Fat-Specific DsbA-L Overexpression Promotes Adiponectin Multimerization and Protects Mice From Diet-Induced Obesity and Insulin Resistance

Corresponding author: Feng Liu, .
Diabetes (Impact Factor: 8.1). 07/2012; 61(11):2776-86. DOI: 10.2337/db12-0169
Source: PubMed


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.

Download full-text


Available from: Feng Liu, Jan 29, 2014
38 Reads
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: When humans eat more and exercise less, they tend to become obese and unhealthy. The molecular pathways that link obesity to serious diseases like Type 2 diabetes and cardiovascular disease have become a subject of intensive scientific investigation because the exploding prevalence of obesity worldwide represents a grave new threat to the health of hundreds of millions of people. However, obesity is not always destiny. Two important clinical populations have been valuable to understand the mechanisms behind this conundrum: individuals who exhibit metabolic dysfunction, diabetes and elevated cardiovascular disease risk despite a lean body type, and individuals who are relatively protected from these dangers despite significant obesity. Study of this second group of 'metabolically healthy obese' people in particular has been revealing because such individuals exhibit specific, identifiable, anatomic, cellular and molecular features that set them apart from the rest of us who suffer declining health with increasing weight. Here, I examine some of these features, including some mouse models that are informative of mechanism, and suggest hypotheses for further study, including the possibility that genes and pathways of the immune system might offer new diagnostic or therapeutic targets.
    Molecular Aspects of Medicine 10/2012; 34(1). DOI:10.1016/j.mam.2012.10.004 · 10.24 Impact Factor
  • Source
    Circulation Research 04/2013; 112(9):1205-7. DOI:10.1161/CIRCRESAHA.113.301316 · 11.02 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Adiponectin is among the most studied adipokines, the collection of molecules secreted from adipose tissue. It is also one of the most architecturally complex adipokines with its various oligomeric states that include trimers, hexamers, nonamers (9mers), dodecamers (12mers), and octadecamers (18mers). The importance of adiponectin in metabolic regulation is underscored by its strong positive associations with improvement in insulin action and also decreased risks for developing type 2 diabetes. Understanding the mechanisms involved in maintaining the steady-state concentrations of adiponectin oligomers in circulation is therefore likely to provide important insight into the development of insulin resistance. This review will discuss the current state of knowledge regarding the biochemical composition of adiponectin oligomers, the commonly used techniques to analyze them, and the known post-translational modifications that affect their assembly. Evidence based on in vitro oligomer assembly reactions in support of a "cystine ratchet" model of adiponectin oligomer formation will be considered along with limitations of the evidence. Secretory pathway proteins that have been shown to affect the distribution of adiponectin oligomers will also be discussed along with hypotheses regarding their potential involvement in the cystine ratchet model of adiponectin oligomerization.
    Reviews in Endocrine and Metabolic Disorders 08/2013; 15(2). DOI:10.1007/s11154-013-9256-6 · 4.89 Impact Factor
Show more