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Hypothalamic CDK4 Regulates Thermogenesis by Modulating the Sympathetic Innervation and Activation of Brown Adipose Tissue

39 Pages Posted: 30 Oct 2019 Sneak Peek Status: Under Review

See all articles by Judit Castillo-Armengol

Judit Castillo-Armengol

University of Lausanne - Center for Integrative Genomics

Valentin Barquissau

University of Lausanne - Center for Integrative Genomics

Honglei Ji

University of Lausanne - Center for Integrative Genomics

Ilenia Severi

Università Politecnica delle Marche - Department of Experimental and Clinical Medicine

Wiebe Venema

Università Politecnica delle Marche - Department of Experimental and Clinical Medicine

Eric Aria-Fernandez

University of Lausanne - Center for Integrative Genomics

Catherine Moret

University of Lausanne - Center for Integrative Genomics

Anita Nasrallah

University of Lausanne - Center for Integrative Genomics

Laia Martinez-Carreres

University of Lausanne - Center for Integrative Genomics

Guy Niederhäuser

University of Lausanne - Center for Integrative Genomics

Patricia Seoane-Collazo

Universidade de Santiago de Compostela - NeurObesity Group

Sylviane Lagarrigue

University of Lausanne - Department of Physiology

Miguel López

Universidade de Santiago de Compostela - Departamento de Fisioloxía

Antonio Giordano

Università Politecnica delle Marche - Department of Experimental and Clinical Medicine

Sophie Croizier

University of Lausanne - Center for Integrative Genomics

Bernard Thorens

University of Lausanne - Center for Integrative Genomics

Isabel C. Lopez Mejia

University of Lausanne - Center for Integrative Genomics

Lluis Fajas

University of Lausanne - Center for Integrative Genomics

More...

Abstract

Cell cycle regulators, such CDK4, have previously been shown to be involved in the regulation of oxidative processes. Oxidative metabolism is indeed required for the thermogenic function of BAT. This study investigated the role of CDK4 in BAT function. To this end, we examined metabolic parameters, thermogenesis, and interscapular BAT (iBAT) morphology in a global Cdk4 knockout (Cdk4-/-) mouse, and BAT- and VMH-specific Cdk4 knockout mice. iBAT from Cdk4-/- mice exhibited fewer lipid droplets, increased mitochondrial volume, and increased expression of canonical thermogenic genes, rendering these animals more thermogenic and resistant to cold exposure. These effects were not cell-autonomous, since the BAT-specific deletion (Ucp1-Cre driven) of Cdk4 did not affect thermogenesis in mice. Brown adipose tissue (BAT) maintains body temperature during cold challenges through non-shivering thermogenesis. This process is tightly regulated by several hypothalamic areas, including the ventromedial hypothalamus (VMH), that modulate BAT activation via the sympathetic nervous system. Indeed, the sympathetic innervation of iBAT was also increased in Cdk4-/- mice, suggesting that CDK4 expressed in the central nervous system may mediate the increased thermogenic capacity of these animals. We thus examined the effects of VMH neuron-specific Cdk4 deletion, and found that these mice display increased iBAT sympathetic innervation and enhanced cold tolerance, similar to Cdk4-/- mice. Overall, these data provide new evidence showing that CDK4 in the VMH modulates thermogenesis by regulating the sympathetic innervation of iBAT. We show for the first time that CDK4, not only negatively regulates directly the oxidative pathways, such as observed in muscle cells, but also have a central control in the control of the metabolism of the whole organism through its action in the brain. This raises a new paradigm in our knowledge of the function of CDK4.

Keywords: Cell cycle, metabolism, CDK4, brown adipose tissue, thermogenesis

Suggested Citation

Castillo-Armengol, Judit and Barquissau, Valentin and Ji, Honglei and Severi, Ilenia and Venema, Wiebe and Aria-Fernandez, Eric and Moret, Catherine and Nasrallah, Anita and Martinez-Carreres, Laia and Niederhäuser, Guy and Seoane-Collazo, Patricia and Lagarrigue, Sylviane and López, Miguel and Giordano, Antonio and Croizier, Sophie and Thorens, Bernard and Lopez Mejia, Isabel C. and Fajas, Lluis, Hypothalamic CDK4 Regulates Thermogenesis by Modulating the Sympathetic Innervation and Activation of Brown Adipose Tissue (October 28, 2019). CELL-REPORTS-D-19-04246. Available at SSRN: https://ssrn.com/abstract=3476737
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Judit Castillo-Armengol

University of Lausanne - Center for Integrative Genomics

Switzerland

Valentin Barquissau

University of Lausanne - Center for Integrative Genomics

Switzerland

Honglei Ji

University of Lausanne - Center for Integrative Genomics

Switzerland

Ilenia Severi

Università Politecnica delle Marche - Department of Experimental and Clinical Medicine

Ancona
Italy

Wiebe Venema

Università Politecnica delle Marche - Department of Experimental and Clinical Medicine

Ancona
Italy

Eric Aria-Fernandez

University of Lausanne - Center for Integrative Genomics

Switzerland

Catherine Moret

University of Lausanne - Center for Integrative Genomics

Switzerland

Anita Nasrallah

University of Lausanne - Center for Integrative Genomics

Switzerland

Laia Martinez-Carreres

University of Lausanne - Center for Integrative Genomics

Switzerland

Guy Niederhäuser

University of Lausanne - Center for Integrative Genomics

Switzerland

Patricia Seoane-Collazo

Universidade de Santiago de Compostela - NeurObesity Group

Spain

Sylviane Lagarrigue

University of Lausanne - Department of Physiology

Switzerland

Miguel López

Universidade de Santiago de Compostela - Departamento de Fisioloxía

15782
Santiago de Compostela
Spain

Antonio Giordano

Università Politecnica delle Marche - Department of Experimental and Clinical Medicine

Ancona
Italy

Sophie Croizier

University of Lausanne - Center for Integrative Genomics

Switzerland

Bernard Thorens

University of Lausanne - Center for Integrative Genomics

Switzerland

Isabel C. Lopez Mejia

University of Lausanne - Center for Integrative Genomics

Switzerland

Lluis Fajas (Contact Author)

University of Lausanne - Center for Integrative Genomics ( email )

Switzerland

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