Adipocyte LDL receptor-related protein-1 expression modulates postprandial lipid transport and glucose homeostasis in mice

Susanna M. Hofmann, Li Zhou, Diego Perez-Tilve, Todd Greer, Erin Grant, Lauren Wancata, Andrew Thomas, Paul T. Pfluger, Joshua E. Basford, Dean Gilham, Joachim Herz, Matthias H. Tschöp, David Y. Hui

Research output: Contribution to journalArticle

105 Citations (Scopus)

Abstract

Diet-induced obesity and its serious consequences such as diabetes, cardiovascular disease, and cancer are rapidly becoming a major global health threat. Therefore, understanding the cellular and molecular mechanisms by which dietary fat causes obesity and diabetes is of paramount importance in order to identify preventive and therapeutic strategies. Increased dietary fat intake results in high plasma levels of triglyceride-rich lipoproteins (TGRL). Tissue uptake of TGRL has been shown to promote glucose intolerance. We generated mice with an adipocyte-specific inactivation of the multifunctional receptor LDL receptor-related protein-1 (LRP1) to determine its role in mediating the effects of TGRL on diet-induced obesity and diabetes. Knockout mice displayed delayed postprandial lipid clearance, reduced body weight, smaller fat stores, lipid-depleted brown adipocytes, improved glucose tolerance, and elevated energy expenditure due to enhanced muscle thermogenesis. We further demonstrated that inactivation of adipocyte LRP1 resulted in resistance to dietary fat-induced obesity and glucose intolerance. These findings identify LRP1 as a critical regulator of adipocyte energy homeostasis, where functional disruption leads to reduced lipid transport, increased insulin sensitivity, and muscular energy expenditure.

Original languageEnglish (US)
Pages (from-to)3271-3282
Number of pages12
JournalJournal of Clinical Investigation
Volume117
Issue number11
DOIs
StatePublished - Nov 1 2007

Fingerprint

Low Density Lipoprotein Receptor-Related Protein-1
Adipocytes
Dietary Fats
Homeostasis
Obesity
Lipoproteins
Lipids
Glucose
Triglycerides
Glucose Intolerance
Energy Metabolism
Brown Adipocytes
Diet
Thermogenesis
Knockout Mice
Insulin Resistance
Cardiovascular Diseases
Fats
Body Weight
Muscles

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Hofmann, S. M., Zhou, L., Perez-Tilve, D., Greer, T., Grant, E., Wancata, L., ... Hui, D. Y. (2007). Adipocyte LDL receptor-related protein-1 expression modulates postprandial lipid transport and glucose homeostasis in mice. Journal of Clinical Investigation, 117(11), 3271-3282. https://doi.org/10.1172/JCI31929

Adipocyte LDL receptor-related protein-1 expression modulates postprandial lipid transport and glucose homeostasis in mice. / Hofmann, Susanna M.; Zhou, Li; Perez-Tilve, Diego; Greer, Todd; Grant, Erin; Wancata, Lauren; Thomas, Andrew; Pfluger, Paul T.; Basford, Joshua E.; Gilham, Dean; Herz, Joachim; Tschöp, Matthias H.; Hui, David Y.

In: Journal of Clinical Investigation, Vol. 117, No. 11, 01.11.2007, p. 3271-3282.

Research output: Contribution to journalArticle

Hofmann, SM, Zhou, L, Perez-Tilve, D, Greer, T, Grant, E, Wancata, L, Thomas, A, Pfluger, PT, Basford, JE, Gilham, D, Herz, J, Tschöp, MH & Hui, DY 2007, 'Adipocyte LDL receptor-related protein-1 expression modulates postprandial lipid transport and glucose homeostasis in mice', Journal of Clinical Investigation, vol. 117, no. 11, pp. 3271-3282. https://doi.org/10.1172/JCI31929
Hofmann, Susanna M. ; Zhou, Li ; Perez-Tilve, Diego ; Greer, Todd ; Grant, Erin ; Wancata, Lauren ; Thomas, Andrew ; Pfluger, Paul T. ; Basford, Joshua E. ; Gilham, Dean ; Herz, Joachim ; Tschöp, Matthias H. ; Hui, David Y. / Adipocyte LDL receptor-related protein-1 expression modulates postprandial lipid transport and glucose homeostasis in mice. In: Journal of Clinical Investigation. 2007 ; Vol. 117, No. 11. pp. 3271-3282.
@article{6bcf4798fffc4407adb9809001ecb147,
title = "Adipocyte LDL receptor-related protein-1 expression modulates postprandial lipid transport and glucose homeostasis in mice",
abstract = "Diet-induced obesity and its serious consequences such as diabetes, cardiovascular disease, and cancer are rapidly becoming a major global health threat. Therefore, understanding the cellular and molecular mechanisms by which dietary fat causes obesity and diabetes is of paramount importance in order to identify preventive and therapeutic strategies. Increased dietary fat intake results in high plasma levels of triglyceride-rich lipoproteins (TGRL). Tissue uptake of TGRL has been shown to promote glucose intolerance. We generated mice with an adipocyte-specific inactivation of the multifunctional receptor LDL receptor-related protein-1 (LRP1) to determine its role in mediating the effects of TGRL on diet-induced obesity and diabetes. Knockout mice displayed delayed postprandial lipid clearance, reduced body weight, smaller fat stores, lipid-depleted brown adipocytes, improved glucose tolerance, and elevated energy expenditure due to enhanced muscle thermogenesis. We further demonstrated that inactivation of adipocyte LRP1 resulted in resistance to dietary fat-induced obesity and glucose intolerance. These findings identify LRP1 as a critical regulator of adipocyte energy homeostasis, where functional disruption leads to reduced lipid transport, increased insulin sensitivity, and muscular energy expenditure.",
author = "Hofmann, {Susanna M.} and Li Zhou and Diego Perez-Tilve and Todd Greer and Erin Grant and Lauren Wancata and Andrew Thomas and Pfluger, {Paul T.} and Basford, {Joshua E.} and Dean Gilham and Joachim Herz and Tsch{\"o}p, {Matthias H.} and Hui, {David Y.}",
year = "2007",
month = "11",
day = "1",
doi = "10.1172/JCI31929",
language = "English (US)",
volume = "117",
pages = "3271--3282",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "11",

}

TY - JOUR

T1 - Adipocyte LDL receptor-related protein-1 expression modulates postprandial lipid transport and glucose homeostasis in mice

AU - Hofmann, Susanna M.

AU - Zhou, Li

AU - Perez-Tilve, Diego

AU - Greer, Todd

AU - Grant, Erin

AU - Wancata, Lauren

AU - Thomas, Andrew

AU - Pfluger, Paul T.

AU - Basford, Joshua E.

AU - Gilham, Dean

AU - Herz, Joachim

AU - Tschöp, Matthias H.

AU - Hui, David Y.

PY - 2007/11/1

Y1 - 2007/11/1

N2 - Diet-induced obesity and its serious consequences such as diabetes, cardiovascular disease, and cancer are rapidly becoming a major global health threat. Therefore, understanding the cellular and molecular mechanisms by which dietary fat causes obesity and diabetes is of paramount importance in order to identify preventive and therapeutic strategies. Increased dietary fat intake results in high plasma levels of triglyceride-rich lipoproteins (TGRL). Tissue uptake of TGRL has been shown to promote glucose intolerance. We generated mice with an adipocyte-specific inactivation of the multifunctional receptor LDL receptor-related protein-1 (LRP1) to determine its role in mediating the effects of TGRL on diet-induced obesity and diabetes. Knockout mice displayed delayed postprandial lipid clearance, reduced body weight, smaller fat stores, lipid-depleted brown adipocytes, improved glucose tolerance, and elevated energy expenditure due to enhanced muscle thermogenesis. We further demonstrated that inactivation of adipocyte LRP1 resulted in resistance to dietary fat-induced obesity and glucose intolerance. These findings identify LRP1 as a critical regulator of adipocyte energy homeostasis, where functional disruption leads to reduced lipid transport, increased insulin sensitivity, and muscular energy expenditure.

AB - Diet-induced obesity and its serious consequences such as diabetes, cardiovascular disease, and cancer are rapidly becoming a major global health threat. Therefore, understanding the cellular and molecular mechanisms by which dietary fat causes obesity and diabetes is of paramount importance in order to identify preventive and therapeutic strategies. Increased dietary fat intake results in high plasma levels of triglyceride-rich lipoproteins (TGRL). Tissue uptake of TGRL has been shown to promote glucose intolerance. We generated mice with an adipocyte-specific inactivation of the multifunctional receptor LDL receptor-related protein-1 (LRP1) to determine its role in mediating the effects of TGRL on diet-induced obesity and diabetes. Knockout mice displayed delayed postprandial lipid clearance, reduced body weight, smaller fat stores, lipid-depleted brown adipocytes, improved glucose tolerance, and elevated energy expenditure due to enhanced muscle thermogenesis. We further demonstrated that inactivation of adipocyte LRP1 resulted in resistance to dietary fat-induced obesity and glucose intolerance. These findings identify LRP1 as a critical regulator of adipocyte energy homeostasis, where functional disruption leads to reduced lipid transport, increased insulin sensitivity, and muscular energy expenditure.

UR - http://www.scopus.com/inward/record.url?scp=36049022385&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=36049022385&partnerID=8YFLogxK

U2 - 10.1172/JCI31929

DO - 10.1172/JCI31929

M3 - Article

VL - 117

SP - 3271

EP - 3282

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 11

ER -