Investigation of CTRP-3 (C1q/TNF-related protein-3) functions in adipose tissue via characterization of a murine adipocyte-specific knockout model

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Background: The 15 identified members of the family of C1q/TNF-related proteins (CTRPs) represent a group of adiponectin paralogs. CTRP-3, a secretory protein mainly expressed in adipose tissue, affects processes in both immunology and metabolism and has been characterized as an endogenous antagonist of lipopolysaccharide (LPS) with anti-inflammatory properties and as an important regulatory factor in adipocyte biology and metabolism.Aims of the study: The anti-inflammatory properties of the adipokine CTRP-3 have been well described in monocytes and in adipocytes in vitro and also recently in LPS-induced inflammation in vivo. The introduced study will comprise the characterization of a recently established Cre/loxP-based mouse model (genetic background: C57BL/6NTac) of an adipocyte-specific CTRP-3 knockout in order to investigate systemic and local tissue functions of CTRP-3. A further aim of the present study is to investigate CTRP-3 regulation in obesity and during adipose tissue reduction due to weight loss. To address these issues, both local adipose tissue and systemic CTRP-3 expression will be analyzed in obese individuals either undergoing bariatric surgery (receiving a gastric bypass or a gastric sleeve, respectively) or participating in a diet-based weight-loss program.Methods: In addition to a phenotypical characterization of the new transgenic mouse model focusing on adipose tissue development, morphology, and metabolism, the impact of dysfunctional adipocyte CTRP-3 expression on LPS-induced inflammation as well as on metabolic status and processes in mice on standard or special diets (defined high-fat and high-sugar diets) will be analyzed. Experimental settings will comprise histological, biochemical, and molecular analysis of different adipose tissue depots and characterization of resident immune system cells in adipose tissue. Glucose tolerance tests as well as lipid analysis will be applied to clarify the role of adipocyte-derived CTRP-3 in whole body metabolism. In the human obesity cohort, CTRP-3 levels will be analyzed with regard to systemic concentrations and to local expression in subcutaneous and in visceral adipose tissue.Perspectives: Molecular characterization of an adipocyte-specific CTRP-3 knockout as well as investigation of CTRP 3 regulation under the conditions of obesity and of diverse approaches aiming on weight-loss will substantially improve our understanding of the role of this protein in metabolism and in adipose tissue inflammation and will help to develop a potential future drug target in obesity and in the Metabolic Syndrome.