Impaired endoplasmic reticulum (ER) and mitochondrial function has been implicated in many of the obesity-induced etiology of insulin resistance and type 2 diabetes. However, the underlying molecular mechanisms remain to be fully elucidated. We have identified Disulfide bond A oxidoreductase-like protein or DsbA-L as a critical regulator of adiponectin assembly and secretion in adipocytes (Liu et al (2008) Proc. Nat. Acad. Sci. USA, 105, 18302-07). DsbA-L expression in adipose tissues is significantly reduced in obese human subjects and animal models of obesity. In addition, fat-specific overexpression of DsbA-L promoted adiponectin multimerization in vivo and reduced high fat diet-induced insulin resistance and hepatosteatosis via an adiponectin-dependent mechanism (Liu et al. (2012) Diabetes, 61, 2776-86). However, how DsbA-L improves insulin resistance and energy homeostasis remains unknown. A novel observation made in our preliminary study is that DsbA-L is localized in both the ER and mitochondria. In addition, we have found that fat-specific knockout of DsbA-L led to suppressed adiponectin multimerization and abundance, impaired ER and mitochondrial function, decreased UCP1 and other brown gene expression in adipose tissues, and reduced energy expenditure. Taken together, these results suggest that DsbA-L may exert its anti-obesity and insulin sensitizing roles by promoting adiponectin biosynthesis and thermogenesis, which may be mediated by improving the integrity and function of both the ER and mitochondria. We will test this hypothesis by using in vitro and ex vivo approaches as well as fat-specific DsbA-L overexpression or knockout mouse models. This research will further our understanding of the mechanisms underlying obesity-induced insulin resistance and dysregulation of energy homeostasis. Results from this study will also lead to the identification of new drug target(s) for innovative therapeutic strategies to prevent obesity-induced metabolic disorders.

Public Health Relevance

Obesity has been well documented as an important factor leading to insulin resistance, but the underlying mechanisms remain elusive. The proposed study is to determine whether and how increasing the function of endoplasmic reticulum and mitochondria in adipose tissues prevents obesity-induced insulin resistance and improves energy homeostasis. Results from this study may lead to the development of new therapeutic strategies to prevent obesity and its associated metabolic disorders.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Cellular Aspects of Diabetes and Obesity Study Section (CADO)
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Haft, Carol R
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University of Texas Health Science Center San Antonio
Schools of Medicine
San Antonio
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Sha, Haibo; Yang, Liu; Liu, Meilian et al. (2014) Adipocyte spliced form of X-box-binding protein 1 promotes adiponectin multimerization and systemic glucose homeostasis. Diabetes 63:867-79
Liu, Meilian; Liu, Feng (2014) Regulation of adiponectin multimerization, signaling and function. Best Pract Res Clin Endocrinol Metab 28:25-31
Ryu, Jiyoon; Galan, Amanda K; Xin, Xiaoban et al. (2014) APPL1 potentiates insulin sensitivity by facilitating the binding of IRS1/2 to the insulin receptor. Cell Rep 7:1227-38
Hu, Fang; Liu, Feng (2011) Mitochondrial stress: a bridge between mitochondrial dysfunction and metabolic diseases? Cell Signal 23:1528-33
Wang, Anping; Liu, Meilian; Liu, Xianling et al. (2011) Up-regulation of adiponectin by resveratrol: the essential roles of the Akt/FOXO1 and AMP-activated protein kinase signaling pathways and DsbA-L. J Biol Chem 286:60-6
Deepa, Sathyaseelan S; Zhou, Lijun; Ryu, Jiyoon et al. (2011) APPL1 mediates adiponectin-induced LKB1 cytosolic localization through the PP2A-PKCzeta signaling pathway. Mol Endocrinol 25:1773-85
Xin, Xiaoban; Zhou, Lijun; Reyes, Caleb M et al. (2011) APPL1 mediates adiponectin-stimulated p38 MAPK activation by scaffolding the TAK1-MKK3-p38 MAPK pathway. Am J Physiol Endocrinol Metab 300:E103-10
Zhou, Lijun; Liu, Meilian; Zhang, Jingjing et al. (2010) DsbA-L alleviates endoplasmic reticulum stress-induced adiponectin downregulation. Diabetes 59:2809-16
Liu, Meilian; Liu, Feng (2010) Transcriptional and post-translational regulation of adiponectin. Biochem J 425:41-52
Zhou, Lijun; Liu, Feng (2010) Autophagy: roles in obesity-induced ER stress and adiponectin downregulation in adipocytes. Autophagy 6:1196-7

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