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

The protein Deleted in Breast Cancer 1 (DBC1), a regulator of several transcription factors and epigenetic modulators, plays determinant roles in metabolism regulation, obesity and aging-related processes. Knockout mice for Dbc1, develop morbid obesity but are protected against liver steatosis, insu...

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Main Author: Santos Costa, Leonardo (author)
Other Authors: Fort Canobra, Rafael S (author), Schlapp, Geraldine (author), Cal, Karina (author), Pérez Torrado, María Valentina (author), Meikle, María Noel (author), Mulet, Ana Paula (author), Sotelo-Silveira, José Roberto (author), Verdes, José Manuel (author), Contreras Chahinian, Paola (author), Calliari Cuadro, Aldo José (author), Crispo, Martina (author), Badano, José L. (author), Escande, Carlos (author)
Format: article
Language:English
Published: 2025
Subjects:
Adipocytes
Mouse models
Diet
Genetically modified animals
Obesity
Adipose tissue
Inflammation
RNA sequencing
Online Access:https://hdl.handle.net/20.500.12008/50449
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Summary:The protein Deleted in Breast Cancer 1 (DBC1), a regulator of several transcription factors and epigenetic modulators, plays determinant roles in metabolism regulation, obesity and aging-related processes. Knockout mice for Dbc1, develop morbid obesity but are protected against liver steatosis, insulin resistance and atherosclerosis. We have proposed that this healthy obesity phenotype was mainly due to the expansion of adipose tissue, avoiding free-fatty acid spillover and metabolic damage in peripheral tissues. To gain more insight about the role of Dbc1 in adipose cells during obesity and its impact on metabolic dysregulation, we generated a conditional Dbc1 KO mouse and backcrossed it with CRE-AdipoQ transgenic mice, aiming to abrogate Dbc1 expression in all mature adipocytes (cAT-Dbc1). cAT-Dbc1 mice showed deletion of Dbc1 specifically in mature adipocytes in different fat depots. We tested the effect of Dbc1 deletion in adipocytes on different aspects of metabolic regulation in male and female mice fed in normal chow and high-fat diets. We found that deletion of Dbc1 in mature adipocytes had no effect on weight gain, glucose tolerance and other markers of metabolic dysregulation, regardless sex. However, Dbc1 KO adipocytes displayed an mRNA expression profile consistent with increased inflammation during obesity. Our results suggest that the healthy phenotype displayed in the whole body Dbc1 KO obese mice is not due to the protein function in mature adipocytes and might involve other cell types present in adipose tissue. Instead, the specific deletion of Dbc1 in mature adipocytes highlights a novel role of Dbc1 in inflammation signaling during obesity.

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