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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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.
Carling, D. AMPK signalling in health and disease. Curr. Opin. Cell Biol. 45, 31–37 (2017).
Hardie, D. G. AMP-activated protein kinase: maintaining energy homeostasis at the cellular and whole-body levels. Annu. Rev. Nutr. 34, 31–55 (2014).
Steinberg, G. R. & Kemp, B. E. AMPK in health and disease. Physiol. Rev. 89, 1025–1078 (2009).
Cool, B. et al. Identification and characterization of a small molecule AMPK activator that treats key components of type 2 diabetes and the metabolic syndrome. Cell Metab. 3, 403–416 (2006).
Xiao, B. et al. Structural basis of AMPK regulation by small molecule activators. Nat. Commun. 4, 3017 (2013).
Woods, A. et al. Liver-specific activation of AMPK prevents steatosis on a high fructose diet. Cell Rep. 18, 3043–3051 (2017).
Andersson, U. et al. AMP-activated protein kinase plays a role in the control of food intake. J. Biol. Chem. 279, 12005–12008 (2004).
Minokoshi, Y. et al. AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature 428, 569–574 (2004).
Nicholls, D. G. & Locke, R. M. Thermogenic mechanisms in brown fat. Physiol. Rev. 64, 1–64 (1984).
Cannon, B. & Nedergaard, J. Brown adipose tissue: function and physiological significance. Physiol. Rev. 84, 277–359 (2004).
Feldmann, H. M., Golozoubova, V., Cannon, B. & Nedergaard, J. UCP1 ablation induces obesity and abolishes diet-induced thermogenesis in mice exempt from thermal stress by living at thermoneutrality. Cell. Metab. 9, 203–209 (2009).
García-Ruiz, E. et al. The intake of high-fat diets induces the acquisition of brown adipocyte gene expression features in white adipose tissue. Int. J. Obes. 39, 1619–1629 (2015).
Gordon, C. J. Thermal physiology of laboratory mice: defining thermoneutrality. J. Therm. Biol. 37, 654–685 (2012).
Walden, T. B., Hansen, I. R., Timmons, J. A., Cannon, B. & Nedergaard, J. Recruited vs. nonrecruited molecular signatures of brown, “brite,” and white adipose tissues. Am. J. Physiol. Endocrinol. Metab. 302, E19–E31 (2012).
Wu, J., Cohen, P. & Spiegelman, B. M. Adaptive thermogenesis in adipocytes: is beige the new brown? Genes Dev. 27, 234–250 (2013).
Harms, M. & Seale, P. Brown and beige fat: development, function and therapeurtic potential. Nat. Med. 19, 1252–1263 (2013).
Wu, J. et al. Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell 150, 366–376 (2012).
Granneman, J. G., Burnazi, M., Zhu, Z. & Schwamb, L. A. White adipose tissue contributes to UCP1-independent thermogenesis. Am. J. Physiol. Endocrinol. Metab. 285, E1230–E1236 (2003).
Ukropec, J., Anunciado, R. P., Ravussin, Y., Hulver, M. W. & Kozak, L. P. UCP1-independent thermogenesis in white adipose tissue of cold-acclimated Ucp1-/- mice. J. Biol. Chem. 281, 31894–31908 (2006).
Kazak, L. et al. A creatine-driven substrate cycle enhances energy expenditure and thermogenesis in beige fat. Cell 163, 643–655 (2015).
Fitch, C. D. & Chevli, R. Inhibition of creatine and phosphocreatine accumulation in skeletal muscle and heart. Metabolism 29, 686–690 (1980).
Block, B. A., O’Brien, J. & Meissner, G. Characterization of the sarcoplasmic reticulum proteins in the thermogenic muscles of fish. J. Cell. Biol. 127, 1275–1287 (1994).
da Costa, D. C. & Landeira-Fernandez, A. M. Thermogenic activity of the Ca2+-ATPase from blue marlin heater organ: regulation by KCl and temperature. Am. J. Physiol. Regul. Integr. Comp. Physiol. 297, R1460–R1468 (2009).
Ikeda, K. et al. UCP1-independent signaling involving SERCA2b-mediated calcium cycling regulates beige fat thermogenesis and systemic glucose homeostasis. Nat. Med. 23, 1454–1465 (2017).
Inagaki, T., Sakai, J. & Kajimura, S. Transcriptional and epigenetic control of brown and beige adipose cell fate and function. Nat. Rev. Mol. Cell Biol. 17, 480–495 (2106).
Sanchez-Gurmaches, J., Hung, C. M. & Guertin, D. A. Emerging complexities in adipocyte origins andidentity. Trends Cell Biol. 26, 313–326 (2016).
Eguchi, J. et al. Transcriptional control of adipose lipid handling by IRF4. Cell. Metab. 13, 249–259 (2011).
Jeffery, E. et al. Characterization of Cre recombinase models for the study of adipose tissue. Adipocyte 3, 206–211 (2014).
Berry, R. & Rodeheffer, M. S. Characterization of the adipocyte cellular lineage in vivo. Nat. Cell Biol. 15, 302–308 (2013).
Yang, Q. et al. AMPK/α-ketoglutarate axis dynamically mediates DNA demethylation in the Prdm16 promoter and brown adipogenesis. Cell Metab. 24, 542–554 (2016).
Wu, L. et al. AMP-activated protein kinase (AMPK) regulates energy metabolism through modulating thermogenesis in adipose tissue. Front. Physiol. 9, 122 (2018).
Mottillo, E. P. et al. Lack of adipocyte AMPK exacerbates insulin resistance and hepatic steatosis through brown and beige adipose tissue function. Cell Metab. 24, 118–129 (2016).
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.
The authors declare no competing interests.
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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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