Preadipocytes Mediate Lipopolysaccharide-Induced Inflammation and Insulin Resistance in Primary Cultures of Newly Differentiated Human Adipocytes

Abstract

Recent data suggest that proinflammatory cytokines secreted from adipose tissue contribute to the morbidity associated with obesity. However, characterization of the cell types involved in inflammation and how these cells promote insulin resistance in human adipocytes are unclear. We simulated acute inflammation using the endotoxin lipopolysaccharide (LPS) to define the roles of nonadipocytes in primary cultures of human adipocytes. LPS induction of the mRNA levels of proinflammatory cytokines (e.g. IL-6, TNF-alpha, and IL-1beta) and chemokines (e.g. IL-8, monocyte chemoattractant protein-1) occurred primarily in the nonadipocyte fraction of newly differentiated human adipocytes. Nonadipocytes were characterized as preadipocytes based on their abundant mRNA levels of preadipocyte markers preadipocyte factor-1 and adipocyte enhancer protein-1 and only trace levels of markers for macrophages and myocytes. The essential role of preadipocytes in inflammation was confirmed by modulating the degree of differentiation in the cultures from approximately 0-90%. LPS-induced proinflammatory cytokine/chemokine expression and nuclear factor-kappaB and MAPK signaling decreased as differentiation increased. LPS-induced cytokine/chemokine expression in preadipocytes was associated with: 1) decreased adipogenic gene expression, 2) decreased ligand-induced activation of a peroxisome proliferator activated receptor (PPAR)-gamma reporter construct and increased phosphorylation of PPARgamma, and 3) decreased insulin-stimulated glucose uptake. Collectively, these data demonstrate that LPS induces nuclear factor-kappaB- and MAPK-dependent proinflammatory cytokine/chemokine expression primarily in preadipocytes, which triggers the suppression of PPARgamma activity and insulin responsiveness in human adipocytes.

Infection-induced inflammatory response of adipocytes in vitro

“…Others already suggested differences in the capacity of adipokine production by pre-adipocytes compared to mature adipocytes. [52][53][54] We demonstrated that adiponectin was mainly produced by adipocytes, while IL-6 and PAI were produced by both adipocytes and pre-adipocytes, but pre-adipocytes produced more IL-6 and PAI than adipocytes.…”

A role for adipocyte-derived lipopolysaccharide-binding protein in inflammation- and obesity-associated adipose tissue dysfunction

“…Recent investigations have shown a relationship between metabolic endotoxaemia and insulin resistance [3][4][5][6]. Proinflammatory actions of lipopolysaccharide (LPS) are known to blunt insulin signalling and to prevent adipogenesis [7,8]. Several mediators of the LPS response (toll-like receptor 4 [TLR4] and cluster of differentiation 14 [CD14]) are increased in AT in association with metabolic disturbances and systemic inflammation [9,10].…”

Hypoxia induces leptin gene expression and secretion in human preadipocytes: differential effects of hypoxia on adipokine expression by preadipocytes

“…Although preadipocytes are considered not to express leptin, they do express and secrete a number of other inflammation-related proteins (Chung et al 2006, Lacasa et al 2007. Indeed, it is suggested that preadipocytes are able to mount a substantial inflammatory response, particularly following stimulation by lipopolysaccharide (Chung et al 2006), and leptin secretion has been reported to be induced in these cells by the proinflammatory cytokines tumour necrosis factor-a (TNF-a) and IL-1b (Simons et al 2005).…”

“…Indeed, it is suggested that preadipocytes are able to mount a substantial inflammatory response, particularly following stimulation by lipopolysaccharide (Chung et al 2006), and leptin secretion has been reported to be induced in these cells by the proinflammatory cytokines tumour necrosis factor-a (TNF-a) and IL-1b (Simons et al 2005). In the present study, we have examined whether leptin production can be induced in human preadipocytes by hypoxia, our recent studies have shown that expression of the metallothionein-3 gene is hypoxia inducible in preadipocytes as well as in adipocytes ).…”