Induction of Adiponectin, a Fat-Derived Antidiabetic and Antiatherogenic Factor, by Nuclear Receptors

Abstract

Adiponectin is a fat-derived hormone with antidiabetic and antiatherogenic properties. Hypoadiponectinemia seen in obesity is associated with insulin-resistant diabetes and atherosclerosis. Thiazolidinediones, peroxisome proliferator-activated receptor-␥ (PPAR-␥) agonists, have been shown to increase plasma adiponectin levels by the transcriptional induction in adipose tissues. However, the precise mechanism of such action is unknown. In this study, we have identified a functional PPAR-responsive element (PPRE) in human adiponectin promoter. PPAR-␥/retinoid X receptor (RXR) heterodimer directly bound to the PPRE and increased the promoter activity in cells. In adipocytes, point mutation of the PPRE markedly reduced the basal transcriptional activity and completely blocked thiazolidinedione-induced transactivation of adiponectin promoter. We have also identified a responsive element of another orphan nuclear receptor, liver receptor homolog-1 (LRH-1), in adiponectin promoter. LRH-1 was expressed in 3T3-L1 cells and rat adipocytes. LRH-1 bound specifically to the identified responsive element (LRH-RE). LRH-1 augmented PPAR-␥-induced transactivation of adiponectin promoter, and point mutation of the LRH-RE significantly decreased the basal and thiazolidinedione-induced activities of adiponectin promoter. Our results indicate that PPAR-␥ and LRH-1 play significant roles in the transcriptional activation of adiponectin gene via the PPRE and the LRH-RE in its promoter.

Adiponectin: a relevant player in PPARγ-agonist-mediated improvements in hepatic insulin sensitivity?

“…However, Maeda et al demonstrated that TZD treatment induces the adiponectin promoter activity by five to 10-fold, suggesting that the induction of adiponectin expression is a consequence of a direct activation of the adiponectin promoter. This work was further confirmed and extended by Iwaki et al, 45 who revealed the existence of a PPRE in the human adiponectin gene. Finally, patients with dominant-negative PPARg mutations responsible for severe insulin resistance and type 2 diabetes have significantly decreased adiponectin levels, again implying that adiponectin is a molecular target of PPARg action.…”

Polyunsaturated fatty acids of marine origin induce adiponectin in mice fed a high-fat diet

“…The induction of adiponectin but not of leptin by EPA/DHA indicates that the mechanisms controlling the expression of genes for these two adipokines are different. As with thiazolidinediones, EPA and DHA may upregulate Adipoq by acting as ligands of peroxisome proliferator-activated receptor-γ, the transcriptional regulator interacting directly with Adipoq promoter [8]. The stimulation of Adipoq may also depend on the activation of AMPK, since AMPK in adipocytes stimulates Adipoq [9] and EPA and DHA activate hepatic AMPK [10].…”

A polymorphism in the adiponectin gene influences adiponectin expression levels in visceral fat in obese subjects

“…47 The Ala-allele of the PPARG Pro12Ala polymorphism has been associated with a reduced risk for type 2 diabetes in several populations. 48 The Pro12Ala polymorphism has also been suggested to affect the adiponectin plasma levels, Ala-carriers having lower APM1 expression in a Japanese population.…”