Role of LRP1 and ERK and cAMP Signaling Pathways in Lactoferrin-Induced Lipolysis in Mature Rat Adipocytes

PLoS One. 2015 Oct 27;10(10):e0141378. doi: 10.1371/journal.pone.0141378. eCollection 2015.

Abstract

Lactoferrin (LF) is a multifunctional glycoprotein present in milk. A clinical study showed that enteric-coated bovine LF tablets decrease visceral fat accumulation. Furthermore, animal studies revealed that ingested LF is partially delivered to mesenteric fat, and in vitro studies showed that LF promotes lipolysis in mature adipocytes. The aim of the present study was to determine the mechanism underlying the induction of lipolysis in mature adipocytes that is induced by LF. To address this question, we used proteomics techniques to analyze protein expression profiles. Mature adipocytes from primary cultures of rat mesenteric fat were collected at various times after exposure to LF. Proteomic analysis revealed that the expression levels of hormone-sensitive lipase (HSL), which catalyzes the rate-limiting step of lipolysis, were upregulated and that HSL was activated by protein kinase A within 15 min after the cells were treated with LF. We previously reported that LF increases the intracellular concentration of cyclic adenosine monophosphate (cAMP), suggesting that LF activates the cAMP signaling pathway. In this study, we show that the expression level and the activity of the components of the extracellular signal-regulated kinase (ERK) signaling pathway were upregulated. Moreover, LF increased the activity of the transcription factor cAMP response element binding protein (CREB), which acts downstream in the cAMP and ERK signaling pathways and regulates the expression levels of adenylyl cyclase and HSL. Moreover, silencing of the putative LF receptor low-density lipoprotein receptor-related protein 1 (LRP1) attenuated lipolysis in LF-treated adipocytes. These results suggest that LF promoted lipolysis in mature adipocytes by regulating the expression levels of proteins involved in lipolysis through controlling the activity of cAMP/ERK signaling pathways via LRP1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / drug effects
  • Adipocytes / metabolism*
  • Animals
  • Cattle
  • Cyclic AMP / biosynthesis
  • Gene Expression Regulation / drug effects
  • Intra-Abdominal Fat / metabolism
  • Lactoferrin / administration & dosage*
  • Lipolysis / drug effects*
  • Lipolysis / genetics
  • Low Density Lipoprotein Receptor-Related Protein-1 / antagonists & inhibitors
  • Low Density Lipoprotein Receptor-Related Protein-1 / genetics*
  • MAP Kinase Signaling System / drug effects
  • Proteomics
  • Rats
  • Sterol Esterase / biosynthesis

Substances

  • Low Density Lipoprotein Receptor-Related Protein-1
  • Cyclic AMP
  • Sterol Esterase
  • Lactoferrin

Grants and funding

KI, KN, SM, TO, and MM are employees of Lion Corporation. HN and KS received consulting fees from Lion Corporation. This work was supported by Lion Corporation and especially Proteomic analysis part was supported by the Establishment of Research Center for Clinical Proteomics of Post-Translational Modifications (a research task of the Creation of "Innovation Centers for Advanced Interdisciplinary Research Areas" Program of Project for Developing Innovation Systems of the Ministry of Education, Culture, Sports, Science and, Technology, Japan (ID: 11800122)). Lion Corporation had role in the study design, conduct of the study, data collection, data interpretation or preparation of the report, and the Establishment of Research Center for Clinical Proteomics of Post-Translational Modifications had a role in the study design, conduct of the study, data collection, data interpretation or preparation of the report in Proteomic analysis part.