['Transgenic overexpression of adipose tissue (AT) transducin-like enhancer of split 3 (TLE3) mimicked peroxisome proliferator-activated receptor gamma (PPARγ) agonists, improving insulin resistance in mice. This study aimed to investigate TLE3 gene expression (qRT-PCR) and protein (Western blot) in subjects with a wide spectrum of obesity and insulin sensitivity and in an independent cohort of obese subjects following surgery-induced weight loss. TLE3 was analyzed in human adipocytes and after treatment with rosiglitazone. Given the findings in humans, TLE3 was also investigated in mice after a high-fat diet (HFD) and in PPARγ knockout mice. Subcutaneous (SC) AT TLE3 was increased in subjects with type 2 diabetes (T2D). In fact, SC TLE3 was associated with increased fasting glucose (r\u2009=\u20090.25, p\u2009=\u20090.015) and S6K1 activity (r\u2009=\u20090.671, p\u2009=\u20090.003), and with decreased Glut4 (r\u2009=\u2009-0.426, p\u2009=\u20090.006) and IRS-1 expression (-31 %, p\u2009=\u20090.007) and activation (P-IRS-1/IRS-1, -17 %, p\u2009=\u20090.024). TLE3 was preferentially expressed in mature adipocytes and increased during in vitro differentiation in parallel to PPARγ. Weight loss led to improved insulin sensitivity, increased AT PPARγ and decreased TLE3 (-24 %, p\u2009=\u20090.0002), while rosiglitazone administration downregulated TLE3 gene expression in fully differentiated adipocytes (-45 %, p\u2009<\u20090.0001). The concept that TLE3 may act as a homeostatic linchpin in AT was also supported by its increased expression in HFD-fed mice (39 %, p\u2009=\u20090.013) and PPARγ knockout (74 %, p\u2009=\u20090.001). In summary, increased AT TLE3 in subjects with T2D and in AT from HFD-fed and PPARγ knockout mice suggest that TLE3 may play an adaptive regulatory role that improves AT function under decreased PPARγ expression.'] Is transducin-like enhancer of split 3 ( TLE3 ) in adipose tissue increased in situations characterized by decreased PPARγ gene expression?