Adipocyte Death, Adipose Tissue Remodeling, and Obesity Complications

Abstract

OBJECTIVE-We sought to determine the role of adipocyte death in obesity-induced adipose tissue (AT) inflammation and obesity complications.RESEARCH DESIGN AND METHODS-Male C57BL/6 mice were fed a high-fat diet for 20 weeks to induce obesity. Every 4 weeks, insulin resistance was assessed by intraperitoneal insulin tolerance tests, and epididymal (eAT) and inguinal subcutaneous AT (iAT) and livers were harvested for histological, immunohistochemical, and gene expression analyses.RESULTS-Frequency of adipocyte death in eAT increased from Ͻ0.1% at baseline to 16% at week 12, coincident with increases in 1) depot weight; 2) AT macrophages (ATM⌽s) expressing F4/80 and CD11c; 3) mRNA for tumor necrosis factor (TNF)-␣, monocyte chemotactic protein (MCP)-1, and interleukin (IL)-10; and 4) insulin resistance. ATM⌽s in crown-like structures surrounding dead adipocytes expressed TNF-␣ and IL-6 proteins. Adipocyte number began to decline at week 12. At week 16, adipocyte death reached ϳ80%, 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 (fourfold), CD11c and MCP-1 gene expression (twofold), and insulin resistance (35%). eAT weight did not increase at week 20 and was inversely correlated with liver weight after week 12 (r ϭ Ϫ0. 85, P Ͻ 0.001). In iAT, adipocyte death was first detected at week 12 and remained Յ3%.CONCLUSIONS-These results implicate depot-selective adipocyte death and M⌽-mediated AT remodeling in inflammatory and metabolic complications of murine obesity. Diabetes

Adipose tissue remodeling and obesity

“…As expected from previous studies, the group initially observed that following 16 weeks of HFD feeding, a high degree (approximately 80%) of adipocyte cell death was evident in epididymal AT (13). However, a fascinating twist to these findings was that at the 20-week stage, the percentage of necrotic cells was reduced to approximately 16%; this was accompanied by an increased emergence of smaller adipocytes (<5,000 μm 2 ), thus restoring the adipocyte number (13). These key findings lend support to a model in which the progression of obesity is associated with AT remodeling, expanding largely through hypertrophy, subsequently requiring adipocytes to undergo an initial "necrotic wave," with later stages relying on hyperplastic expansion.…”

“…Strissel and colleagues provided key answers to this question by assessing the progression of adipocytes and macrophages in AT of HFD-fed mice. As expected from previous studies, the group initially observed that following 16 weeks of HFD feeding, a high degree (approximately 80%) of adipocyte cell death was evident in epididymal AT (13). However, a fascinating twist to these findings was that at the 20-week stage, the percentage of necrotic cells was reduced to approximately 16%; this was accompanied by an increased emergence of smaller adipocytes (<5,000 μm 2 ), thus restoring the adipocyte number (13).…”

“…The initial surge of cell death was shown to be associated with the presence of M1-like ATMΦs. In contrast, progressing on to the hyperplastic stage of AT transition, a reduction in M1-type markers was evident with a concomitant appearance of M2 macrophages (13).…”

Adipose tissue inflammation and ectopic lipid accumulation [Review]

“…In this regard, Khan et al reported that mice lacking collagen VI, which is expressed abundantly in adipose tissue, exhibit the uninhibited adipose tissue expansion and substantial improvements in insulin sensitivity on a high-fat diet [67]. These findings suggest that reduced lipid storage in obese adipose tissue may contribute to ectopic lipid accumulation in non-adipose tissues such as the liver, skeletal muscle, and pancreas, where lipotoxicity impairs their metabolic functions [10,[71][72][73]. Although the molecular mechanisms underlying adipose tissue fibrosis are still largely unknown, recent evidence suggests that a PPARγ-fibroblast growth factor 1 (FGF1) axis is required for obesity-induced adipose tissue remodeling [74].…”

The global diabetes epidemic as a consequence of lifestyle-induced low-grade inflammation

“…This is more pronounced in visceral, hepatic and epicardial than in subcutaneous fat [54]. Concomitantly, there is death of single adipocytes and secretion of pro-inflammatory cytokines, chemokines and other adipokines from immune cells and/or adipocytes [55] that contributes to further recruitment of macrophages and adipositis. Other associated changes are ectopic fat deposition in several organs, including beta cells, endoplasmic reticulum stress, compromised fatty acid oxidation, increased levels of circulating non-esterified fatty acids and other lipids [24] and as observed in mice, dysfunction of neural regulatory systems such as leptin resistance, again closely linked with local inflammation [56].…”