Different cells of adipose tissue secrete compounds which regulate various biological processes. Changes in body weight, body composition, and amount of fat mass can alter the secretory profile and function of adipose tissue. Comparison of adipose tissue mRNA expression profiles before versus after weight loss or between obese and lean subjects has promoted the identification of novel adipokines. Weight loss decreases the expression of the tenomodulin (TNMD) mRNA in the adipose tissue, and the expression level is strongly correlated with body mass index. TNMD (locus Xq22) is expressed in both adipocyte and stromal vascular fraction of adipose tissue. Tenomodulin inhibits angiogenesis, but its specific function in adipose tissue is still unknown. We have reported modest association between TNMD sequence variation and different obesity-related phenotypes, including anthropometric measurements, inflammation, glucose and lipid metabolism, and age-related macular degeneration. In this review, the potential mechanisms that could link TNMD with the pathogenesis of obesity and related disorders are discussed.