Promoting Adipose Specificity: The Adiponectin Promoter

In the modern obesogenic environment, obesity, insulin resistance and type 2 diabetes mellitus are becoming a global epidemic. At the organismal level, obesity is causally linked to the metabolic dysfunction of energy balance and homeostasis in the adipose tissue (reviewed in Refs. 1–3). Thus, it is becoming more and more important to have an improved and comprehensive biological knowledge of the fat cell in an attempt to understand the associated pathologies. In mammals, adipose tissue depots have been classified into two distinct types: white adipose tissue (WAT), the primary site of energy storage, and brown adipose tissue, specialized for energy expenditure (4). Over the last 2 decades, with the discovery of WAT’s capacity to secrete an array of hormones, a significant importance has been attributed to its endocrinal role. These hormones, known as adipokines, have revolutionized the conception of WAT biological function, consolidating the idea that it is not just a supplier and storer of energy but a dynamic organ that is central to metabolic regulation (reviewed in Refs. 5 and 6). The numbers of adipokines are expanding rapidly and include leptin, adiponectin, resistin, visfatin, serpin, lipocalin-2, omentin, vaspin, plasminogen activator inhibitor-1, retinol binding protein 4, etc. that exert systemic effects. WAT also secretes TNF , IL-6, and macrophage chemoattractant protein 4 that exert inflammatory responses or cell migration. One important experimental tool in conducting research on adipose tissue in vivo has been the adiposespecific transgenic or knockout mouse models. The major technical challenge to develop such genetic mouse model is to select the tissue-specific promoter that would drive the expression of transgene or cyclization recombination (Cre) recombinase exclusively in the adipose tissue. Wang et al. (7) took advantage of promoter segments from the adiponectin gene, the expression of which is selectively localized to the adipocytes. Adiponectin (also described as Adipo Q, Acrp30, apM1), a 30-kDa adipokine, was discovered in both human and rodent adipose tissue as well as in the cultured adipocytes by three different groups (8–10). Screening by Northern blotting for adiponectin mRNA expression in different mammalian tissues in all three groups had independently shown that adiponectin was almost exclusively expressed in adipocytes. Adiponectin is now considered to play an important role in enhancing insulin sensitivity, decreasing influx of nonesterified fatty acids (FAs), increasing FA oxidation in liver and muscle and decreasing expression of adhesion molecules within the vascular wall, resulting in the decrease in atherogenic risk (5). The plasma levels of adiponectin were found to positively correlate with the improved metabolic function (11, 12). The production of adiponectin in the adipocytes is under considerable transcriptional control mechanisms. For example, transcription of adiponectin has been shown to be up-regulated by peroxisome proliferator-activated receptor, CCAAT/enhancer-binding protein, sterol-responsive-element-binding protein-1c, forkhead box 1, and specificity protein 1 and down-regulated by reactive oxygen species, TNF , and IL-6 (reviewed in Ref. 13). To achieve adipose-specific expression of a target gene, Wang et al. (7) used a 4.9-kb adiponectin promoter cassette containing the upstream promoter region, exon 1, and two ends of intron 1 of the adiponectin gene. Adipocyte-specific expression of the transgene was more efficient compared with the promoter cassette carrying only the upstream promoter region. Furthermore, using the adiponectin promoter cassette, the authors have shown that expression of functional Cre recombinase specifically