B7 - Role of Trib1 in obesity and metabolism - Tissue-specific effects and target molecules

We had previously identified the gene Trib1 (encoding Tribbles homolog-1) as a novel regulator of lipoprotein metabolism in mice. Initial data from the literature and our group suggested that Trib1 might fulfill a broader function in the control of metabolism. During the first funding period we established that Trib1 affects glycemic control, insulin resistance, adipose tissue function and overall susceptibility to high-fat diet-induced obesity.

Our findings suggest that Trib1 is involved in the regulation of multiple metabolic pathways. To reduce the complexity of the phenotype observed in whole-body Trib1 knockout mice, we now aim to delineate tissue-specific effects and contributions of Trib1. Metabolic and functional characterization of these models will elucidate how Trib1-depletion influences insulin sensitivity, obesity associated adipose tissue dysfunction and ectopic fat deposition in relevant tissues.

In a second related aim, we propose to follow-up promising candidate genes/molecules that are likely to be important in mediating the phenotype of Trib1-/- mice. We will capitalize on data obtained during the first funding period, where we identified several regulators of lipid metabolism as promising candidates. In addition to their role in metabolism, these factors have been described to modulate cellular stress and tissue inflammation, important mechanisms contributing to adipose tissue dysfunction. However, their role in adipose tissue biology has not been studied in detail and is not entirely understood. We will use samples from the human adipose tissue biobank (Project B1), well-phenotyped lean and obese participants from cross-sectional (Leipzig LIFE studies) and different weight-loss intervention cohorts (e.g. CENTRAL RCT, project B8), combined with mechanistic studies in tissue culture and appropriate mouse models, to unravel the function of these candidate molecules in the pathogenesis of obesity.

Figure 1. Hematoxylin eosin staining of white adipose tissue from male KO and Trib1-WT mice after 16 weeks of high-fat feeding.

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