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Topical Area: Energy and Macronutrient Metabolism

Energy and Macronutrient Metabolism (Poster Session)

(P16-009-23) Extracellular Matrix Remodelling in Brown Adipose Tissue Adipogenesis and Activation: Role of Cyr61

Sunday, July 23, 2023
11:45 AM – 12:45 PM ET
Location: Poster Board 173

    Presenting Author(s)

  • EF

    Elizabeth I. Figueroa-Juarez, MRes MSc BSc (she/her/hers)

    PhD candidate
    University of Cambridge
    Cambridge, England, United Kingdom

    • Co-Author(s)

  • VP

    Vanessa Pellegrinelli, PhD

    Wellcome-MRC Institute of Metabolic Science and Medical Research Council Metabolic Diseases Unit, University of Cambridge

  • IK

    Ioannis Kamzolas, PhD

    Wellcome-MRC Institute of Metabolic Science and Medical Research Council Metabolic Diseases Unit, University of Cambridge

  • SR

    Sergio Rodriguez-Cuenca, PhD

    Wellcome-MRC Institute of Metabolic Science and Medical Research Council Metabolic Diseases Unit, University of Cambridge

  • MD

    Martin Dale

    Wellcome-MRC Institute of Metabolic Science and Medical Research Council Metabolic Diseases Unit, University of Cambridge

  • SR

    Sonia Rodriguez-Fernandez

    Wellcome-MRC Institute of Metabolic Science and Medical Research Council Metabolic Diseases Unit, University of Cambridge

  • AV

    Antonio Vidal-Puig, PhD

    Wellcome-MRC Institute of Metabolic Science and Medical Research Council Metabolic Diseases Unit, University of Cambridge

Disclosure(s):
Elizabeth I. Figueroa-Juarez, MRes MSc BSc: No relevant financial relationship(s) with ineligible companies to disclose.


Objectives: Brown adipose tissue (BAT) atrophy is a hallmark of obesity. The extracellular matrix (ECM) is an ancillary network maintained by a remodelling process (ECMr). Impaired white AT ECMr occurs in obesity. A relation between ECMr and BAT functions has been suggested. Our aims were 1) To determine if/how ECM components are regulated in BAT activation/differentiation; 2) From a data integration analysis, select and characterize an ECM-related candidate in BAT functions.

Methods: The role of ECMr in BAT adipogenesis and activation with norepinephrine (NE) was determined by qPCR of ECM components and degradation proteases using pBAT mouse cell line and mouse primary preadipocytes.

To obtain a list of ECM-related candidates we performed a data integration analysis of BAT activation/adipogenesis models using R. We selected Cyr61. Validation was performed by qPCR in BAT adipogenesis (cells differentiation), activation (NE and cold exposed mice) and inactivation (Mφ conditioned media and HFD mice).

The role of Cyr61 was evaluated using a siRNA knockdown (KD) in pBAT and primary cells upon differentiation, NE, Seahorse XF analysis, mitochondrial content and ROS production.

Results: First, we observed that ECMr is required during brown adipogenesis as Col4A1 and Col6A1 were enriched in mature cells while Col1A2, Col3A1, Col8A1 and MMPs were downregulated/maintained in the in vitro models used. Upon NE, Col4A1, Col8A1 and MMP9 were downregulated in primary cells.

Then, we performed a data integration analysis that led us to Cyr61. Its relevance validation showed a strong regulation in BAT adipogenesis, activation and inactivation.

Next, we determined the impact of Cyr61 KD. During adipogenesis, in pBAT, Cyr61 KD altered the expression pattern of Elovl3; while in primary cells, it downregulated the expression of Col1A2, Col4A1, Col6A1 and MMPs 2 and 9, and upregulated the expression of Pgc1a. Upon NE, Cyr61 KD modified the expression of Col4A1, Col6A1 and MMP2 in PBAT cells.

Furthermore, Cyr61 KD also impaired mitochondrial respiration parameters and increased ROS production in both models.

Conclusions: ECMr is important for BAT adipogenesis and activation. Cyr61 is an ECM-related protein involved in brown cell differentiation and activation, and mitochondrial respiration.

Funding Sources: Wellcome strategic award, MRC MDU, British Heart Foundation and Cambridge Trust