Adipocyte LDL receptor–related protein–1 expression modulates postprandial lipid transport and glucose homeostasis in mice
Susanna M. Hofmann, … , Matthias H. Tschöp, David Y. Hui
Susanna M. Hofmann, … , Matthias H. Tschöp, David Y. Hui
Published November 1, 2007
Citation Information: J Clin Invest. 2007;117(11):3271-3282. https://doi.org/10.1172/JCI31929.
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Categories: Research Article Metabolism

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.

Authors

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

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Figure 1

Characteristics of 2 independently generated ad-Lrp1+/+ and ad-Lrp1–/– mouse colonies.

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Characteristics of 2 independently generated ad-Lrp1+/+ and ad-Lrp1–/– m...
Adipose tissue–specific LRP1 gene inactivation was performed both on a mixed background (Dallas) and on an inbred C57BL/6 background (Cincinnati) by crossing aP2 Cre transgenic mice with Lrp1flox/flox mice. (A) Detection of the Cre transgene in mice with the mixed background by PCR. A fragment of 400 bp was amplified from mouse tail genomic DNA when the Cre transgene driven by the aP2 promoter was present. A 200-bp fragment amplified from the aP2 gene was observed in both PCR products as control. (B) Detection of wild-type (+/+) and mutant (–/–) mRNA of mice (mixed background) by quantitative real-time PCR. (C) Western blot identification of the β subunit of LRP1 in epididymal WAT (eWAT), BAT, and brain of ad-Lrp1+/+ and ad-Lrp1–/– mice (mixed background). β-Actin was used as loading control. (D) Ponceau S staining and Western blot of the β subunit of LRP1 in the stromal-vascular cells (sv) and mature adipocytes of subcutaneous (sWAT) and eWAT adipose tissue in ad-Lrp1+/+ and ad-Lrp1–/– mice. (E) Western blot of the β subunit of LRP1 in BAT (lanes 1 and 2), epididymal WAT (eWAT) (lanes 3 and 4), liver (lanes 5 and 6), skeletal muscle (lanes 7 and 8), and peritoneal macrophages (lanes 9, 10) of ad-Lrp1+/+ (lanes 1, 3, 5, 7, and 9) and ad-Lrp1–/– (lanes 2, 4, 6, 8, and 10) mice (inbred background). Molecular size markers (Mr) were applied to the lane flanking the sample lanes as indicated.