AMPK as a Therapeutic Target for Treating Metabolic Diseases

Trends in Endocrinology and Metabolism

Volumn 28, Issue 8, 2017, Pages 545-560

  Day, Emily A ^a   Ford, Rebecca J ^a   Steinberg, Gregory R ^a  

^a MCMASTER UNIVERSITY   (Canada)

Author keywords

adipose tissue; atherosclerosis; beige adipose tissue; brown adipose tissue; macrophages; NAFLD; NASH

Indexed keywords

HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE KINASE; ADENYLATE KINASE;

BROWN ADIPOSE TISSUE; GLUCOSE HOMEOSTASIS; HUMAN; IMMUNOCOMPETENT CELL; INFLAMMATION; LIPID METABOLISM; METABOLIC DISORDER; NONHUMAN; PHENOTYPE; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN STRUCTURE; REVIEW; WHITE ADIPOSE TISSUE; ANIMAL; GENETICS; INSULIN RESISTANCE; METABOLISM; MOLECULARLY TARGETED THERAPY; MOUSE; NON INSULIN DEPENDENT DIABETES MELLITUS; NONALCOHOLIC FATTY LIVER; OBESITY; PHYSIOLOGY; PROCEDURES; TRANSGENIC MOUSE;

ADENYLATE KINASE; ANIMALS; DIABETES MELLITUS, TYPE 2; HUMANS; INSULIN RESISTANCE; LIPID METABOLISM; METABOLIC DISEASES; MICE; MICE, TRANSGENIC; MOLECULAR TARGETED THERAPY; NON-ALCOHOLIC FATTY LIVER DISEASE; OBESITY;

EID: 85021056480     PISSN: 10432760     EISSN: 18793061     Source Type: Journal    
DOI: 10.1016/j.tem.2017.05.004     Document Type: Review

References (171)

1. Hardie, D.G., et al. AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat. Rev. Mol. Cell Biol. 13 (2012), 251–262.
2. Carling, D., et al. AMP-activated protein kinase: new regulation, new roles?. Biochem. J. 445 (2012), 11–27.
3. Ruderman, N.B., et al. AMPK, insulin resistance, and the metabolic syndrome. J. Clin. Invest. 123 (2013), 2764–2772.
4. Ganeshan, K., Chawla, A., Metabolic regulation of immune responses. Annu. Rev. Immunol. 32 (2014), 609–634.
5. Steinberg, G.R., Schertzer, J.D., AMPK promotes macrophage fatty acid oxidative metabolism to mitigate inflammation: implications for diabetes and cardiovascular disease. Immunol. Cell Biol. 92 (2014), 340–345.
6. Steinberg, G.R., et al. Tumor necrosis factor α-induced skeletal muscle insulin resistance involves suppression of AMP-kinase signaling. Cell Metab. 4 (2006), 465–474.
7. Woo, S.-L., et al. Metformin ameliorates hepatic steatosis and inflammation without altering adipose phenotype in diet-induced obesity. PLoS One, 9, 2014, e91111.
8. Lindholm, C.R., et al. A high-fat diet decreases AMPK activity in multiple tissues in the absence of hyperglycemia or systemic inflammation in rats. J. Physiol. Biochem. 69 (2013), 165–175.
9. Yang, Z., et al. Macrophage 1 AMP-activated protein kinase (1AMPK) antagonizes fatty acid-induced inflammation through SIRT1. J. Biol. Chem. 285 (2010), 19051–19059.
10. 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 (2016), 118–129.
11. Sag, D., et al. Adenosine 5′-monophosphate-activated protein kinase promotes macrophage polarization to an anti-inflammatory functional phenotype. J. Immunol. 181 (2008), 8633–8641.
12. Galic, S., et al. Hematopoietic AMPK β1 reduces mouse adipose tissue macrophage inflammation and insulin resistance in obesity. J. Clin. Invest. 121 (2011), 4903–4915.
13. Bäckhed, F., et al. Mechanisms underlying the resistance to diet-induced obesity in germ-free mice. Proc. Natl. Acad. Sci. U. S. A. 104 (2007), 979–984.
14. Gauthier, M.-S., et al. Decreased AMP-activated protein kinase activity is associated with increased inflammation in visceral adipose tissue and with whole-body insulin resistance in morbidly obese humans. Biochem. Biophys. Res. Commun. 404 (2011), 382–387.
15. Fritzen, A.M., et al. New Nordic diet-induced weight loss is accompanied by changes in metabolism and AMPK signaling in adipose tissue. J. Clin. Endocrinol. Metab. 100 (2015), 3509–3519.
16. Xu, X.J., et al. Improved insulin sensitivity 3 months after RYGB surgery is associated with increased subcutaneous adipose tissue AMPK activity and decreased oxidative stress. Diabetes 64 (2015), 3155–3159.
17. Albers, P.H., et al. Enhanced insulin signaling in human skeletal muscle and adipose tissue following gastric bypass surgery. Am. J. Physiol. Regul. Integr. Comp. Physiol. 309 (2015), R510–R524.
18. Wu, Y., et al. Activation of protein phosphatase 2A by palmitate inhibits AMP-activated protein kinase. J. Biol. Chem. 282 (2007), 9777–9788.
19. Suzuki, T., et al. Inhibition of AMPK catabolic action by GSK3. Mol. Cell 50 (2013), 407–419.
20. Cao, J., et al. Low concentrations of metformin suppress glucose production in hepatocytes through AMP-activated protein kinase (AMPK). J. Biol. Chem. 289 (2014), 20435–20446.
21. Hurley, R.L., et al. Regulation of AMP-activated protein kinase by multisite phosphorylation in response to agents that elevate cellular cAMP. J. Biol. Chem. 281 (2006), 36662–36672.
22. Coughlan, K.A., et al. PKD1 inhibits AMPKα2 through phosphorylation of serine 491 and impairs insulin signaling in skeletal muscle cells. J. Biol. Chem. 291 (2016), 5664–5675.
23. Kim, B., et al. Insulin resistance prevents AMPK-induced Tau dephosphorylation through Akt-mediated increase in AMPKSer-485 phosphorylation. J. Biol. Chem. 290 (2015), 19146–19157.
24. Hawley, S.A., et al. Phosphorylation by Akt within the ST loop of AMPK-α1 down-regulates its activation in tumour cells. Biochem. J. 459 (2014), 275–287.
25. Ning, J., et al. Suppression of AMPK activation via S485 phosphorylation by IGF-I during hyperglycemia is mediated by AKT activation in vascular smooth muscle cells. Endocrinology 152 (2011), 3143–3154.
26. Horman, S., et al. Insulin antagonizes ischemia-induced Thr172 phosphorylation of AMP-activated protein kinase alpha-subunits in heart via hierarchical phosphorylation of Ser485/491. J. Biol. Chem. 281 (2006), 5335–5340.
27. Dagon, Y., et al. p70S6 kinase phosphorylates AMPK on serine 491 to mediate leptin's effect on food intake. Cell Metab. 16 (2012), 104–112.
28. Kelly, B., O'Neill, L.A., Metabolic reprogramming in macrophages and dendritic cells in innate immunity. Cell Res. 25 (2015), 771–784.
29. Cao, Q., et al. Myeloid deletion of α1AMPK exacerbates atherosclerosis in LDL receptor knockout (LDLRKO) mice. Diabetes 65 (2016), 1565–1576.
30. Mounier, R., et al. AMPKα1 regulates macrophage skewing at the time of resolution of inflammation during skeletal muscle regeneration. Cell Metab. 18 (2013), 251–264.
31. Fullerton, M.D., et al. Salicylate improves macrophage cholesterol homeostasis via activation of AMPK. J. Lipid Res. 56 (2015), 1025–1033.
32. Pinkosky, S.L., et al. Liver-specific ATP-citrate lyase inhibition by bempedoic acid decreases LDL-C and attenuates atherosclerosis. Nat. Commun., 7, 2016, 13457.
33. Dong, Y., et al. Activation of AMP-activated protein kinase inhibits oxidized LDL-triggered endoplasmic reticulum stress in vivo. Diabetes 59 (2010), 1386–1396.
34. Dong, Y., et al. Reduction of AMP-activated protein kinase α2 increases endoplasmic reticulum stress and atherosclerosis in vivo. Circulation 121 (2010), 792–803.
35. Wang, Q., et al. Activation of AMP-activated protein kinase is required for berberine-induced reduction of atherosclerosis in mice: the role of uncoupling protein 2. PLoS One, 6, 2011, e25436.
36. Cai, Z., et al. Ablation of adenosine monophosphate-activated protein kinase α1 in vascular smooth muscle cells promotes diet-induced atherosclerotic calcification in vivo. Circ. Res. 119 (2016), 422–433.
37. Ding, Y., et al. AMP-activated protein kinase alpha 2 deletion induces VSMC phenotypic switching and reduces features of atherosclerotic plaque stability. Circ. Res. 119 (2016), 718–730.
38. Kelly, B., et al. Metformin inhibits the production of reactive oxygen species from NADH:Ubiquinone oxidoreductase to limit induction of interleukin-1β (IL-1β) and boosts interleukin-10 (IL-10) in lipopolysaccharide (LPS)-activated macrophages. J. Biol. Chem. 290 (2015), 20348–20359.
39. Boß, M., et al. AMPK-independent inhibition of human macrophage ER stress response by AICAR. Sci. Rep., 6, 2016, 32111.
40. Cameron, A.R., et al. Anti-inflammatory effects of metformin irrespective of diabetes status. Circ. Res. 119 (2016), 652–665.
41. Yang, Z., et al. The full capacity of AICAR to reduce obesity-induced inflammation and insulin resistance requires myeloid SIRT1. PLoS One, 7, 2012, e49935.
42. Namgaladze, D., et al. AICAR inhibits PPAR during monocyte differentiation to attenuate inflammatory responses to atherogenic lipids. Cardiovasc. Res. 98 (2013), 479–487.
43. Ouimet, M., et al. MicroRNA-33-dependent regulation of macrophage metabolism directs immune cell polarization in atherosclerosis. J. Clin. Invest. 125 (2015), 4334–4348.
44. Chan, K.L., et al. Palmitoleate reverses high fat-induced proinflammatory macrophage polarization via amp-activated protein kinase (AMPK). J. Biol. Chem. 290 (2015), 16979–16988.
45. Berod, L., et al. De novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells. Nat. Med. 20 (2014), 1327–1333.
46. Wang, Q., et al. Metformin suppresses diabetes-accelerated atherosclerosis via the inhibition of Drp1-mediated mitochondrial fission. Diabetes 66 (2017), 193–205.
47. Davis, B.J., et al. Activation of the AMP-activated kinase by antidiabetes drug metformin stimulates nitric oxide synthesis in vivo by promoting the association of heat shock protein 90 and endothelial nitric oxide synthase. Diabetes 55 (2006), 495–505.
48. Chen, Z.-P., et al. AMP-activated protein kinase phosphorylation of endothelial NO synthase. FEBS Lett. 443 (1999), 285–289.
49. Jung, T.W., et al. AMPK activator-mediated inhibition of endoplasmic reticulum stress ameliorates carrageenan-induced insulin resistance through the suppression of selenoprotein P in HepG2 hepatocytes. Mol. Cell. Endocrinol. 382 (2014), 66–73.
50. Dai, X., et al. Phosphorylation of CHOP (C/EBP homologous protein) by the AMP-activated protein kinase alpha 1 in macrophages promotes CHOP degradation and reduces injury-induced neointimal disruption in vivo. Circ. Res. 119 (2016), 1089–1100.
51. Rutherford, C., et al. Phosphorylation of Janus kinase 1 (JAK1) by AMP-activated protein kinase (AMPK) links energy sensing to anti-inflammatory signaling. Sci. Signal., 9, 2016, ra109.
52. Wu, Y., et al. Activation of AMPKα2 in adipocytes is essential for nicotine-induced insulin resistance in vivo. Nat. Med. 21 (2015), 373–382.
53. Greer, E.L., et al. The energy sensor AMP-activated protein kinase directly regulates the mammalian FOXO3 transcription factor. J. Biol. Chem. 282 (2007), 30107–30119.
54. Yang, Z., et al. Macrophage alpha1 AMP-activated protein kinase (alpha1AMPK) antagonizes fatty acid-induced inflammation through SIRT1. J. Biol. Chem. 285 (2010), 19051–19059.
55. Alvarez-Guardia, D., et al. The p65 subunit of NF- B binds to PGC-1, linking inflammation and metabolic disturbances in cardiac cells. Cardiovasc. Res. 87 (2010), 449–458.
56. Antonucci, L., et al. Basal autophagy maintains pancreatic acinar cell homeostasis and protein synthesis and prevents ER stress. Proc. Natl. Acad. Sci. U. S. A. 112 (2015), E6166–E6174.
57. Liu, K., et al. Impaired macrophage autophagy increases the immune response in obese mice by promoting proinflammatory macrophage polarization. Autophagy 12 (2016), 245–260.
58. Razani, B., et al. Autophagy links inflammasomes to atherosclerotic progression. Cell Metab. 15 (2012), 534–544.
59. Liao, X., et al. Macrophage autophagy plays a protective role in advanced atherosclerosis. Cell Metab. 15 (2012), 545–553.
60. Schrijvers, D.M., et al. Autophagy in atherosclerosis: a potential drug target for plaque stabilization. Arterioscler. Thromb. Vasc. Biol. 31 (2011), 2787–2791.
61. Kim, J., et al. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat. Cell Biol. 13 (2011), 132–141.
62. Egan, D.F., et al. Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science 331 (2011), 456–461.
63. Gwinn, D.M., et al. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol. Cell 30 (2008), 214–226.
64. Stephenne, X., et al. Metformin activates AMP-activated protein kinase in primary human hepatocytes by decreasing cellular energy status. Diabetologia 54 (2011), 3101–3110.
65. Dzamko, N., et al. AMPK beta1 deletion reduces appetite, preventing obesity and hepatic insulin resistance. J. Biol. Chem. 285 (2010), 115–122.
66. Ford, R.J., et al. Metformin and salicylate synergistically activate liver AMPK, inhibit lipogenesis and improve insulin sensitivity. Biochem. J. 468 (2015), 125–132.
67. Viollet, B., et al. The AMP-activated protein kinase alpha2 catalytic subunit controls whole-body insulin sensitivity. J. Clin. Invest. 111 (2003), 91–98.
68. Jørgensen, S.B., et al. Knockout of the α2 but not α1 5′-AMP-activated protein kinase isoform abolishes 5-aminoimidazole-4-carboxamide-1-β-4- ribofuranoside-but not contraction-induced glucose uptake in skeletal muscle. J. Biol. Chem. 279 (2003), 1070–1079.
69. Steinberg, G.R., et al. Whole body deletion of AMP-activated protein kinase β2 reduces muscle AMPK activity and exercise capacity. J. Biol. Chem. 285 (2010), 37198–37209.
70. O'Brien, R.M., Granner, D.K., Regulation of gene expression by insulin. Physiol. Rev. 76 (1996), 1109–1161.
71. Bergeron, R., et al. Effect of 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside infusion on in vivo glucose and lipid metabolism in lean and obese Zucker rats. Diabetes 50 (2001), 1076–1082.
72. Lochhead, P.A., et al. 5-Aminoimidazole-4-carboxamide riboside mimics the effects of insulin on the expression of the 2 key gluconeogenic genes PEPCK and glucose-6-phosphatase. Diabetes 49 (2000), 896–903.
73. Vincent, M.F., et al. Inhibition of glycolysis by 5-amino-4-imidazolecarboxamide riboside in isolated rat hepatocytes. Biochem. J. 281 (1992), 267–272.
74. Foretz, M., et al. Short-term overexpression of a constitutively active form of AMP-activated protein kinase in the liver leads to mild hypoglycemia and fatty liver. Diabetes 54 (2005), 1331–1339.
75. Andreelli, F., et al. Liver adenosine monophosphate-activated kinase-α2 catalytic subunit is a key target for the control of hepatic glucose production by adiponectin and leptin but not insulin. Endocrinology 147 (2006), 2432–2441.
76. Foretz, M., et al. Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J. Clin. Invest. 120 (2010), 2355–2369.
77. Miller, R.A., et al. Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP. Nature 494 (2013), 256–260.
78. Hasenour, C.M., et al. 5-Aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) effect on glucose production, but not energy metabolism, is independent of hepatic AMPK in vivo. J. Biol. Chem., 289, 2014 5950–5059.
79. Hasenour, C.M., et al. Liver AMP-activated protein kinase is unnecessary for gluconeogenesis but protects energy state during nutrient deprivation. PLoS One, 12, 2017, e0170382.
80. Vincent, M.F., et al. Inhibition by AICA riboside of gluconeogenesis in isolated rat hepatocytes. Diabetes 40 (1991), 1259–1266.
81. Smith, B.K., et al. Treatment of nonalcoholic fatty liver disease: role of AMPK. Am. J. Physiol. Endocrinol. Metab. 311 (2016), E730–E740.
82. Cusi, K., Role of obesity and lipotoxicity in the development of nonalcoholic steatohepatitis: pathophysiology and clinical implications. Gastroenterology 142 (2012), 711–725.
83. Seo, E., et al. Overexpression of AMPKalpha1 ameliorates fatty liver in hyperlipidemic diabetic rats. Korean J. Physiol. Pharmacol. 13 (2009), 449–454.
84. Zhang, H.-A., et al. AMPKα1 overexpression alleviates the hepatocyte model of nonalcoholic fatty liver disease via inactivating p38MAPK pathway. Biochem. Biophys. Res. Commun. 474 (2016), 364–370.
85. Woods, A., et al. Liver-specific activation of AMPK prevents steatosis on a high-fructose diet. Cell Rep. 18 (2017), 3043–3051.
86. Fullerton, M.D., et al. Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin. Nat. Med. 19 (2013), 1649–1654.
87. Harriman, G., et al. Acetyl-CoA carboxylase inhibition by ND-630 reduces hepatic steatosis, improves insulin sensitivity, and modulates dyslipidemia in rats. Proc. Natl. Acad. Sci. U. S. A. 113 (2016), E1796–E17805.
88. 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 (2006), 403–416.
89. Foretz, M., et al. AMP-activated protein kinase inhibits the glucose-activated expression of fatty acid synthase gene in rat hepatocytes. J. Biol. Chem. 273 (1998), 14767–14771.
90. Li, Y., et al. AMPK phosphorylates and inhibits SREBP activity to attenuate hepatic steatosis and atherosclerosis in diet-induced insulin-resistant mice. Cell Metab. 13 (2011), 376–388.
91. Liu, S., et al. AICAR-induced activation of AMPK inhibits TSH/SREBP-2/HMGCR pathway in liver. PLoS One, 10, 2015, e0124951.
92. Viollet, B., et al. Cellular and molecular mechanisms of metformin: an overview. Clin. Sci. 122 (2012), 253–270.
93. Rena, G., et al. Molecular mechanism of action of metformin: old or new insights?. Diabetologia 56 (2013), 1898–1906.
94. Zhou, G., et al. Role of AMP-activated protein kinase in mechanism of metformin action. J. Clin. Invest. 108 (2001), 1167–1174.
95. Shaw, R.J., et al. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 310 (2005), 1642–1646.
96. He, L., Wondisford, F.E., Metformin action: concentrations matter. Cell Metab. 21 (2015), 159–162.
97. Zhang, C.-S., et al. Metformin activates AMPK through the lysosomal pathway. Cell Metab. 24 (2016), 521–522.
98. Duca, F.A., et al. Metformin activates a duodenal AMPK–dependent pathway to lower hepatic glucose production in rats. Nat. Med. 21 (2015), 506–511.
99. Smith, B.K., Steinberg, G.R., Duodenal energy sensing regulates hepatic glucose output. Nat. Med. 21 (2015), 428–429.
100. Wood, A.J.J., et al. Metformin. N. Engl. J. Med. 334 (1996), 574–579.
101. Natali, A., Ferrannini, E., Effects of metformin and thiazolidinediones on suppression of hepatic glucose production and stimulation of glucose uptake in type 2 diabetes: a systematic review. Diabetologia 49 (2006), 434–441.
102. Al Khalifah, R.A., et al. The effect of adding metformin to insulin therapy for type 1 diabetes mellitus children: a systematic review and meta-analysis. Pediatr. Diabetes, 2017, 10.1111/pedi.12493 Published online February 1, 2017.
103. Lucas-Herald, A.K., Robertson, K.J., Metformin with insulin does not improve the glycaemic control of overweight/obese adolescents with type 1 diabetes. Arch. Dis. Child. Educ. Pract. Ed., 2016, 10.1136/archdischild-2016-312326 Published online December 14, 2016.
104. Lambert, J.E., et al. Increased de novo lipogenesis is a distinct characteristic of individuals with nonalcoholic fatty liver disease. Gastroenterology 146 (2014), 726–735.
105. Wilke, M.S., et al. Synthesis of specific fatty acids contributes to VLDL-triacylglycerol composition in humans with and without type 2 diabetes. Diabetologia 52 (2009), 1628–1637.
106. Marques-Lopes, I., et al. Postprandial de novo lipogenesis and metabolic changes induced by a high-carbohydrate, low-fat meal in lean and overweight men. Am. J. Clin. Nutr. 73 (2001), 253–261.
107. Marcinko, K., et al. High intensity interval training improves liver and adipose tissue insulin sensitivity. Mol. Metab. 4 (2015), 903–915.
108. Smith, B.K., et al. Salsalate (salicylate) uncouples mitochondria, improves glucose homeostasis, and reduces liver lipids independent of AMPK-β1. Diabetes 65 (2016), 3352–3361.
109. Jäger, S., et al. AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha. Proc. Natl. Acad. Sci. U. S. A. 104 (2007), 12017–12022.
110. Ducommun, S., et al. Motif affinity and mass spectrometry proteomic approach for the discovery of cellular AMPK targets: identification of mitochondrial fission factor as a new AMPK substrate. Cell. Signal. 27 (2015), 978–988.
111. Toyama, E.Q., et al. AMP-activated protein kinase mediates mitochondrial fission in response to energy stress. Science 351 (2016), 275–281.
112. Gariani, K., et al. Non-alcoholic fatty liver disease and insulin resistance: from bench to bedside. Diabetes Metab. 39 (2013), 16–26.
113. Sinha, R.A., Yen, P.M., Thyroid hormone-mediated autophagy and mitochondrial turnover in NAFLD. Cell Biosci., 6, 2016, 46.
114. Flores-Toro, J.A., et al. Autophagy in the liver: cell's cannibalism and beyond. Arch. Pharm. Res. 39 (2016), 1050–1061.
115. Galloway, C.A., et al. Decreasing mitochondrial fission alleviates hepatic steatosis in a murine model of nonalcoholic fatty liver disease. Am. J. Physiol. Gastrointest. Liver Physiol. 307 (2014), G632–G641.
116. Ward, C., et al. Autophagy, lipophagy and lysosomal lipid storage disorders. Biochim. Biophys. Acta Mol. Cell Biol. Lipids 1861 (2016), 269–284.
117. Kaushik, S., Cuervo, A.M., AMPK-dependent phosphorylation of lipid droplet protein PLIN2 triggers its degradation by CMA. Autophagy 12 (2016), 432–438.
118. Chondronikola, M., et al. Brown adipose tissue improves whole-body glucose homeostasis and insulin sensitivity in humans. Diabetes 63 (2014), 4089–4099.
119. Blondin, D.P., et al. Selective impairment of glucose but not fatty acid or oxidative metabolism in brown adipose tissue of subjects with type 2 diabetes. Diabetes 64 (2015), 2388–2397.
120. Lowell, B.B., et al. Development of obesity in transgenic mice after genetic ablation of brown adipose tissue. Nature 366 (1993), 740–742.
121. Sidossis, L., Kajimura, S., Brown and beige fat in humans: thermogenic adipocytes that control energy and glucose homeostasis. J. Clin. Invest. 125 (2015), 478–486.
122. Watt, M.J., Steinberg, G.R., Regulation and function of triacylglycerol lipases in cellular metabolism. Biochem. J. 414 (2008), 313–325.
123. Sullivan, J.E., et al. Inhibition of lipolysis and lipogenesis in isolated rat adipocytes with AICAR, a cell-permeable activator of AMP-activated protein kinase. FEBS Lett. 353 (1994), 33–36.
124. Elia, M., et al. The energy cost of triglyceride-fatty acid recycling in nonobese subjects after an overnight fast and four days of starvation. Metabolism 36 (1987), 251–255.
125. Livesey, G., et al. The energy equivalents of ATP and the energy values of food proteins and fats. Br. J. Nutr., 51, 1984, 15.
126. Park, H., et al. Coordinate regulation of malonyl-CoA decarboxylase, sn-glycerol-3-phosphate acyltransferase, and acetyl-CoA carboxylase by AMP-activated protein kinase in rat tissues in response to exercise. J. Biol. Chem. 277 (2002), 32571–32577.
127. Watt, M.J., et al. Regulation of HSL serine phosphorylation in skeletal muscle and adipose tissue. Am. J. Physiol. Endocrinol. Metab. 290 (2006), E500–E508.
128. Daval, M., et al. Anti-lipolytic action of AMP-activated protein kinase in rodent adipocytes. J. Biol. Chem. 280 (2005), 25250–25257.
129. Moule, S.K., Denton, R.M., The activation of p38 MAPK by the beta-adrenergic agonist isoproterenol in rat epididymal fat cells. FEBS Lett. 439 (1998), 287–290.
130. Yin, W., et al. Role of AMP-activated protein kinase in cyclic AMP-dependent lipolysis In 3T3-L1 adipocytes. J. Biol. Chem. 278 (2003), 43074–43080.
131. MacPherson, R.E.K., et al. Reduced ATGL-mediated lipolysis attenuates β-adrenergic-induced AMPK signaling, but not the induction of PKA-targeted genes, in adipocytes and adipose tissue. Am. J. Physiol. Cell Physiol. 311 (2016), C269–C276.
132. Mahlapuu, M., et al. Expression profiling of the γ-subunit isoforms of AMP-activated protein kinase suggests a major role for γ3 in white skeletal muscle. Am. J. Physiol. Endocrinol. Metab. 286 (2003), 2328–2337.
133. Kim, S.-J., et al. AMPK phosphorylates desnutrin/ATGL and hormone-sensitive lipase to regulate lipolysis and fatty acid oxidation within adipose tissue. Mol. Cell. Biol. 36 (2016), 1961–1976.
134. Rohm, M., et al. An AMP-activated protein kinase–stabilizing peptide ameliorates adipose tissue wasting in cancer cachexia in mice. Nat. Med. 22 (2016), 1120–1130.
135. Pagnon, J., et al. Identification and functional characterization of protein kinase A phosphorylation sites in the major lipolytic protein, adipose triglyceride lipase. Endocrinology 153 (2012), 4278–4289.
136. Garton, A.J., Yeaman, S.J., Identification and role of the basal phosphorylation site on hormone-sensitive lipase. Eur. J. Biochem. 191 (1990), 245–250.
137. Garton, A.J., et al. Phosphorylation of bovine hormone-sensitive lipase by the AMP-activated protein kinase. A possible antilipolytic mechanism. Eur. J. Biochem. 179 (1989), 249–254.
138. Nedergaard, J., Cannon, B., The browning of white adipose tissue: some burning issues. Cell Metab. 20 (2014), 396–407.
139. Wu, J., et al. Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell 150 (2012), 366–376.
140. Seale, P., et al. Transcriptional control of brown fat determination by PRDM16. Cell Metab. 6 (2007), 38–54.
141. Seale, P., et al. PRDM16 controls a brown fat/skeletal muscle switch. Nature 454 (2008), 961–967.
142. Wan, Z., et al. Evidence for the role of AMPK in regulating PGC-1 Alpha expression and mitochondrial proteins in mouse epididymal adipose tissue. Obesity 22 (2014), 730–738.
143. Yang, Q., et al. AMPK/α–ketoglutarate axis dynamically mediates DNA demethylation in the Prdm16 promoter and brown adipogenesis. Cell Metab. 24 (2016), 542–554.
144. Yan, M., et al. Chronic AMPK activation via loss of FLCN induces functional beige adipose tissue through PGC-1α/ERRα. Genes Dev. 30 (2016), 1034–1046.
145. Zhang, H., et al. MicroRNA-455 regulates brown adipogenesis via a novel HIF1an–AMPK–PGC1α signaling network. EMBO Rep. 16 (2015), 1378–1393.
146. Wang, S., et al. Resveratrol enhances brown adipocyte formation and function by activating AMP-activated protein kinase (AMPK) α1 in mice fed high-fat diet. Mol. Nutr. Food Res., 2017, 10.1002/mnfr.201600746 Published online November 22, 2016.
147. Wang, S., et al. Resveratrol induces brown-like adipocyte formation in white fat through activation of AMP-activated protein kinase (AMPK) α1. Int. J. Obes. 39 (2015), 967–976.
148. Li, A., et al. Metformin and resveratrol inhibit Drp1-mediated mitochondrial fission and prevent ER stress-associated NLRP3 inflammasome activation in the adipose tissue of diabetic mice. Mol. Cell. Endocrinol. 434 (2016), 36–47.
149. Yang, J., et al. Corosolic acid inhibits adipose tissue inflammation and ameliorates insulin resistance via AMPK activation in high-fat fed mice. Phytomedicine 23 (2016), 181–190.
150. Zhou, X., et al. The beneficial effects of betaine on dysfunctional adipose tissue and N6-methyladenosine mRNA methylation requires the AMP-activated protein kinase α1 subunit. J. Nutr. Biochem. 26 (2015), 1678–1684.
151. Doan, K.V., et al. Gallic acid regulates body weight and glucose homeostasis through AMPK activation. Endocrinology 156 (2015), 157–168.
152. Luo, T., et al. AMPK activation by metformin suppresses abnormal extracellular matrix remodeling in adipose tissue and ameliorates insulin resistance in obesity. Diabetes 65 (2016), 2295–2310.
153. Jeong, H.W., et al. Berberine suppresses proinflammatory responses through AMPK activation in macrophages. Am. J. Physiol. Endocrinol. Metab. 296 (2009), E955–E964.
154. Mo, C., et al. The crosstalk between Nrf2 and AMPK signal pathways is important for the anti-inflammatory effect of berberine in LPS-stimulated macrophages and endotoxin-shocked mice. Antioxid. Redox Signal. 20 (2014), 574–588.
155. Fan, X., et al. Berberine alleviates ox-LDL induced inflammatory factors by up-regulation of autophagy via AMPK/mTOR signaling pathway. J. Transl. Med., 13, 2015, 92.
156. Li, D., et al. Adenosine monophosphate-activated protein kinase induces cholesterol efflux from macrophage-derived foam cells and alleviates atherosclerosis in apolipoprotein E-deficient mice. J. Biol. Chem. 285 (2010), 33499–33509.
157. Vasamsetti, S.B., et al. Resveratrol attenuates monocyte-to-macrophage differentiation and associated inflammation via modulation of intracellular GSH homeostasis: relevance in atherosclerosis. Free Radic. Biol. Med. 96 (2016), 392–405.
158. Vasamsetti, S.B., et al. Metformin inhibits monocyte-to-macrophage differentiation via AMPK-mediated inhibition of STAT3 activation: potential role in atherosclerosis. Diabetes 64 (2015), 2028–2041.
159. Tsai, J.-S., et al. Troglitazone and Δ2-troglitazone enhance adiponectin expression in monocytes/macrophages through the AMP-activated protein kinase pathway. Mediators Inflamm., 2014, 2014, 726068.
160. Kemmerer, M., et al. AMP-activated protein kinase interacts with the peroxisome proliferator-activated receptor delta to induce genes affecting fatty acid oxidation in human macrophages. PLoS One, 10, 2015, e0130893.
161. Kemmerer, M., et al. AMPK activates LXRα and ABCA1 expression in human macrophages. Int. J. Biochem. Cell. Biol. 78 (2016), 1–9.
162. Zhou, Z., et al. Metformin inhibits advanced glycation end products-induced inflammatory response in murine macrophages partly through AMPK activation and RAGE/NF-κB pathway suppression. J. Diabetes Res., 2016, 4847812.
163. Lee, H.-M., et al. Upregulated NLRP3 inflammasome activation in patients with type 2 diabetes. Diabetes 62 (2013), 194–204.
164. Chang, M.-Y., et al. AICAR induces cyclooxygenase-2 expression through AMP-activated protein kinase–transforming growth factor-β–activated kinase 1–p38 mitogen-activated protein kinase signaling pathway. Biochem. Pharmacol. 80 (2010), 1210–1220.
165. Namgaladze, D., et al. AMP-activated protein kinase suppresses arachidonate 15-lipoxygenase expression in interleukin 4-polarized human macrophages. J. Biol. Chem. 290 (2015), 24484–24494.
166. Zhu, Y.P., et al. Adenosine 5′-monophosphate-activated protein kinase regulates IL-10-mediated anti-inflammatory signaling pathways in macrophages. J. Immunol. 194 (2015), 584–594.
167. Wen, H., et al. Fatty acid-induced NLRP3–ASC inflammasome activation interferes with insulin signaling. Nat. Immunol. 12 (2011), 408–415.
168. Wan, X., et al. 5′-AMP-activated protein kinase-activating transcription factor 1 cascade modulates human monocyte-derived macrophages to atheroprotective functions in response to heme or metformin. Arterioscler. Thromb. Vasc. Biol. 33 (2013), 2470–2480.
169. Lu, J., et al. Astragalus polysaccharide induces anti-inflammatory effects dependent on AMPK activity in palmitate-treated RAW264.7 cells. Int. J. Mol. Med. 31 (2013), 1463–1470.
170. Ji, G., et al. Genistein suppresses LPS-induced inflammatory response through inhibiting NF-κB following AMP kinase activation in RAW 264.7 macrophages. PLoS One, 7, 2012, e53101.
171. Huang, B.-P., et al. AMPK activation inhibits expression of proinflammatory mediators through downregulation of PI3 K/p38 MAPK and NF-κB signaling in murine macrophages. DNA Cell Biol. 34 (2015), 133–141.