Profiling Gene Transcription In Vivo Reveals Adipose Tissue as an Immediate Target of Tumor Necrosis Factor-α

Abstract

Despite extensive studies implicating tumor necrosis factor (TNF)-alpha as a contributing cause of insulin resistance, the mechanism(s) by which TNF-alpha alters energy metabolism in vivo and the tissue specificity of TNF-alpha action are unclear. Here, we investigated the effects of TNF-alpha infusion on gene expression and energy metabolism in adult rats. A 1-day TNF-alpha treatment decreased overall insulin sensitivity and caused a 70% increase (P = 0.005) in plasma levels of free fatty acids (FFAs) and a 46% decrease (P = 0.01) in ACRP30. A 4-day TNF-alpha infusion caused insulin resistance and significant elevation of plasma levels of FFAs and triglycerides and reduction of ACRP30. Plasma glucose concentration was not altered following TNF-alpha infusion for up to 4 days. As revealed by oligonucleotide microarrays, TNF-alpha evoked major and rapid changes in adipocyte gene expression, favoring FFA release and cytokine production, and fewer changes in liver gene expression, but favoring FFA and cholesterol synthesis and VLDL production. There was only a moderate repressive effect on skeletal muscle gene expression. We demonstrate that TNF-alpha antagonizes the actions of insulin, at least in part, through regulation of adipocyte gene expression including reduction in ACRP30 mRNA and induction of lipolysis resulting in increased plasma FFAs. TNF-alpha later alters systemic energy homeostasis that closely resembles the insulin resistance phenotype. Our data suggest that blockade of TNF-alpha action in adipose tissue may prevent TNF-alpha-induced insulin resistance in vivo.

Adipose tissue inflammation induced by high-fat diet in obese diabetic mice is prevented by n−3 polyunsaturated fatty acids

“…Blood glucose concentrations were not significantly changed by HF/S in our study, making it difficult to detect significant improvements by n−3 PUFA that appear to only prevent HF/Sinduced changes. However, adiponectin, which is positively correlated with insulin sensitivity and negatively associated with obesity [24,29,46,47], was expressed to a significantly lesser extent in adipose tissue of db/db mice fed HF/S but restored by n−3 PUFA (Fig. 7).…”

“…We used a model of genetic obesity (db/db mice) to compare white adipose tissue alterations in animals closely resembling the metabolic syndrome, although excluding leptin effects. Typical inflammatory cytokines such as TNF-α are known to interfere with insulin sensitivity [26][27][28][29] and antagonise the release of the adipocyte-derived hormone adiponectin that improves insulin sensitivity. Only a few inflammatory changes were observed in db/+ animals under HF/S, presumably due to the short duration of treatment and the lower dietary fat content that provoked only minimal body weight gain [10,11].…”

Fat poetry: a kingdom for PPARγ

“…Besides its role in WAT, TNF-α increases the expression of genes involved in the de novo synthesis of FA, and decreases that of genes involved in FA oxidation in liver. The autocrine and paracrine effects of TNF-α are responsible for the insulin resistance observed in humans and rats to whom this cytokine has been administrated [90][91][92]. TNF-α also regulates the expression of other adipokines in WAT.…”

Differentiation-dependent expression of Adhfe1 in adipogenesis

“…As expected, a rapid and robust downregulation of PPARγ, ATGL, resistin, and SCD1 is noted within 12 h of TNFα exposure. Given the large proportion of adipocyte-abundant transcripts that DNA oligonucleotide microarray studies have indicated are TNFα-responsive in 3T3-L1 adipocytes [60][61][62], we were rather surprised to find that Adhfe1 transcript level was refractory to alteration by TNFα treatment. Exposure of 3T3-L1 adipocytes to nanomolar through micromolar concentrations of TNFα for 24 h ( Figure 4B) was consistent with data in Figure 4A in that while ATGL, resistin, and SCD1 were responsive to TNFα, Adhfe1 transcript level was not altered by either low or high concentrations of TNFα.…”

“…To begin to investigate the signals that might regulate Adhfe1 transcript level in adipocytes, we treated 3T3-L1 adipocytes with an agent closely tied to adipocyte function and phenotype, TNFα [22,52,61,62]. Treatment of preadipocytes with TNFα inhibits adipogenic conversion [71,81] and treatment of adipocytes results in what has been termed "dedifferentiation" [70,71,75].…”