Adipocyte-specific deletion of Dbc1 does not recapitulate healthy obesity phenotype but suggests regulation of inflammation signaling

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Abstract
The protein Deleted in Breast Cancer 1 (Dbc1) is an important regulator of various transcription factors and epigenetic modulators, significantly influencing metabolism, obesity, and aging-related processes. Knockout mice lacking Dbc1 exhibit severe obesity but remain protected from liver steatosis, insulin resistance, and atherosclerosis. We hypothesized that this phenotype of “healthy obesity” results from adipose tissue expansion, which prevents free fatty acid spillover and subsequent metabolic damage to peripheral tissues. To further investigate the putative role of Dbc1 in adipose cells during obesity and its effects on metabolic dysregulation, we generated conditional Dbc1 knockout (KO) mice by backcrossing with AdipoQ-CRE transgenic mice to selectively abrogate Dbc1 expression in all mature adipocytes (Dbc1LoxP/LoxP;CRE). These mice demonstrated effective deletion of Dbc1 in mature adipocytes across various fat depots. We assessed the impact of Dbc1 deletion on metabolic regulation in male and female mice fed standard chow and high-fat diets. Our findings revealed that Dbc1 knockout in mature adipocytes did not influence weight gain, glucose tolerance, or other metabolic dysregulation markers, irrespective of sex. However, Dbc1 KO adipocytes exhibited an mRNA expression profile indicative of heightened inflammation during obesity. These results suggest that the protective phenotype observed in whole-body Dbc1 KO obese mice is not attributable to Dbc1’s function within mature adipocytes but likely involves other cell types in adipose tissue. Moreover, the specific deletion of Dbc1 in mature adipocytes unveils a novel role of Dbc1 in inflammation signaling during obesity.
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Funding Information
  • Agencia Nacional de Investigación e Innovación (FCE_1_2014_1_104002)
  • FOCEM (COF 03/11)
  • CSIC-DT program
  • Ministerio de Educación y Cultura (FVF_2023_504)
  • CSIC Uruguay
  • PEDECIBA UdelaR

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