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. IntroductionThe chronic consumption of meals rich in fat and carbohydrates is a major causative factor of obesity and diabetes. The prevailing view on the mechanism by which these dietary factors contribute to obesity and diabetes is that when energy intake surpasses expenditure, the excess calories are deposited as fat in adipose tissues and its subsequent mobilization to nonadipose tissues causes insulin resistance that ultimately leads to type 2 diabetes (1-3). High fat and carbohydrate intake also leads to plasma lipid abnormalities, including high plasma levels of nonesterified fatty acids (NEFAs) and triglyceride-rich lipoproteins (TGRL) as well as reduced plasma levels of HDL (2, 3). Numerous past studies have shown that elevated plasma NEFA levels directly induce insulin resistance and thus play a causative role in the pathogenesis of obesity-related diabetes (1,4,5). However, only sporadic attention has been paid to the role of TGRL in obesity and diabetes. The TGRL are generally thought of primarily as triglyceride carriers in the circulation, delivering substrates to tissues where lipoprotein lipase-catalyzed (LpL-catalyzed) hydrolysis liberates NEFAs prior to their uptake by cells through CD36 and other pathways (6). It is important to note that TGRL as well as lipase-hydrolyzed TGRL remnants can also be internalized by cells directly via whole-particle uptake and provide triglyceride-derived fatty acids via mechanisms mediated by LDL receptor family member proteins (7). Results showing

Proteomic Analysis of GLUT4 Storage Vesicles Reveals LRP1 to Be an Important Vesicle Component and Target of Insulin Signaling

“…Indeed, LRP1 was also known to show insulin-sensitive trafficking in primary adipocytes as shown by ligand binding assays (41), but its location in GSVs was not investigated in these prior studies. Adipocyte-specific LRP1 Ϫ/Ϫ mice display abnormalities of lipid clearance and energy balance in vivo (32,49). Our data showing decreased GLUT4 expression in adipocytes from the tissue-specific knock-out (Fig.…”

“…Epididymal Adipose Tissue from Lrp1 Adipose-specific Knock-out Mice Show Decreased Expression of GLUT4 and Sortilin-An Lrp1 gene knock-out in mice is embryonically lethal, but an LRP1 adipose tissue-specific knock-out mouse has been created and characterized to be resistant to dietary fat-induced obesity and has improved glucose tolerance due to secondary muscle effects (32). This whole animal study did not, however, assess fat cell glucose transport in vitro nor did a more recent study of adipocyte differentiation from Lrp1 Ϫ/Ϫ fibroblasts (49).…”

Retinoic Acid Receptor β Stimulates Hepatic Induction of Fibroblast Growth Factor 21 to Promote Fatty Acid Oxidation and Control Whole-body Energy Homeostasis in Mice

“…The rates of VO 2 and VCO 2 were expressed as average values measured every 18 min over a 12-h block of light and dark cycles. The energy expenditure (kcal/kg/h) was calculated with the formula, (3.815 ϩ 1.232 ϫ VCO 2 /VO 2 ) ϫ VO 2 ϫ 0.001, as described previously (27,28). Physical activity was measured on x and y axes using infrared beams to count the bean breaks in CLAMS cages.…”

Hepatic Deficiency of Low Density Lipoprotein Receptor-related Protein-1 Reduces High Density Lipoprotein Secretion and Plasma Levels in Mice

“…All mice were maintained on alternating 12-h light and dark cycles under controlled environmental conditions with free access to food and water. The Lrp1 flox/flox mice were originally obtained from Dr. Joachim Herz at the University of Texas Southwestern Medical Center and were backcrossed in our facility with C57BL/6 mice for 10 generations to achieve congenic Lrp1 flox/flox mice (10,14). Liver-specific LRP1-null (hLrp1 Ϫ/Ϫ ) mice were generated by cross-breeding Lrp1 flox/flox mice with albumin promoterdriven cre recombinase transgenic mice in the C57BL/6 background (The Jackson Laboratory, Bar Harbor, ME).…”

“…For example, LRP1 serves as a signaling receptor during adipocyte differentiation via activation of Wnt5a/␤-catenin pathway and inhibition of acetyl-CoA carboxylase phosphorylation (11). In contrast, LRP1 is a cargo transporting receptor in mature adipocytes responsible for the uptake of lipid nutrients from triglyceride-rich lipoproteins for storage and utilization (14). The function of LRP1 in smooth muscle cells is also unrelated to cargo transport, but its modulation of PDGF receptor and TGF␤-1 receptor activities is essential for maintenance of vascular reactivity and limiting hypercholesterolemia-induced atherosclerosis and injury-induced neointimal hyperplasia (8 -10).…”