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

Research output: Contribution to journalArticleResearchpeer-review

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.

LanguageEnglish
PagesH879-H884
JournalAmerican Journal of Physiology / Heart and Circulatory Physiology
Volume315
Issue number4
DOIs
StatusPublished - 1 Oct 2018

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

Keywords

  • Journal Article

Fields of Expertise

  • Human- & Biotechnology

Cite this

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, Vol. 315, No. 4, 01.10.2018, p. H879-H884.

Research output: Contribution to journalArticleResearchpeer-review

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 ; Vol. 315, No. 4. pp. H879-H884.
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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.

AB - 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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