Recent findings indicate that endoplasmic reticulum (ER) stress is significantly increased in adipose tissue of obese human subjects and is critical to the initiation and integration of pathways of inflammation and insulin action. But the factors inducing ER stress in human adipose tissue are unknown. The common factors increased in obesity and linked to insulin resistance are hyperglycaemia, hyperlipidemia and also endotoxemia. Therefore, our aims were to investigate: (1) the role of lipopolysaccharide (LPS), high glucose (HG) and saturated fatty acids (SFA) as inducers of ER stress in primary human adipocytes and (2) whether salicylate, a known anti-inflammatory compound, can alleviate this effect. Components of the ER stress pathways were studied in human abdominal subcutaneous (AbSc) adipose tissue (AT) from obese and lean. Following the culture and differentiation of primary human preadipocytes, these adipocytes were treated with LPS, HG, tunicamycin (Tun) and SFA either alone or in combination with sodium salicylate (Sal). Markers of ER stress were significantly increased in AbSc AT of obese. Differentiated human adipocytes treated with LPS, Tun, HG and SFA showed significant activation of eukaryotic translation initiation factor 2 alpha, (eIF2 alpha) and activating transcription factor 6 (ATF6) and their down-stream targets. Sal alleviated this effect and activated AktSer473 phosphorylation. This study presents important evidence that: (1) there is increased ER stress in adipose tissue of obese individuals, (2) LPS, hyperglycaemia and saturated fatty acids induce significant ER stress in primary human adipocytes and (3) this induction is alleviated by salicylate. (C) 2010 Elsevier Inc. All rights reserved.