Comments for:

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Response to Aguilar-Salinas

Submitter: David Hui | huidy@email.uc.edu

University of Cincinnati College of Medicine

Published November 20, 2007

We appreciate the interest of Dr. Aguilar-Salinas and his colleagues in our paper and their thoughtful comments. In our paper, we demonstrated that inactivation of adipose LRP1 reduces fat storage in both white and brown adipose tissues in protecting against diet-induced obesity. We also showed increased energy expenditure in the ad-Lrp1-/- mice due to the shifting of brown adipose thermogenesis to increased muscular shivering activity for maintenance of body temperature. Our data presented in Figure 10C illustrated an increase in glucose uptake by skeletal muscle in ad-Lrp1-/- mice compared to that observed in wild type mice, which is consistent with their increase in energy demand for muscular thermogenesis. This increase in glucose assimilation is clearly one mechanism by which the ad-Lrp1-/- mice have improved glucose tolerance. Obviously, several additional mechanisms may act in concert to protect these animals against high fat diet-induced insulin resistance. For example, the reduced adiposity may directly lead to improved insulin sensitivity in the ad-Lrp1-/- mice compared to their wild type counterpart. Moreover, and as suggested by Dr. Aguilar-Salinas and colleagues, cell size differences may also have a direct impact on the humoral functions of the adipocytes. In our manuscript, we reported observations of lower plasma leptin levels in the mutant mice made in Dallas and in Cincinnati. Adiponectin levels were measured (but not reported) and showed no detectable differences between ad-Lrp1+/+ and ad-Lrp1-/- mice produced in Cincinnati. At this time, we abstained from analyzing visfatin levels in these animals because its role in adipocyte physiology is still quite controversial. However, we are cognizant of the potential differences in adipose humoral functions in influencing the phenotype observed in our mutant mice, and therefore are monitoring plasma levels of various adipokines over an extensive period. We thank Dr. Aguilar-Salinas and his colleagues for their comments and will report on additional differences between these animals as data become available.

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Inactivation of adipocyte LRP1 and increased insulin sensitivity: effect mediated by adiponectin?

Submitter: Carlos A. Aguilar-Salinas | caguilarsalinas@yahoo.com

Instituto Nacional de Ciencias Medicas y Nutricion. Mexico City

Published October 26, 2007

To the editors:
Hofmann and co-workers (1) demonstrate that LDL receptor-related protein-1 (LRP1) has a relevant role in the adipocyte biology. LRP1 participates in the triglycerides-rich lipoproteins uptake by the adipocyte. The inactivation of adipocyte LRP1 resulted in decreased body fat content and decreased fat cell diameter. These changes had important systemic effects; it resulted in increased insulin sensitivity and resistance to dietary fat-induced obesity. Their animal model had an increased sensitivity to cold; as a result, an increased muscular activity was observed to maintain body core temperature. The authors assumed that the increased muscular activity may be the reason for the improved insulin action. However, other potential mechanisms should be considered. The absence of LRP-1 may cause changes in the secretion of some of the multiple hormones produced by the fatty tissue. Hormone production varies depending on the size of the adipocytes (2). Small-sized adipocytes are the main source of adiponectin, a hormone with insulin-sensitizing actions (3). The shift in fat cell diameter described in the ad-Lrp1-/- mice suggest that the improvement in insulin sensitivity could be explained also by an increased adiponectin synthesis. Regrettably, only leptin concentrations were included in the manuscript. In addition, changes in plasma levels of other adipose-tissue derived hormones (i.e visfatin) may participate in the improvement of insulin sensitivity, as well. In summary, the inactivation of adipocyte LRP1 may decrease the capacity of the fat cell to sequester lipids and for generating heat, but also, it may trigger changes in adiponectin synthesis. The ad-Lrp1-/- mice may be a valuable tool to generate new knowledge about the effect of variations of the size of adipocytes on the humoral functions of the fat cells. References:
1.Hofman S et al. Adipocyte LDL receptor-related protein-1 expression modulates postprandial lipid transport and glucose homeostasis in mice. J Clin Invest doi:10.1172/JCI31929.
2.Skurk T et al. 2007. Relationship between adipocyte size and adipokine expression and secretion. J Clin Endoc Metab 92: 1023-1033
3.Lara-Castro C et al. 2007. Adiponectin and the metabolic syndrome: mechanisms mediating risk for metabolic and cardiovascular diseases. Curr Opin Lipidol 18:263-270