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AMPK activation protects against diet-induced obesity through Ucp1-independent thermogenesis in subcutaneous white adipose tissue

Abstract

Obesity results from a chronic imbalance between energy intake and energy output but remains difficult to prevent or treat in humans. Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is an important regulator of energy homeostasis1,2,3 and is a molecular target of drugs used for the treatment of metabolic diseases, including obesity4,5. Here we show that mice expressing a gain-of-function AMPK mutant6 display a change in morphology of subcutaneous white adipocytes that is reminiscent of browning. However, despite a dramatic increase in mitochondrial content, Ucp1 expression is undetectable in these adipocytes. In response to a high-fat diet (HFD), expression of skeletal muscle–associated genes is induced in subcutaneous white adipocytes from the gain-of-function AMPK mutant mice. Chronic genetic AMPK activation results in protection against diet-induced obesity due to an increase in whole-body energy expenditure, most probably because of a substantial increase in the oxygen consumption rate of white adipose tissue. These results suggest that AMPK activation enriches, or leads to the emergence of, a population of subcutaneous white adipocytes that produce heat via Ucp1-independent uncoupling of adenosine triphosphate (ATP) production on a HFD. Our findings indicate that AMPK activation specifically in adipose tissue may have therapeutic potential for the treatment of obesity.

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Fig. 1: AMPK activation protects against diet-induced obesity by increasing energy expenditure.
Fig. 2: AMPK activation protects against diet-induced obesity through a brown adipose tissue–independent mechanism.
Fig. 3: AMPK activation increases subcutaneous white adipose mitochondrial content and Ucp1-independent respiration.
Fig. 4: AMPK activation induces a skeletal muscle–like gene signature in WATsc in mice fed a HFD.

Data availability

The datasets that support the findings of this study are available from the corresponding author upon request. RNA-sequence datasets used in this study are available from Gene Expression Omnibus with the accession number GSE120429.

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Acknowledgements

This work was funded by the Medical Research Council UK (grant MC-A654-5QB10 to D.C.). A.E.P. was funded by a BBSRC-CASE Studentship Award (BB/L502662/1). L.W. was funded by a British Heart Foundation Studentship Award. We would like to thank the MRC London Institute of Medical Sciences Whole Animal Physiology Team for their assistance.

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A.E.P., L.M., P.J.M., T.A., M.B., L.W. and R.F. carried out the in vivo and in vitro studies. S.K., A.B. and M.C. carried out the RNA sequencing and analysis. C.W. and D.S. helped with immunohistochemistry analysis. A.S. and M.B.Y. helped with the metabolic phenotyping. L.P. and A.W. helped perform phenotypic analysis of mice. A.E.P., L.M., W.K. and M.R.D. carried out the cellular respiration studies. A.E.P., L.M., A.W., D.M.S., J.A.R., M.A.S. and D.C. designed and planned the study. All authors contributed to the preparation of the manuscript.

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Correspondence to Angela Woods or David Carling.

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Pollard, A.E., Martins, L., Muckett, P.J. et al. AMPK activation protects against diet-induced obesity through Ucp1-independent thermogenesis in subcutaneous white adipose tissue. Nat Metab 1, 340–349 (2019). https://doi.org/10.1038/s42255-019-0036-9

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