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

Hofmann, Susanna M.; Li Zhou; 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.; Zhou, Li; Tschöp, Matthias H

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.

METABOLIC disorders; EATING disorders; OBESITY; DIET in disease; HOMEOSTASIS; PHYSIOLOGICAL control systems

Journal of Clinical Investigation, 2007, Vol 117, Issue 11, p3271

0021-9738

Academic Journal

10.1172/JCI31929