Regulation and Function of Adiponectin Oligomerization

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.