ARS | Publication request: Adipocyte Death, Adipose Tissue Remodeling and Obesity Complications

Submitted to: Diabetes
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: August 27, 2007
Publication Date: September 11, 2007
Citation: Strissel, K.J., Stancheva, Z., Miyoshi, H., Perfield, J.W., Defuria, J., Jick, Z., Greenberg, A.S., Obin, M. 2007. Adipocyte Death, Adipose Tissue Remodeling and Obesity Complications. Diabetes. 56(12):2910-2918.

Interpretive Summary: As fat tissue becomes obese, cells of the immune system infiltrate the fat tissue and the synthesis and release of proteins involved in immune cell activation and inflammation are greatly increased. Previous work from our lab showed that the immune cells that came into obese fat tissue associated specifically with and actively scavenged and cleared dying fat cells and their cellular debris. The results of experiments presented in this manuscript elaborated this finding; aimed at determining the role of obesity-induced fat cell death and its accompanying inflammatory immune response in the promotion of insulin resistance, a first step in progression towards several serious metabolic diseases. Our study identified that it is those immune cells which are engaged in the scavenging of dead fat cells within obese fat tissue that are the primary source of inflammatory proteins. The incidence of fat cell death and immune cell infiltration are tightly correlated with the progression of obesity and with the onset of insulin resistance. In a circumstance of continuous over-nutrition for extended time periods, the obese fat tissue undergoes dramatic tissue remodeling that involves massive fat cell death, extra-cellular matrix turnover and subsequent tissue repair- with the immune cells intimately associated at each step. Additionally, we observed that the incidence of fat cell death and the immune cell response was different depending upon which area of the body the fat tissue was found, with internal abdominal fat regions being more susceptible than those located under the skin, for example. We concluded that the major role for fat cell death and the associated immune cell infiltration is part of a tissue response to maintain normal fat cell and tissue size. Such changes in these parameters require the production of inflammation proteins that may serve as a means for cells to communicate and/or coordinate their activities with each other during this process. Our interpretation of obesity-associated inflammation within the context of tissue remodeling represents a somewhat non-standard view of these phenomena and encourages alternate approaches to be considered when treatments and strategies to prevent obesity complications are under development.

Technical Abstract: The objective of this study was to determine the role of adipocyte death in obesity-induced adipose tissue (AT) inflammation and obesity complications. Male C57BL/6 mice were fed a high fat diet for 20 weeks to induce obesity. Every four weeks, insulin resistance (IR) was assessed by intraperitoneal insulin tolerance tests (ITT), and epididymal and inguinal subcutaneous AT (eAT, iAT) and livers were harvested for histological, immunohistochemical and gene expression analyses. It was found that the frequency of adipocyte death in eAT increased from <0.1% at baseline to 16% at week 12 coincident with increases in 1) depot weight, 2) AT macrophages (ATM PHI s) expressing F4/80 and CD11c, 3) mRNA for tumor necrosis factor-alpha (TNF-alpha), monocyte chemotactic protein-1 (MCP-1) and interleukin-10, and 4) IR. ATM PHI s in crown-like structures surrounding dead adipocytes expressed TNF-alpha and interleukin-6 proteins. Adipocyte number began to decline at week 12. At week 16 adipocyte death reached 80%, coincident with maximal expression of CD11c and inflammatory genes, loss (40%) of eAT mass, widespread collagen deposition and accelerated hepatic macrosteatosis. By week 20 adipocyte number was restored with small adipocytes, coincident with reduced adipocyte death (4-fold), CD11c and MCP-1 gene expression (2-fold), and IR (35%). eAT weight did not increase at week 20 and was inversely correlated with liver weight after week 12 (r = -0. 85, P < 0.001). In iAT adipocyte death was first detected at week 12 and remained +/= 3%. These results implicate depot-selective adipocyte death and MPhi-mediated AT remodeling in inflammatory and metabolic complications of murine obesity.