Brilliant Blue G The Cebu Longitudinal Health and Nutrition

The Cebu Longitudinal Health and Nutrition Survey (CLHNS) genome-wide association study investigated the genetic loci associated with plasma adiponectin in 1776 unrelated Filipino women. Adiponectin was strongly associated with three genetic positions: the gene CDH13 (rs3865188, P ≤ 7.2 × 10−16), near the ADIPOQ gene (rs864265, P = 3.8 × 10−9) and 100 kb upstream near KNG1 (rs11924390, P = 7.6 × 10−7). All three signals were also observed in 1774 young adult CLHNS offspring and in combined analysis including all 3550 mothers and offspring samples (all P ≤ 1.6 × 10−9). An uncommon haplotype of rs11924390 and rs864265 (haplotype frequency = 0.050) was strongly associated with lower adiponectin compared with the most common C-G haplotype in both CLHNS mothers (P = 1.8 × 10−25) and offspring (P = 8.7 × 10−32). This is the first genome-wide study to provide evidence associating plasma adiponectin at the CDH13 locus, and with the KNG1-ADIPOQ haplotype with adiponectin levels in Filipinos [21]. Further genetic investigations were performed, looking at Mexican-American Brilliant Blue G with type 2 diabetes from the Veterans Administration Genetic Epidemiology Study (VAGES). Results revealed that heritability for plasma triglycerides was 46 ± 7% (P < 0.0001) with the strongest evidence for linkage of plasma triglycerides near marker D12S391 on chromosome 12p (logarithm of odds [LOD] = 2.4). Results from San Antonio Family Diabetes Study (SAFDS) also demonstrated a linkage signal on chromosome 12p. Combining results from the VAGES and SAFDS studies demonstrated significant evidence for linkage of plasma triglycerides to a genetic location between markers GATA49D12 and D12S391 on 12p (LOD = 3.8, empirical P value = 2.0 × 10−5). The gene-encoding AdipoR2 has also been confirmed on 12p [22].
Possible other receptors and pathways T-cadherin has been reported to bind adiponectin in C2C12 myoblasts and muscle although it is not expressed in the liver [3,10,23,24]. Since T-cadherin does not have an intracellular domain it is not thought to exert a direct effect on adiponectin cellular signaling or function, but rather may be an adiponectin-binding protein. This is supported by studies showing that adiponectin failed to associate with cardiac tissue in T-cadherin–deficient mice. Interestingly, T-cadherin is critical for adiponectin-mediated cardioprotection in mice [25] (Fig. 1). Adiponectin has been reported to modulate inflammatory reactions via calreticulin, which along with CD91 are involved in the adiponectin-mediated uptake of apoptotic cells [26]. Pretreatment with anti-calreticulin antibodies has also been demonstrated to reduce the adiponectin binding to cardiac myocytes and inhibited adiponectin-stimulated increase in Akt activation and survival in cardiomyocytes.
Adiponectin and receptors in disease AdipoR1 and AdipoR2 modulate fatty acid metabolisms in the liver. This is demonstrated by the development of nonalcoholic steatohepatitis (NASH, fatty liver with inflammation and fibrosis) in obese fa/fa Zucker rats fed a high-fat/high-cholesterol diet. Expression of AdipoR1/R2 is significantly decreased in NASH, which was associated with decreased AMPKα1/α2 and PPARα. Increased synthesis and decreased oxidation of fatty acids by down-regulation of AdipoR may contribute to the progression of NASH [27] (Fig. 2). Adiponectin has also been reported to promote the development of an anti-inflammatory phenotype of macrophages, Kupffer cells and RAW264.7 macrophages, in a mechanism that is partially dependent on AMP-activated kinase [28,29]. The AMPK inactivation induced by saturated fatty acids decreased activation of unc-51–like kinase-1 (ULK1) resulting in decreased autophagy, and the generation of mitochondrial ROS. This then activates the NLRP3-ASC inflammasome, causing caspase-1, IL-1β, and IL-18 production, which finally leads to insulin resistance [30].