TNF-alpha Is Required for the Attraction of Mesenchymal Precursors to White Adipose Tissue in Ob/ob Mice

Abstract

Most adult tissues harbour a stem cell subpopulation (Mesenchymal Precursors or MPs) that represent a small proportion of the total cell number and have the potential to differentiate into several cell types within the mesenchymal lineage. In adipose tissue, adipocytes account for two-thirds of the total cell number. The remaining cells include blood and endothelial cells, along with adipocyte precursors (adipose MPs). Obesity is defined as an excess of body fat that frequently results in a significant impairment of health. The ob/ob mice bear a mutation in the ob gene that causes a deficiency in the hormone leptin and hence obesity. Here, we present evidence that ob/ob mice have a dramatic decrease in the resident MP pool of several tissues, including squeletal muscle, heart, lung and adipose tissue. Moreover, we show that that there is a migration of MP cells from distant organs, as well as homing of these cells to the adipose tissue mass of the ob/ob mice. We call this process adipotaxis. Once in the adipose tissue, migrant MPs undergoe adipose differentiation, giving rise to new differentiated adipocytes within the adipose mass. Finally, we provide evidence that adipotaxis is largely explained by the production of high levels of Tumor Necrosis Factor-alpha (TNF-α) within the ob/ob adipose tissue. The therapeutic implications for human obesity as well as for regenerative medicine are further discussed in this paper.

Method for Obtaining Committed Adult Mesenchymal Precursors from Skin and Lung Tissue

“…Similar outcomes were obtained with explants from the other control adult tissues (data not shown), and the mesenchymal cells obtained from cardiac, skeletal muscle and adipose tissue had similar properties to those described in previous studies [15], [28], [29]. Here, we present a minimally invasive non-enzymatic method for isolating similar mesenchymal precursors from skin or lung adult tissues.…”

“…Here, we present a minimally invasive non-enzymatic method for isolating similar mesenchymal precursors from skin or lung adult tissues. Independently of the source, we found that a modification of the explant technique [14], [28] yielded higher numbers of mesenchymal precursors in short time.…”

“…Independently of the source, we found that a modification of the explant technique [14], [28] yielded high numbers of mesenchymal precursors in short time; moreover, populations from different sources were highly similar in surface and epithelial markers and were committed to differentiate into epithelium.…”

Cytohesin-2/ARNO, through Its Interaction with Focal Adhesion Adaptor Protein Paxillin, Regulates Preadipocyte Migration via the Downstream Activation of Arf6

“…Preadipocytes differentiate from multipotent mesenchymal stem cells, then migrate to various sites where they undergo adipogenesis into mature adipocytes (3,39). Although an array of transcription factors are known to control adipocyte differentiation, the mechanism underlying preadipocyte migration remains poorly understood.…”

Pref-1, a Gatekeeper of Adipogenesis

“…Inflammatory cytokines such as TNF-α and IL-6 are also secreted from adipocytes (12). TNFα may help recruit mesenchymal precursors from other organs to the adipose tissue, which may then undergo differentiation to form new adipocytes (13). We originally identified Preadipocyte factor-1 [Pref-1; also called Dlk1 (Delta-like protein-1), fetal antigen-1 (FA1)] as a preadipocyte factor that prevents adipocyte differentiation and Pref-1 expression is decreased during differentiation to allow adipogenesis (14–16).…”