To Boost or to Reset: The Role of Lactoferrin in Energy Metabolism

Abstract

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.

Keywords: glucose metabolism; iron metabolism; lactoferrin; lipid metabolism; metabolic syndrome.

Figure 1

Schematic representation of systemic glycemic disorders in the absence (A) or presence (B) of lactoferrin. (A) Insulin resistance is a clinical condition where insulin’s ability to promote glucose absorption and utilization is impaired, resulting in elevated blood glucose levels. This condition hampers IR autophosphorylation, which impairs the IRS-1/PI3-kinase/AKT pathway and results in aberrant downstream signals, including GSK3 activation and the consequent inhibition of glycogen synthesis via the phosphorylation of GS; the reduction of mTOR-mediated protein synthesis, cell growth and proliferation; as well as FOX01nuclear translocation, which promotes gluconeogenesis and the inflammatory response. Stimulation of TLRs by TNF-α, IL-6, and IL-1β exacerbates insulin resistance through the inflammatory IKβ/NF-κB pathway, increasing cytokine expression. (B) Lactoferrin treatment counteracts these detrimental effects by boosting insulin binding to IR, thereby activating the IRS-1/PI3-kinase/Akt pathway. Akt activation results in AS160 phosphorylation, prompting GLUT to relocate from intracellular vesicles to the cell membrane, thus improving glucose uptake. Simultaneously, Akt-mediated FOX01 phosphorylation inactivates its nuclear translocation, while GSK3 and mTOR phosphorylation promote glycogen and protein synthesis, respectively. In addition, the protective effect of Lf could be explored by its ability to bind glucose and by virtue of its anti-inflammatory activity, thus counteracting TLR-mediated detrimental signaling. Abbreviations: insulin receptor (IR); insulin receptor substrate-1 (IRS-1); phosphatidyl inositol 3-kinase (PI3-Kinase); Akt, also known as protein kinase B; GSK3 (glycogen synthase kinase-3); GS (glycogen synthase); FOX01 (forkhead-box protein 01); Toll-like receptors (TLRs); tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6); interleukin-1β (IL-1β); nuclear factor kappa B (NF-κB); inhibitor of NF-κB (IKβ); glucose transporter (GLUT). Created with BioRender.com (accessed on 15 June 2023).

Figure 2

Schematic representation of systemic lipidic disorders in the absence (A) or presence (B) of lactoferrin. (A) Dietary fats, after emulsification and hydrolysis by bile acids, are taken up by enterocytes. Luminal cholesterol is transported across the brush border via NPC1L1 and, together with other lipids, is packed into nascent Cm particles. Once in the bloodstream, the Cm particles undergo transformations and are subject to the influence of LPL, which assists in converting Cm triglycerides into fatty acids and glycerol. Subsequently, hepatocytes internalize the Cm remnants through Cm receptors. In the context of systemic lipid disorders, upregulation of PPARγ, C/EBP-α, and SREBP-1 pathways and of other adipogenesis markers, such as ACC, FAS, and HMGCR, occurs, along with an increase in the levels of intracellular lipid droplets. Hepatic cells release abnormal quantities of VLDL, which are converted to LDL by LPL to release triglycerides to various tissues. This process elevates circulating LDL levels, contributing to the development of atherosclerotic plaques. On the other hand, low levels of circulating HDL are recorded. (B) Upon oral Lf treatment, a reduction in cholesterol absorption in the intestine is observed. In accordance with the downregulation of C/EBP-α, PPARγ, and SREBP-1pathways and the reduction of specific lipogenic enzymes, including FAS and ACC, a decrease in lipid droplet levels and circulating LDL is found. Interestingly, higher serum levels of HDL are observed. See text for further details. Abbreviations: Neiman–Pick C1-like 1 (NPC1L1); chylomicron (Cm); lipoprotein lipase (LPL); peroxisome proliferator-activated receptor γ (PPARγ); CCAAT/enhancer-binding protein (C/EBP-α); sterol-regulatory-element-binding protein-1 (SREBP-1); acetyl-CoA carboxylase (ACC); fatty-acid synthase (FAS); 3-hydroxy-3-methyl glutaryl CoA reductase (HMGCR), very-low-density lipoprotein (VLDL); low-density lipoprotein (LDL); high-density lipoprotein (HDL). Created with BioRender.com (accessed on 15 June 2023).