Emerging Role of AMPK in Brown and Beige Adipose Tissue (BAT): Implications for Obesity, Insulin Resistance, and Type 2 Diabetes
- 392 Downloads
Purpose of Review
The global prevalence of type 2 diabetes (T2D) is escalating at alarming rates, demanding the development of additional classes of therapeutics to further reduce the burden of disease. Recent studies have indicated that increasing the metabolic activity of brown and beige adipose tissue may represent a novel means to reduce circulating glucose and lipids in people with T2D. The AMP-activated protein kinase (AMPK) is a cellular energy sensor that has recently been demonstrated to be important in potentially regulating the metabolic activity of brown and beige adipose tissue. The goal of this review is to summarize recent work describing the role of AMPK in brown and beige adipose tissue, focusing on its role in adipogenesis and non-shivering thermogenesis.
Ablation of AMPK in mouse adipocytes results in cold intolerance, a reduction in non-shivering thermogenesis in brown adipose tissue (BAT), and the development of non-alcoholic fatty liver disease (NAFLD) and insulin resistance; effects associated with a defect in mitochondrial specific autophagy (mitophagy) within BAT. The effects of a β3-adrenergic agonist on the induction of BAT thermogenesis and the browning of white adipose tissue (WAT) are also blunted in mice lacking adipose tissue AMPK. A specific AMPK activator, A-769662, also results in the activation of BAT and the browning of WAT, effects which may involve demethylation of the PR domain containing 16 (Prdm16) promoter region, which is important for BAT development.
AMPK plays an important role in the development and maintenance of brown and beige adipose tissue. Adipose tissue AMPK is reduced in people with insulin resistance, consistent with findings that mice lacking adipocyte AMPK develop greater NAFLD and insulin resistance. These data suggest that pharmacologically targeting adipose tissue AMPK may represent a promising strategy to enhance energy expenditure and reduce circulating glucose and lipids, which may be effective for the treatment of NAFLD and T2D.
KeywordsAMPK Adipose tissue Adipogenesis Lipolysis Non-shivering thermogenesis
The authors would like to express their gratitude to all the researchers who have contributed to the field of AMPK in brown/beige adipose tissue, especially those whose research they could not cite due to constraints on review length.
Compliance with Ethical Standards
Conflict of Interest
Eric Desjardins declares no conflicts of interest. Dr. Steinberg reports grants, personal fees, and non-financial support from Esperion Therapeutics; non-financial support from Pfizer, Merck, Sanofi, and Nestle; and personal fees from Novo Nordisk and Eli Lilly.
This article does not contain any experiments with human or animal subjects.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 10.O’Neill HM, Maarbjerg SJ, Crane JD, Jeppesen J, Jørgensen SB, Schertzer JD, et al. AMP-activated protein kinase (AMPK) beta1beta2 muscle null mice reveal an essential role for AMPK in maintaining mitochondrial content and glucose uptake during exercise. Proc Natl Acad Sci U S A. 2011;108:16092–7.CrossRefPubMedPubMedCentralGoogle Scholar
- 14.Madiraju AK, Qiu Y, Perry RJ, Rahimi Y, Zhang X-M, Zhang D, et al. Metformin inhibits gluconeogenesis via a redox-dependent mechanism in vivo. Nat Med. 2018;1Google Scholar
- 15.Kim EK, Lee SH, Jhun JY, Byun JK, Jeong JH, Lee SY, et al. Metformin prevents fatty liver and improves balance of white/brown adipose in an obesity mouse model by inducing FGF21. Mediators Inflamm. 2016;ID5813030.Google Scholar
- 16.Salastekar N, Desai T, Hauser T, Schaefer EJ, Fowler K, Joseph S, et al. Salsalate improves glycaemia in overweight persons with diabetes risk factors of stable statin-treated cardiovascular disease: a 30-month randomized placebo-controlled trial. Diabetes Obes Metab. 2017;19:1458–62.CrossRefPubMedGoogle Scholar
- 23.Steneberg P, Edlund T, Edlund H. PAN-AMPK activator O304 improves glucose homeostasis and microvascular perfusion in mice and type 2 diabetes patients. 2018; 3:e99114Google Scholar
- 30.MacPherson REK, Dragos SM, Ramos S, Sutton C, Frendo-Cumbo S, Castellani L, 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 Phys Cell Phys. 2016;311:C269–76.CrossRefGoogle Scholar
- 32.• Mottillo EP, Desjardins EM, Crane JD, Smith BK, Green AE, Ducommun S, et al. Lack of adipocyte AMPK exacerbates insulin resistance and hepatic steatosis through brown and beige adipose tissue function. Cell Metab. 2016;24:118–29. Characterization of an inducible, adipocyte-specific AMPK β1β2 knockout mouse model showing that AMPK is required for cold and β-adrenergic-stimulated thermogenesis, required for the browning of WAT, and, when absent, results in aggravated insulin resistance and hepatic lipid accumulation in response to high-fat diet. This characterization is explained through the role of AMPK in maintaining mitochondrial homeostasis through the regulation of mitophagy CrossRefPubMedPubMedCentralGoogle Scholar
- 34.Ong FJ, Ahmed BA, Oreskovich SM, Blondin DP, Haq T, Konyer NB, et al. Recent advances in the detection of brown adipose tissue in adult humans: a review 2018;132:1039–54.Google Scholar
- 38.Albers PH, Bojsen-Møller KN, Dirksen C, Serup AK, Kristensen DE, Frystyk J, et al. Enhanced insulin signaling in human skeletal muscle and adipose tissue following gastric bypass surgery. Am J Phys Regul Integr Comp Phys. 2015;309:R510–24.Google Scholar
- 42.•• Yang Q, Liang X, Sun X, Zhang L, Fu X, Rogers CJ, et al. AMPK/α-Ketoglutarate axis dynamically mediates DNA demethylation in the Prdm16 promoter and brown adipogenesis. Cell Metab. 2016;24:542–54. The authors show a novel mechanism by which AMPK is essential in brown adipose tissue development through elevating α-ketoglutarate production and subsequently increasing the demethylation of the Prdm16 promoter CrossRefPubMedPubMedCentralGoogle Scholar
- 55.Imran KM, Rahman N, Yoon D, Jeon M, Lee BT, Kim YS. Cryptotanshinone promotes commitment to the brown adipocyte lineage and mitochondrial biogenesis in C3H10T1/2 mesenchymal stem cells via AMPK and p38-MAPK signaling. Biochim Biophys Acta Mol Cell Biol Lipids. 1862;2017:1110–20.Google Scholar
- 57.Wang S, Liang X, Yang Q, Fu X, Zhu M, Rodgers BD, 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;61:1–11.Google Scholar
- 58.• Wu L, Zhang L, Li B, Jiang H, Duan Y, Xie Z, et al. AMP-activated protein kinase (AMPK) regulates energy metabolism through modulating thermogenesis in adipose tissue. Front Physiol. 2018;9:1–11. This report demonstrates that chronic administration of A-769662, an AMPK activator, reduces body weight gain, increases energy expenditure, improves cold tolerance, and promotes the browning of inguinal WAT in high-fat diet-fed mice Google Scholar
- 74.Berti L, Irmler M, Zdichavsky M, Meile T, Böhm A, Stefan N, et al. Fibroblast growth factor 21 is elevated in metabolically unhealthy obesity and affects lipid deposition, adipogenesis, and adipokine secretion of human abdominal subcutaneous adipocytes. Mol Metab. 2015;4:519–27.CrossRefPubMedPubMedCentralGoogle Scholar
- 76.Mottillo EP, Desjardins EM, Fritzen AM, Zou VZ, Crane JD, Yabut JM, et al. FGF21 does not require adipocyte AMP-activated protein kinase (AMPK) or the phosphorylation of acetyl-CoA carboxylase (ACC) to mediate improvements in whole-body glucose homeostasis. Mol Metab. 2017;6:471–81.CrossRefPubMedPubMedCentralGoogle Scholar
- 78.Wu L, Zhang L, Li B, Jiang H, Duan Y, Xie Z, et al. AMP-activated protein kinase (AMPK) regulates energy metabolism through modulating thermogenesis in adipose tissue. Front Physiol. 2018;9:1–23.Google Scholar