Chronic Activation of γ2 AMPK Induces Obesity and Reduces β Cell Function

Arash Yavari; Claire J. Stocker; Sahar Ghaffari; Edward T. Wargent; Violetta Steeples; Gabor Czibik; Katalin Pinter; Mohamed Bellahcene; Angela Woods; Pablo B. Martínez de Morentin; Céline Cansell; Brian Y. H. Lam; André Chuster; Kasparas Petkevicius; Marie-Sophie Nguyen-Tu; Aida Martinez-Sanchez; Timothy J. Pullen; Peter L. Oliver; Alexander Stockenhuber; Chinh Nguyen; Merzaka Lazdam; Jacqueline F. O'Dowd; Parvathy Harikumar; Mónika Tóth; Craig Beall; Theodosios Kyriakou; Julia Parnis; Dhruv Sarma; George Katritsis; Diana D. J. Wortmann; Andrew R. Harper; Laurence A. Brown; Robin Willows; Silvia Gandra; Victor Poncio; Márcio J. de Oliveira Figueiredo; Nathan R. Qi; Stuart N. Peirson; Rory J. McCrimmon; Balázs Gereben; László Tretter; Csaba Fekete; Charles Redwood; Giles S. H. Yeo; Lora K. Heisler; Guy A. Rutter; Mark A. Smith; Dominic J. Withers; David Carling; Eduardo B. Sternick; Jonathan R. S. Arch; Michael A. Cawthorne; Hugh Watkins; Houman Ashrafian

doi:10.1016/j.cmet.2016.04.003

Chronic Activation of γ2 AMPK Induces Obesity and Reduces β Cell Function

Arash Yavari, Claire J. Stocker, Sahar Ghaffari, Edward T. Wargent, Violetta Steeples, Gabor Czibik, Katalin Pinter, Mohamed Bellahcene, Angela Woods, Pablo B. Martínez de Morentin, Céline Cansell, Brian Y. H. Lam, André Chuster, Kasparas Petkevicius, Marie-Sophie Nguyen-Tu, Aida Martinez-Sanchez, Timothy J. Pullen, Peter L. Oliver, Alexander Stockenhuber, Chinh NguyenMerzaka Lazdam, Jacqueline F. O'Dowd, Parvathy Harikumar, Mónika Tóth, Craig Beall, Theodosios Kyriakou, Julia Parnis, Dhruv Sarma, George Katritsis, Diana D. J. Wortmann, Andrew R. Harper, Laurence A. Brown, Robin Willows, Silvia Gandra, Victor Poncio, Márcio J. de Oliveira Figueiredo, Nathan R. Qi, Stuart N. Peirson, Rory J. McCrimmon, Balázs Gereben, László Tretter, Csaba Fekete, Charles Redwood, Giles S. H. Yeo, Lora K. Heisler, Guy A. Rutter, Mark A. Smith, Dominic J. Withers, David Carling, Eduardo B. Sternick, Jonathan R. S. Arch, Michael A. Cawthorne, Hugh Watkins, Houman Ashrafian^* (Corresponding Author)

^*Corresponding author for this work

The Rowett Institute of Nutrition and Health

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Abstract

Despite significant advances in our understanding of the biology determining systemic energy homeostasis, the treatment of obesity remains a medical challenge. Activation of AMP-activated protein kinase (AMPK) has been proposed as an attractive strategy for the treatment of obesity and its complications. AMPK is a conserved, ubiquitously expressed, heterotrimeric serine/threonine kinase whose short-term activation has multiple beneficial metabolic effects. Whether these translate into long-term benefits for obesity and its complications is unknown. Here, we observe that mice with chronic AMPK activation, resulting from mutation of the AMPK γ2 subunit, exhibit ghrelin signaling-dependent hyperphagia, obesity, and impaired pancreatic islet insulin secretion. Humans bearing the homologous mutation manifest a congruent phenotype. Our studies highlight that long-term AMPK activation throughout all tissues can have adverse metabolic consequences, with implications for pharmacological strategies seeking to chronically activate AMPK systemically to treat metabolic disease.

Original language	English
Pages (from-to)	821-836
Number of pages	17
Journal	Cell Metabolism
Volume	23
Issue number	5
Early online date	28 Apr 2016
DOIs	https://doi.org/10.1016/j.cmet.2016.04.003
Publication status	Published - 10 May 2016

Bibliographical note

Acknowledgments
We thank Sandra Stobrawa and colleagues (Genoway Lyon) for generating R299Q γ2 mice; families participating in the R302Q phenotyping study; Wellcome Trust Centre for Human Genetics High-Throughput Genomics Group (grant 090532/Z/09/Z) for sequencing data; Hermes Pardini for human biochemistry; Karen McGuire, Kate Thomson, and Jessica Woodley (Oxford Medical Genetics Laboratories) for R302Q genotyping; Keith Burling (Core Biochemical Assay Laboratory Cambridge) and Tertius Hough (MRC, Harwell Oxford) for murine biochemistry; Paul Trayhurn for comments; and Parisa Yavari for artwork support. This work utilized Core Services supported by grants DK089503 (MNORC) and DK020572 (MDRC) of the NIH to the University of Michigan. C.B. is supported by a Diabetes UK RD Lawrence Fellowship (13/0004647). C.F. and B.G. are supported by the Hungarian National Brain Research Program. L.K.H. is supported by the Wellcome Trust (WT098012) and BBSRC (BB/K001418/1). G.A.R. was supported by a Wellcome Trust Senior Investigator Award (WT098424AIA), MRC Programme Grant (MR/J0003042/1), and a Royal Society Wolfson Research Merit Award. A.Y. was funded by a Wellcome Trust Research Training Fellowship (086632/Z/08/Z) and is supported by the UK National Institute for Health Research. A.Y. (RE/08/004), H.W., and H.A. acknowledge support from the BHF Centre of Research Excellence, Oxford. This work was supported by a grant from the MRC to H.A. and H.W. (MR/K019023/1).
This paper is dedicated to the memory of the late Professor Michael A.
Cawthorne.

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Chronic Activation of γ2 AMPK Induces Obesity and Reduces β Cell Function
© 2016 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
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Yavari, A., Stocker, C. J., Ghaffari, S., Wargent, E. T., Steeples, V., Czibik, G., Pinter, K., Bellahcene, M., Woods, A., Martínez de Morentin, P. B., Cansell, C., Lam, B. Y. H., Chuster, A., Petkevicius, K., Nguyen-Tu, M.-S., Martinez-Sanchez, A., Pullen, T. J., Oliver, P. L., Stockenhuber, A., ... Ashrafian, H. (2016). Chronic Activation of γ2 AMPK Induces Obesity and Reduces β Cell Function. Cell Metabolism, 23(5), 821-836. https://doi.org/10.1016/j.cmet.2016.04.003

Yavari, A, Stocker, CJ, Ghaffari, S, Wargent, ET, Steeples, V, Czibik, G, Pinter, K, Bellahcene, M, Woods, A, Martínez de Morentin, PB, Cansell, C, Lam, BYH, Chuster, A, Petkevicius, K, Nguyen-Tu, M-S, Martinez-Sanchez, A, Pullen, TJ, Oliver, PL, Stockenhuber, A, Nguyen, C, Lazdam, M, O'Dowd, JF, Harikumar, P, Tóth, M, Beall, C, Kyriakou, T, Parnis, J, Sarma, D, Katritsis, G, Wortmann, DDJ, Harper, AR, Brown, LA, Willows, R, Gandra, S, Poncio, V, de Oliveira Figueiredo, MJ, Qi, NR, Peirson, SN, McCrimmon, RJ, Gereben, B, Tretter, L, Fekete, C, Redwood, C, Yeo, GSH, Heisler, LK, Rutter, GA, Smith, MA, Withers, DJ, Carling, D, Sternick, EB, Arch, JRS, Cawthorne, MA, Watkins, H & Ashrafian, H 2016, 'Chronic Activation of γ2 AMPK Induces Obesity and Reduces β Cell Function', Cell Metabolism, vol. 23, no. 5, pp. 821-836. https://doi.org/10.1016/j.cmet.2016.04.003

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title = "Chronic Activation of γ2 AMPK Induces Obesity and Reduces β Cell Function",

abstract = "Despite significant advances in our understanding of the biology determining systemic energy homeostasis, the treatment of obesity remains a medical challenge. Activation of AMP-activated protein kinase (AMPK) has been proposed as an attractive strategy for the treatment of obesity and its complications. AMPK is a conserved, ubiquitously expressed, heterotrimeric serine/threonine kinase whose short-term activation has multiple beneficial metabolic effects. Whether these translate into long-term benefits for obesity and its complications is unknown. Here, we observe that mice with chronic AMPK activation, resulting from mutation of the AMPK γ2 subunit, exhibit ghrelin signaling-dependent hyperphagia, obesity, and impaired pancreatic islet insulin secretion. Humans bearing the homologous mutation manifest a congruent phenotype. Our studies highlight that long-term AMPK activation throughout all tissues can have adverse metabolic consequences, with implications for pharmacological strategies seeking to chronically activate AMPK systemically to treat metabolic disease.",

author = "Arash Yavari and Stocker, {Claire J.} and Sahar Ghaffari and Wargent, {Edward T.} and Violetta Steeples and Gabor Czibik and Katalin Pinter and Mohamed Bellahcene and Angela Woods and {Mart{\'i}nez de Morentin}, {Pablo B.} and C{\'e}line Cansell and Lam, {Brian Y. H.} and Andr{\'e} Chuster and Kasparas Petkevicius and Marie-Sophie Nguyen-Tu and Aida Martinez-Sanchez and Pullen, {Timothy J.} and Oliver, {Peter L.} and Alexander Stockenhuber and Chinh Nguyen and Merzaka Lazdam and O'Dowd, {Jacqueline F.} and Parvathy Harikumar and M{\'o}nika T{\'o}th and Craig Beall and Theodosios Kyriakou and Julia Parnis and Dhruv Sarma and George Katritsis and Wortmann, {Diana D. J.} and Harper, {Andrew R.} and Brown, {Laurence A.} and Robin Willows and Silvia Gandra and Victor Poncio and {de Oliveira Figueiredo}, {M{\'a}rcio J.} and Qi, {Nathan R.} and Peirson, {Stuart N.} and McCrimmon, {Rory J.} and Bal{\'a}zs Gereben and L{\'a}szl{\'o} Tretter and Csaba Fekete and Charles Redwood and Yeo, {Giles S. H.} and Heisler, {Lora K.} and Rutter, {Guy A.} and Smith, {Mark A.} and Withers, {Dominic J.} and David Carling and Sternick, {Eduardo B.} and Arch, {Jonathan R. S.} and Cawthorne, {Michael A.} and Hugh Watkins and Houman Ashrafian",

note = "Acknowledgments We thank Sandra Stobrawa and colleagues (Genoway Lyon) for generating R299Q γ2 mice; families participating in the R302Q phenotyping study; Wellcome Trust Centre for Human Genetics High-Throughput Genomics Group (grant 090532/Z/09/Z) for sequencing data; Hermes Pardini for human biochemistry; Karen McGuire, Kate Thomson, and Jessica Woodley (Oxford Medical Genetics Laboratories) for R302Q genotyping; Keith Burling (Core Biochemical Assay Laboratory Cambridge) and Tertius Hough (MRC, Harwell Oxford) for murine biochemistry; Paul Trayhurn for comments; and Parisa Yavari for artwork support. This work utilized Core Services supported by grants DK089503 (MNORC) and DK020572 (MDRC) of the NIH to the University of Michigan. C.B. is supported by a Diabetes UK RD Lawrence Fellowship (13/0004647). C.F. and B.G. are supported by the Hungarian National Brain Research Program. L.K.H. is supported by the Wellcome Trust (WT098012) and BBSRC (BB/K001418/1). G.A.R. was supported by a Wellcome Trust Senior Investigator Award (WT098424AIA), MRC Programme Grant (MR/J0003042/1), and a Royal Society Wolfson Research Merit Award. A.Y. was funded by a Wellcome Trust Research Training Fellowship (086632/Z/08/Z) and is supported by the UK National Institute for Health Research. A.Y. (RE/08/004), H.W., and H.A. acknowledge support from the BHF Centre of Research Excellence, Oxford. This work was supported by a grant from the MRC to H.A. and H.W. (MR/K019023/1). This paper is dedicated to the memory of the late Professor Michael A. Cawthorne.",

year = "2016",

month = may,

day = "10",

doi = "10.1016/j.cmet.2016.04.003",

language = "English",

volume = "23",

pages = "821--836",

journal = "Cell Metabolism",

issn = "1550-4131",

publisher = "Cell Press",

number = "5",

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TY - JOUR

T1 - Chronic Activation of γ2 AMPK Induces Obesity and Reduces β Cell Function

AU - Yavari, Arash

AU - Stocker, Claire J.

AU - Ghaffari, Sahar

AU - Wargent, Edward T.

AU - Steeples, Violetta

AU - Czibik, Gabor

AU - Pinter, Katalin

AU - Bellahcene, Mohamed

AU - Woods, Angela

AU - Martínez de Morentin, Pablo B.

AU - Cansell, Céline

AU - Lam, Brian Y. H.

AU - Chuster, André

AU - Petkevicius, Kasparas

AU - Nguyen-Tu, Marie-Sophie

AU - Martinez-Sanchez, Aida

AU - Pullen, Timothy J.

AU - Oliver, Peter L.

AU - Stockenhuber, Alexander

AU - Nguyen, Chinh

AU - Lazdam, Merzaka

AU - O'Dowd, Jacqueline F.

AU - Harikumar, Parvathy

AU - Tóth, Mónika

AU - Beall, Craig

AU - Kyriakou, Theodosios

AU - Parnis, Julia

AU - Sarma, Dhruv

AU - Katritsis, George

AU - Wortmann, Diana D. J.

AU - Harper, Andrew R.

AU - Brown, Laurence A.

AU - Willows, Robin

AU - Gandra, Silvia

AU - Poncio, Victor

AU - de Oliveira Figueiredo, Márcio J.

AU - Qi, Nathan R.

AU - Peirson, Stuart N.

AU - McCrimmon, Rory J.

AU - Gereben, Balázs

AU - Tretter, László

AU - Fekete, Csaba

AU - Redwood, Charles

AU - Yeo, Giles S. H.

AU - Heisler, Lora K.

AU - Rutter, Guy A.

AU - Smith, Mark A.

AU - Withers, Dominic J.

AU - Carling, David

AU - Sternick, Eduardo B.

AU - Arch, Jonathan R. S.

AU - Cawthorne, Michael A.

AU - Watkins, Hugh

AU - Ashrafian, Houman

N1 - Acknowledgments We thank Sandra Stobrawa and colleagues (Genoway Lyon) for generating R299Q γ2 mice; families participating in the R302Q phenotyping study; Wellcome Trust Centre for Human Genetics High-Throughput Genomics Group (grant 090532/Z/09/Z) for sequencing data; Hermes Pardini for human biochemistry; Karen McGuire, Kate Thomson, and Jessica Woodley (Oxford Medical Genetics Laboratories) for R302Q genotyping; Keith Burling (Core Biochemical Assay Laboratory Cambridge) and Tertius Hough (MRC, Harwell Oxford) for murine biochemistry; Paul Trayhurn for comments; and Parisa Yavari for artwork support. This work utilized Core Services supported by grants DK089503 (MNORC) and DK020572 (MDRC) of the NIH to the University of Michigan. C.B. is supported by a Diabetes UK RD Lawrence Fellowship (13/0004647). C.F. and B.G. are supported by the Hungarian National Brain Research Program. L.K.H. is supported by the Wellcome Trust (WT098012) and BBSRC (BB/K001418/1). G.A.R. was supported by a Wellcome Trust Senior Investigator Award (WT098424AIA), MRC Programme Grant (MR/J0003042/1), and a Royal Society Wolfson Research Merit Award. A.Y. was funded by a Wellcome Trust Research Training Fellowship (086632/Z/08/Z) and is supported by the UK National Institute for Health Research. A.Y. (RE/08/004), H.W., and H.A. acknowledge support from the BHF Centre of Research Excellence, Oxford. This work was supported by a grant from the MRC to H.A. and H.W. (MR/K019023/1). This paper is dedicated to the memory of the late Professor Michael A. Cawthorne.

PY - 2016/5/10

Y1 - 2016/5/10

N2 - Despite significant advances in our understanding of the biology determining systemic energy homeostasis, the treatment of obesity remains a medical challenge. Activation of AMP-activated protein kinase (AMPK) has been proposed as an attractive strategy for the treatment of obesity and its complications. AMPK is a conserved, ubiquitously expressed, heterotrimeric serine/threonine kinase whose short-term activation has multiple beneficial metabolic effects. Whether these translate into long-term benefits for obesity and its complications is unknown. Here, we observe that mice with chronic AMPK activation, resulting from mutation of the AMPK γ2 subunit, exhibit ghrelin signaling-dependent hyperphagia, obesity, and impaired pancreatic islet insulin secretion. Humans bearing the homologous mutation manifest a congruent phenotype. Our studies highlight that long-term AMPK activation throughout all tissues can have adverse metabolic consequences, with implications for pharmacological strategies seeking to chronically activate AMPK systemically to treat metabolic disease.

AB - Despite significant advances in our understanding of the biology determining systemic energy homeostasis, the treatment of obesity remains a medical challenge. Activation of AMP-activated protein kinase (AMPK) has been proposed as an attractive strategy for the treatment of obesity and its complications. AMPK is a conserved, ubiquitously expressed, heterotrimeric serine/threonine kinase whose short-term activation has multiple beneficial metabolic effects. Whether these translate into long-term benefits for obesity and its complications is unknown. Here, we observe that mice with chronic AMPK activation, resulting from mutation of the AMPK γ2 subunit, exhibit ghrelin signaling-dependent hyperphagia, obesity, and impaired pancreatic islet insulin secretion. Humans bearing the homologous mutation manifest a congruent phenotype. Our studies highlight that long-term AMPK activation throughout all tissues can have adverse metabolic consequences, with implications for pharmacological strategies seeking to chronically activate AMPK systemically to treat metabolic disease.

U2 - 10.1016/j.cmet.2016.04.003

DO - 10.1016/j.cmet.2016.04.003

M3 - Article

C2 - 27133129

SN - 1550-4131

VL - 23

SP - 821

EP - 836

JO - Cell Metabolism

JF - Cell Metabolism

IS - 5

ER -

Chronic Activation of γ2 AMPK Induces Obesity and Reduces β Cell Function

Abstract

Bibliographical note

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