Atglistatin ameliorates functional decline in heart failure via adipocyte-specific inhibition of adipose triglyceride lipase

Nirmal Parajuli, Shingo Takahara, Nobutoshi Matsumura, Ty T Kim, Mourad Ferdaoussi, Anna K Migglautsch, Rudolf Zechner, Rolf Breinbauer, Erin E Kershaw, Jason R B Dyck

Publikation: Beitrag in einer FachzeitschriftArtikelForschungBegutachtung

Abstract

Despite advancements in therapies for cardiovascular disease and heart failure (HF), the incidence and prevalence of HF are increasing. Previous work has suggested that inhibiting adipose triglyceride lipase (ATGL) in adipose tissue during HF development may assist in the treatment of HF. The ability to specifically target the adipocyte as a potential treatment for HF is a novel approach that could significantly influence the management of HF in the future. Our objectives were to assess the cardiac structural and functional effects of pharmacological inhibition of ATGL in mice with HF, to assess whether ATGL inhibition works in an adipocyte-autonomous manner, and to determine the role that adiposity and glucose homeostasis play in this HF treatment approach. Using a known ATGL inhibitor, atglistatin, as well as mice with germline deletion of adipocyte-specific ATGL, we tested the effectiveness of ATGL inhibition in mice with pressure overload-induced HF. Here, we show that atglistatin can prevent the functional decline in HF and provide evidence that specifically targeting ATGL in the adipocyte is sufficient to prevent worsening of HF. We further demonstrate that the benefit resulting from atglistatin in HF is not dependent on previously suggested improvements in glucose homeostasis, nor are the benefits derived from increased adiposity. Overall, the results of this study suggest that adipocyte-specific pharmacological inhibition of ATGL may represent a novel therapeutic option for HF. NEW & NOTEWORTHY This work shows for the first time that the adipose triglyceride lipase (ATGL)-specific inhibitor atglistatin can prevent worsening heart failure. Furthermore, using mice with adipocyte-specific ATGL ablation, this study demonstrates that ATGL inhibition works in an adipocyte-autonomous manner to ameliorate a functional decline in heart failure. Overall, this work demonstrates that specifically targeting the adipocyte to inhibit ATGL is a potential treatment for heart failure.

Originalspracheenglisch
Seiten (von - bis)H879-H884
FachzeitschriftAmerican Journal of Physiology / Heart and Circulatory Physiology
Jahrgang315
Ausgabenummer4
DOIs
PublikationsstatusVeröffentlicht - 1 Okt 2018

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Lipase
Adipocytes
Heart Failure
Treatment Failure
atglistatin
Adiposity
Homeostasis
Pharmacology
Glucose
Adipose Tissue

Schlagwörter

    Fields of Expertise

    • Human- & Biotechnology

    Dies zitieren

    Atglistatin ameliorates functional decline in heart failure via adipocyte-specific inhibition of adipose triglyceride lipase. / Parajuli, Nirmal; Takahara, Shingo; Matsumura, Nobutoshi; Kim, Ty T; Ferdaoussi, Mourad; Migglautsch, Anna K; Zechner, Rudolf; Breinbauer, Rolf; Kershaw, Erin E; Dyck, Jason R B.

    in: American Journal of Physiology / Heart and Circulatory Physiology, Jahrgang 315, Nr. 4, 01.10.2018, S. H879-H884.

    Publikation: Beitrag in einer FachzeitschriftArtikelForschungBegutachtung

    Parajuli, Nirmal ; Takahara, Shingo ; Matsumura, Nobutoshi ; Kim, Ty T ; Ferdaoussi, Mourad ; Migglautsch, Anna K ; Zechner, Rudolf ; Breinbauer, Rolf ; Kershaw, Erin E ; Dyck, Jason R B. / Atglistatin ameliorates functional decline in heart failure via adipocyte-specific inhibition of adipose triglyceride lipase. in: American Journal of Physiology / Heart and Circulatory Physiology. 2018 ; Jahrgang 315, Nr. 4. S. H879-H884.
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    abstract = "Despite advancements in therapies for cardiovascular disease and heart failure (HF), the incidence and prevalence of HF are increasing. Previous work has suggested that inhibiting adipose triglyceride lipase (ATGL) in adipose tissue during HF development may assist in the treatment of HF. The ability to specifically target the adipocyte as a potential treatment for HF is a novel approach that could significantly influence the management of HF in the future. Our objectives were to assess the cardiac structural and functional effects of pharmacological inhibition of ATGL in mice with HF, to assess whether ATGL inhibition works in an adipocyte-autonomous manner, and to determine the role that adiposity and glucose homeostasis play in this HF treatment approach. Using a known ATGL inhibitor, atglistatin, as well as mice with germline deletion of adipocyte-specific ATGL, we tested the effectiveness of ATGL inhibition in mice with pressure overload-induced HF. Here, we show that atglistatin can prevent the functional decline in HF and provide evidence that specifically targeting ATGL in the adipocyte is sufficient to prevent worsening of HF. We further demonstrate that the benefit resulting from atglistatin in HF is not dependent on previously suggested improvements in glucose homeostasis, nor are the benefits derived from increased adiposity. Overall, the results of this study suggest that adipocyte-specific pharmacological inhibition of ATGL may represent a novel therapeutic option for HF. NEW & NOTEWORTHY This work shows for the first time that the adipose triglyceride lipase (ATGL)-specific inhibitor atglistatin can prevent worsening heart failure. Furthermore, using mice with adipocyte-specific ATGL ablation, this study demonstrates that ATGL inhibition works in an adipocyte-autonomous manner to ameliorate a functional decline in heart failure. Overall, this work demonstrates that specifically targeting the adipocyte to inhibit ATGL is a potential treatment for heart failure.",
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    AU - Parajuli, Nirmal

    AU - Takahara, Shingo

    AU - Matsumura, Nobutoshi

    AU - Kim, Ty T

    AU - Ferdaoussi, Mourad

    AU - Migglautsch, Anna K

    AU - Zechner, Rudolf

    AU - Breinbauer, Rolf

    AU - Kershaw, Erin E

    AU - Dyck, Jason R B

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    N2 - Despite advancements in therapies for cardiovascular disease and heart failure (HF), the incidence and prevalence of HF are increasing. Previous work has suggested that inhibiting adipose triglyceride lipase (ATGL) in adipose tissue during HF development may assist in the treatment of HF. The ability to specifically target the adipocyte as a potential treatment for HF is a novel approach that could significantly influence the management of HF in the future. Our objectives were to assess the cardiac structural and functional effects of pharmacological inhibition of ATGL in mice with HF, to assess whether ATGL inhibition works in an adipocyte-autonomous manner, and to determine the role that adiposity and glucose homeostasis play in this HF treatment approach. Using a known ATGL inhibitor, atglistatin, as well as mice with germline deletion of adipocyte-specific ATGL, we tested the effectiveness of ATGL inhibition in mice with pressure overload-induced HF. Here, we show that atglistatin can prevent the functional decline in HF and provide evidence that specifically targeting ATGL in the adipocyte is sufficient to prevent worsening of HF. We further demonstrate that the benefit resulting from atglistatin in HF is not dependent on previously suggested improvements in glucose homeostasis, nor are the benefits derived from increased adiposity. Overall, the results of this study suggest that adipocyte-specific pharmacological inhibition of ATGL may represent a novel therapeutic option for HF. NEW & NOTEWORTHY This work shows for the first time that the adipose triglyceride lipase (ATGL)-specific inhibitor atglistatin can prevent worsening heart failure. Furthermore, using mice with adipocyte-specific ATGL ablation, this study demonstrates that ATGL inhibition works in an adipocyte-autonomous manner to ameliorate a functional decline in heart failure. Overall, this work demonstrates that specifically targeting the adipocyte to inhibit ATGL is a potential treatment for heart failure.

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    JF - American Journal of Physiology / Heart and Circulatory Physiology

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