Lrp4 expression by adipocytes and osteoblasts differentially impacts sclerostin’s endocrine effects on body composition and glucose metabolism

Abstract

Sclerostin exerts profound local control over bone acquisition and also mediates endocrine communication between fat and bone. In bone, sclerostin's anti-osteoanabolic activity is enhanced by low-density lipoprotein receptor-related protein 4 (Lrp4), which facilitates its interaction with the Lrp5 and Lrp6 Wnt co-receptors. To determine whether Lrp4 similarly affects sclerostin's endocrine function, we examined body composition as well as glucose and fatty acid metabolism in mice rendered deficient of Lrp4 in the adipocyte (Ad⌬Lrp4) or the osteoblast (Ob⌬Lrp4). Ad⌬Lrp4 mice exhibit a reduction in adipocyte hypertrophy and improved glucose and lipid homeostasis, marked by increased glucose and insulin tolerance and reduced serum fatty acids, and mirror the effect of sclerostin deficiency on whole-body metabolism. Indeed, epistasis studies place adipocyte-expressed Lrp4 and sclerostin in the same genetic cascade that regulates adipocyte function. Intriguingly, Ob⌬Lrp4 mice, which exhibit dramatic increases in serum sclerostin, accumulate body fat and develop impairments in glucose tolerance and insulin sensitivity despite development of a high bone mass phenotype. These data indicate that expression of Lrp4 by both the adipocyte and osteoblast is required for normal sclerostin endocrine function and that the impact of sclerostin deficiency on adipocyte physiology is distinct from the effect on osteoblast function.

An Integrative Phenotype–Genotype Approach Using Phenotypic Characteristics from the UAE National Diabetes Study Identifies HSD17B12 as a Candidate Gene for Obesity and Type 2 Diabetes

“…LRP4 loss of function has been associated with developmental anomalies associated with Cenani-Lenz syndrome (CLS) disease, which includes limb malformation and renal agenesis [33]. Furthermore, adipocytes in LRP4 deficient mice were characterized by an improvement of glucose and insulin tolerance, lipid homeostasis, less adipocyte hypertrophy as well as reduction of serum fatty acids, thus confirming the role of LRP4 in regulating glucose metabolism [34]. FES gene encodes for a non-receptor protein with tyrosine-specific activity.…”

Roles of bone-derived hormones in type 2 diabetes and cardiovascular pathophysiology

“…Outside the bone, sclerostin is abundantly expressed in the general circulation, with normal physiological levels below 1 ng/mL [ 135 ]. Because Wnt/β-catenin signaling pathway is a key regulator of cellular functions, including proliferation, differentiation, and migration in various tissues [ 136 ], an endocrine role of bone-derived sclerostin has also been demonstrated [ 9 , 137 ].…”

“…Consistent with these clinical reports, a recent mechanistic study demonstrated that sclerostin deficiency in mice resulted in reduced adipose tissue accumulation, improved whole-body and muscle insulin sensitivity and decreased hepatic gluconeogenesis [ 9 ]. In another study, the loss of the functional receptor LRP4 in fat tissue led to smaller adipocyte size and increased whole-body insulin response [ 137 ]. Additionally, in several mice models with sclerostin overproduction, enhanced fat mass and compromised insulin sensitivity were observed [ 9 , 137 , 142 ].…”

“…In another study, the loss of the functional receptor LRP4 in fat tissue led to smaller adipocyte size and increased whole-body insulin response [ 137 ]. Additionally, in several mice models with sclerostin overproduction, enhanced fat mass and compromised insulin sensitivity were observed [ 9 , 137 , 142 ]. However, another recent study reported that sclerostin overexpression may have beneficial effects on energy metabolism by facilitating beige adipogenesis [ 143 ], indicating that the physiological roles of sclerostin may be more complex than originally perceived.…”

The lncRNA Rhno1/miR-6979-5p/BMP2 Axis Modulates Osteoblast Differentiation

“…we combined the results of the above three databases to enhance the strength of the evidence, and in order to show the process of the method of selecting target gene more clearly, we produced a Venn diagram and as shown in Figure 3A, three candidate genes were identified of interest -PI3KR1, BMP2, and LRP5. Following a literature review, although LRP5 is involved in Wnt/LRP5/β-Catenin signaling pathway, and thereby mediate the osteoblast differentiation process [22], BMP2 is a osteogenic mediator demonstrated widely in much more previous researches [23][24][25]. Thus, we select BMP2 from the three candidates as a target gene for miR-6979-5p.…”