in our MIMETIBODY platform. It retains many activities of native GLP-1 yet has a significantly enhanced pharmacokinetic profile. Our goal was to develop a long-acting GLP-1 receptor agonist with sustained efficacy.. In vitro and in vivo activity of CNTO736 was evaluated using a variety of rodent cell lines and diabetic animal models.. Acute pharmacodynamic studies in diabetic rodents demonstrate that CNTO736 reduces fasting and postprandial glucose, decreases gastric emptying, and inhibits food intake in a GLP-1 receptor-specific manner. Reduction of food intake following CNTO736 dosing is coincident with detection of the molecule in the circumventricular organs of the brain and activation of c-fos in regions protected by the blood-brain barrier. Diabetic rodents dosed chronically with CNTO736 have lower fasting and postprandial glucose and reduced body weight.. Taken together, our data demonstrate that CNTO736 produces a spectrum of GLP-1 receptor-dependent actions while exhibiting significantly improved pharmacokinetics relative to the native GLP-1 peptide.

Topics: Adipose Tissue; Amino Acid Sequence; Animal Feed; Animals; Cell Line; Glucagon-Like Peptide-1 Receptor; Glucose; Homeostasis; Humans; Kidney; Lactoferrin; Mice; Mice, Inbred C57BL; Molecular Sequence Data; Obesity; Protein Engineering; Receptors, Glucagon; Transferrin