Lactoferrin increases 172ThrAMPK phosphorylation and insulin-induced p473SerAKT while impairing adipocyte differentiation

Abstract

Objective: Lactoferrin is a pleiotropic glycoprotein of the innate immune system with known effects on immunomodulation and cell differentiation. To gain an insight into the interaction among obesity, inflammation and insulin action, we aimed to examine the effects of lactoferrin on adipogenesis and the response to insulin in human hepatocarcinoma (HepG2) and 3T3-L1 cell lines. Design: The cells were cultured with increasing lactoferrin concentration under non-inflammatory, inflammatory and standard conditions. The response to insulin was evaluated through 473Ser AKT phosphorylation. The effects of lactoferrin on adipogenesis were studied through the expression of different lipogenic markers, AMP-activated protein kinase (AMPK) activation, retinoblastoma (Rb) activity and Oil Red O staining in 3T3-L1 cells. Results: Lactoferrin increased dose-dependent insulin-induced 473Ser AKT phosphorylation in both cell lines. Inflammationinduced decreased 473Ser AKT phosphorylation was also rescued by lactoferrin. In addition, lactoferrin led to increased p172Thr AMPK during 3T3-L1 differentiation and to decreased adipogenesis (as shown by decreased expression of fatty acid synthase, acetyl-coenzyme A carboxylase-a and peroxisome proliferator-activated receptor-g in parallel with decreased formation of lipid droplets). Lactoferrin also increased dose-dependent Rb activity (expression and hypophosphorylation) during 3T3-L1 differentiation. Conclusion: Lactoferrin administration increased insulin-induced 473Ser AKT phosphorylation, even in those conditions wherein the response to insulin was downregulated, and led to blunted adipogenesis in the context of increased p172Thr AMPK and Rb activity.

Bovine lactoferrin reduces visceral fat and liver triglycerides in ICR mice

“…Yagi et al and Moreno-Navarrete et al reported similar effects of LF on the differentiation of 3T3L1 and MC3T3-G2/PA6 cell lines into adipocytes 9,11 . This phenomenon may involve low-density lipoprotein-related protein 1 LRP1 .…”

“…However, these previous studies were not focused on visceral fat. Recently, two studies have demonstrated the in vitro effects of LF on preadipocytes, where LF suppressed the differentiation of adipocytes in MC3T3-G2/PA6 cell lines 9 derived from the calvaria of mice 10 , as well as the differentiation of 3T3-L1 adipocytes established from a mouse embryo 11 . We reported the effects of bLF metabolites produced in the stomach and small intestine by the digestive enzymes pepsin and trypsin in an in vitro study 12 .…”

Protective effects of maternal nutritional supplementation with lactoferrin on growth and brain metabolism

“…More work is needed to determine whether bLf presents a doseresponse action and whether early bLf exposition allows symmetrical catch-up growth, including a proportional gain of lean, fat, and bone mass. In this sense, the activator effects of bLf on osteoblasts in rodents (20) and the presence of endogenous Lf during the early phases of the human endochondral ossification (21) suggest that Lf harbors a bone-promoting action whereas its effects on adipogenesis remain more elusive (22,23).…”

Prevention and Intervention Trials for Colorectal Cancer

“…All of these results suggest that bLF treatment can reduce the risk of colon carcinogenesis and have anti-tumor activity in humans. (iv) Lactoferrin is also reported to increase AMPK phosphorylation (91).…”