Chronic inflammation in adipose tissue plays a key role in obesity-induced insulin resistance. However, the mechanisms underlying obesity-induced inflammation remain elusive. Here we show that obesity promotes mtDNA release into the cytosol, where it triggers inflammatory responses by activating the DNA-sensing cGAS-cGAMP-STING pathway. Fat-specific knockout of disulfide-bond A oxidoreductase-like protein (DsbA-L), a chaperone-like protein originally identified in the mitochondrial matrix, impaired mitochondrial function and promoted mtDNA release, leading to activation of the cGAS-cGAMP-STING pathway and inflammatory responses. Conversely, fat-specific overexpression of DsbA-L protected mice against high-fat diet-induced activation of the cGAS-cGAMP-STING pathway and inflammation. Taken together, we identify DsbA-L as a key molecule that maintains mitochondrial integrity. DsbA-L deficiency promotes inflammation and insulin resistance by activating the cGAS-cGAMP-STING pathway. Our study also reveals that, in addition to its well-characterized roles in innate immune surveillance, the cGAS-cGAMP-STING pathway plays an important role in mediating obesity-induced metabolic dysfunction.
APPL1 is a newly identified adiponectin receptor-binding protein that positively mediates adiponectin signaling in cells.Here we report that APPL2, an isoform of APPL1 that forms a dimer with APPL1, can interacts with both AdipoR1 and AdipoR2 and acts as a negative regulator of adiponectin signaling in muscle cells. Overexpression of APPL2 inhibits the interaction between APPL1 and AdipoR1, leading to down-regulation of adiponectin signaling in C2C12 myotubes. In contrast, suppressing APPL2 expression by RNAi significantly enhances adiponectin-stimulated glucose uptake and fatty acid oxidation. In addition to targeting directly to and competing with APPL1 in binding with the adiponectin receptors, APPL2 also suppresses adiponectin and insulin signaling by sequestrating APPL1 from these two pathways. In addition to adiponectin, metformin also induces APPL1-APPL2 dissociation. Taken together, our results reveal that APPL isoforms function as an integrated YinYang regulator of adiponectin signaling and mediate the crosstalk between adiponectin and insulin signaling pathways in muscle cells.Adiponectin, an adipocyte-secreted hormone that regulates energy homeostasis and insulin sensitivity, has been shown to be a promising therapeutic drug target for the treatment of type 2 diabetes (1-3). Adiponectin binds to its membrane receptors (AdipoR1 and AdipoR2) 3 and regulates lipid and glucose metabolism by activating downstream signaling molecules, such as AMP-activated protein kinase (AMPK), p38 MAP kinase (MAPK), and PPAR␣, in the muscle and liver (1, 4). Activation of AMPK by adiponectin reduces S6 kinase-mediated IRS-1 serine phosphorylation and increases IRS-1 tyrosine phosphorylation thus sensitizes insulin signaling in C2C12 myotubes (5), suggesting a direct cross-talk between the adiponectin and insulin signaling pathways.We have recently identified APPL1 (adaptor protein-containing PH domain, PTB domain, and leucine zipper motif) as a signaling protein immediately downstream of adiponectin receptors and positively mediates adiponectin signaling in muscle cells (6). This adaptor protein was previously shown to interact with the catalytic subunit of PI 3-kinase (p110) and Akt, which are two key kinases in the PI 3-kinase pathway downstream of the insulin receptor (7). The interaction between APPL1 and Akt is required for insulin-stimulated GLUT4 translocation (8) and for controlling Akt substrate selectivity (9). It has been shown that APPL1-potentiated Akt activity to suppress androgen receptor transactivation in prostate cancer cells (10). APPL1 has also been suggested to function as an adaptor protein in regulating follicle-stimulated hormone (FSH)-mediated PI 3-kinase/ Akt signaling pathway (11, 12). Our results showed that APPL1 binds directly to the intracellular part of the adiponectin receptors and positively mediates adiponectin signaling to the AMPK and p38 MAPK pathways, leading to increased glucose uptake and fatty acid oxidation in muscle cells (6). In addition, we found that APPL1 plays a critical ro...
OBJECTIVEObesity impairs adiponectin expression, assembly, and secretion, yet the underlying mechanisms remain elusive. The aims of this study were 1) to determine the molecular mechanisms by which obesity impairs adiponectin multimerization and stability, and 2) to determine the potential role of disulfide-bond-A oxidoreductase-like protein (DsbA-L), a recently identified adiponectin interactive protein that promotes adiponectin multimerization and stability in obesity-induced endoplasmic reticulum (ER) stress and adiponectin downregulation.RESEARCH DESIGN AND METHODSTauroursodeoxycholic acid (TUDCA), a chemical chaperone that alleviates ER stress, was used to study the mechanism underlying obesity-induced adiponectin downregulation in db/db mice, high-fat diet-induced obese mice, and in ER-stressed 3T3-L1 adipocytes. The cellular levels of DsbA-L were altered by RNAi-mediated suppression or adenovirus-mediated overexpression. The protective role of DsbA-L in obesity- and ER stress–induced adiponectin downregulation was characterized.RESULTSTreating db/db mice and diet-induced obese mice with TUDCA increased the cellular and serum levels of adiponectin. In addition, inducing ER stress is sufficient to downregulate adiponectin levels in 3T3-L1 adipocytes, which could be protected by treating cells with the autophagy inhibitor 3-methyladenine or by overexpression of DsbA-L.CONCLUSIONSER stress plays a key role in obesity-induced adiponectin downregulation. In addition, DsbA-L facilitates adiponectin folding and assembly and provides a protective effect against ER stress–mediated adiponectin downregulation in obesity.
The antidiabetic and antiatherosclerotic effects of adiponectin make it a desirable drug target for the treatment of metabolic and cardiovascular diseases. However, the adiponectin-based drug development approach turns out to be difficult due to extremely high serum levels of this adipokine. On the other hand, a significant correlation between adiponectin multimerization and its insulin-sensitizing effects has been demonstrated, suggesting a promising alternative therapeutic strategy. Here we show that transgenic mice overexpressing disulfide bond A oxidoreductase-like protein in fat (fDsbA-L) exhibited increased levels of total and the high-molecular-weight form of adiponectin compared with wild-type (WT) littermates. The fDsbA-L mice also displayed resistance to diet-induced obesity, insulin resistance, and hepatic steatosis compared with WT control mice. The protective effects of DsbA-L overexpression on diet-induced insulin resistance, but not increased body weight and fat cell size, were significantly decreased in adiponectin-deficient fDsbA-L mice (fDsbA-L/Ad−/−). In addition, the fDsbA-L/Ad−/− mice displayed greater activity and energy expenditure compared with adiponectin knockout mice under a high-fat diet. Taken together, our results demonstrate that DsbA-L protects mice from diet-induced obesity and insulin resistance through adiponectin-dependent and independent mechanisms. In addition, upregulation of DsbA-L could be an effective therapeutic approach for the treatment of obesity and its associated metabolic disorders.
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