Abstract
The group of adipokines comprises hundreds of biological active proteins and peptides released from adipose tissue. Alterations of those complex protein signatures are suggested to play a crucial role in the pathophysiology of multifactorial, metabolic diseases. We hypothesized that also the pathophysiology of type-2-diabetes is linked to the dysregulation of the adipocyte secretome. To test this, we investigated mouse models with monogenic defects in leptin signaling which are susceptible to adipositas (C57BL/6 Cg-Lepob (obob)) or adipositas with diabetes (C57BL/KS Cg-Leprdb (dbdb)) according to their genetic background. At the age of 17 weeks, visceral fat was obtained and primary murine adipocytes were isolated to harvest secretomes. Quantitative proteome analyses (LC-ESI-MS/MS) identified more than 800 potential secreted proteins. The secretome patterns revealed significant differences connected to the pathophysiology of obese mice. Pathway analyses indicated that these differences focus on exosome modelling, but failed to provide more precise specifications. To investigate the relationship of secretome data to insulin sensitivity, we examined the content of diabetogenic lipids, i.e., diacylglycerols (DAGs), identified as key players in lipid-induced insulin resistance. In contrast to obob mice, fat tissue of dbdb mice showed elevated DAG content, especially of DAG species with saturated fatty acid C16:0 and C18:0, while unsaturated fatty acid C16:1 were only changed in obob. Furthermore, DAG signatures of the models specifically correlate to secreted regulated adipokines indicating specific pathways. In conclusion, our data further support the concept that the fat tissue is an endocrine organ that releases bioactive factors corresponding to adipose tissue health status.
Highlights
Obesity is a worldwide health burden caused by increased energy intake and sedentary lifestyle
C57BL/KS.Cg-Leprdb mice on C57BL/KS (BKS) genetic background, a well-accepted mouse model of hyperphagia induced obesity with overt diabetes, and C57BL/6.Cg-Lepob mice on C57BL/6 (C57) background which are protected from diabetes [6,7,11,12,13,14,15] were selected for this study
Triglycerides, insulin, and HOMA-IR were each significantly higher in dbdb compared to BKS mice, indicating the definitions of overt diabetes in the dbdb model compared to obob mice
Summary
Obesity is a worldwide health burden caused by increased energy intake and sedentary lifestyle. It increases the overall risk for life threatening comorbidities including cardiovascular risk, hypertension, pulmonary obstructive syndrome, dyslipidemia, metabolic syndrome or diabetes, and cancer [1,2,3]. A recent investigation described the secretome of visceral adipose tissue from two closely related, well-characterized and metabolically healthy mouse strains, i.e., C57BL/Ks (BKS) and C57BL/6 (C57) by combining state-of-the-art protein identification and quantification tools [5]. A reference map comprising about 600 adipokines was generated (http://www.diabesityprot.org). Both commonly used experimental “wild-type” mouse strains differ in their response to metabolic stress. Mouse models with genetic defects in leptin signaling are obese (obob; loss of function mutation in leptin) or obese and diabetic (dbdb; loss of function mutation in leptin receptor), depending on genetic background
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