Alpha-Lipoic Acid Induces Adipose Tissue Browning through AMP-Activated Protein Kinase Signaling in Vivo and in Vitro

다국어 초록 (Multilingual Abstract)

Background: AMP-activated protein kinase (AMPK) is a key enzyme for cellular energy homeostasis and improves metabolic disorders. Brown and beige adipose tissues exert thermogenesis capacities to dissipate energy in the form of heat. Here, we investigated the beneficial effects of the antioxidant alpha-lipoic acid (ALA) in menopausal obesity and the underlying mechanisms.
Methods: Female Wistar rats (8 weeks old) were subjected to bilateral ovariectomy (Ovx) and divided into four groups: Sham (n=8), Ovx (n=11), Ovx+ALA2 (n=10), and Ovx+ALA3 (n=6) (ALA 200 and 300 mg/kg/day, respectively; gavage) for 8 weeks. 3T3-L1 cells were used for in vitro study.
Results: Rats receiving ALA2 and ALA3 treatment showed significantly lower levels of body weight and white adipose tissue (WAT) mass than those of the Ovx group. ALA improved plasma lipid profiles including triglycerides, total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol. Hematoxylin & eosin staining of inguinal WAT showed that ALA treatment reduced Ovx-induced adipocyte size and enhanced uncoupling protein 1 (UCP1) expression. Moreover, plasma levels of irisin were markedly increased in ALA-treated Ovx rats. Protein expression of brown fat-specific markers including UCP1, PRDM16, and CIDEA was downregulated by Ovx but markedly increased by ALA. Phosphorylation of AMPK, its downstream acetyl-CoA carboxylase, and its upstream LKB1 were all significantly increased by ALA treatment. In 3T3-L1 cells, administration of ALA (100 and 250 μM) reduced lipid accumulation and enhanced oxygen consumption and UCP1 protein expression, while inhibition of AMPK by dorsomorphin (5 μM) significantly reversed these effects.
Conclusion: ALA improves estrogen deficiency-induced obesity via browning of WAT through AMPK signaling.

참고문헌 (Reference)

• 1 Fernández-Galilea M, "α-Lipoic acid treatment increases mitochondrial biogenesis and promotes beige adipose features in subcutaneous adipocytes from overweight/obese subjects" 1851 : 273-281, 2015
• 2 Giralt M, "White, brown, beige/brite : different adipose cells for different functions?" 154 : 2992-3000, 2013
• 3 Rosen ED, "What we talk about when we talk about fat" 156 : 20-44, 2014
• 4 Carr MC, "The emergence of the metabolic syndrome with menopause" 88 : 2404-2411, 2003
• 5 Nedergaard J, "The browning of white adipose tissue : some burning issues" 20 : 396-407, 2014
• 6 Fullerton MD, "Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin" 19 : 1649-1654, 2013
• 7 Shen HH, "Raloxifene inhibits adipose tissue inflammation and adipogenesis through Wnt regulation in ovariectomized rats and 3 T3-L1 cells" 26 : 62-, 2019
• 8 Barbera MJ, "Peroxisome proliferator-activated receptor alpha activates transcription of the brown fat uncoupling protein-1gene : a link between regulation of the thermogenic and lipid oxidation pathways in the brown fat cell" 276 : 1486-1493, 2001
• 9 Zhang S, "Natural polyphenols in metabolic syndrome : protective mechanisms and clinical applications" 22 : 6110-, 2021
• 10 Delgobo M, "N-acetylcysteine and alpha-lipoic acid improve antioxidant defenses and decrease oxidative stress, inflammation and serum lipid levels in ovariectomized rats via estrogen-independent mechanisms" 67 : 190-200, 2019
• 11 Saha AK, "Malonyl-CoA and AMP-activated protein kinase : an expanding partnership" 253 : 65-70, 2003
• 12 Woods A, "LKB1 is the upstream kinase in the AMPactivated protein kinase cascade" 13 : 2004-2008, 2003
• 13 Zhang Y, "Irisin stimulates browning of white adipocytes through mitogen-activated protein kinase p38 MAP kinase and ERK MAP kinase signaling" 63 : 514-525, 2014
• 14 Xu XJ, "Insulin sensitive and resistant obesity in humans : AMPK activity, oxidative stress, and depot-specific changes in gene expression in adipose tissue" 53 : 792-801, 2012
• 15 Lovejoy JC, "Increased visceral fat and decreased energy expenditure during the menopausal transition" 32 : 949-958, 2008
• 16 Ribas V, "Impaired oxidative metabolism and inflammation are associated with insulin resistance in ERalpha-deficient mice" 298 : E304-E319, 2010
• 17 Shen HH, "Genistein ameliorated obesity accompanied with adipose tissue browning and attenuation of hepatic lipogenesis in ovariectomized rats with high-fat diet" 67 : 111-122, 2019
• 18 Roca-Rivada A, "FNDC5/irisin is not only a myokine but also an adipokine" 8 : e60563-, 2013
• 19 Stubbins RE, "Estrogen modulates abdominal adiposity and protects female mice from obesity and impaired glucose tolerance" 51 : 861-870, 2012
• 20 Sul OJ, "Estrogen enhances browning in adipose tissue by M2 macrophage polarization via heme oxygenase-1" 236 : 1875-1888, 2021
• 21 Lizcano F, "Estrogen deficiency and the origin of obesity during menopause" 2014 : 757461-, 2014
• 22 Gupte AA, "Estrogen : an emerging regulator of insulin action and mitochondrial function" 2015 : 916585-, 2015
• 23 Martínez de Morentin PB, "Estradiol regulates brown adipose tissue thermogenesis via hypothalamic AMPK" 20 : 41-53, 2014
• 24 Li N, "Effects of oral α-lipoic acid administration on body weight in overweight or obese subjects : a crossover randomized, double-blind, placebo-controlled trial" 86 : 680-687, 2017
• 25 Fernández-Galilea M, "Effects of lipoic acid on lipolysis in 3T3-L1 adipocytes" 53 : 2296-2306, 2012
• 26 Harms M, "Brown and beige fat : development, function and therapeutic potential" 19 : 1252-1263, 2013
• 27 Khedoe PP, "Brown adipose tissue takes up plasma triglycerides mostly after lipolysis" 56 : 51-59, 2015
• 28 Wu J, "Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human" 150 : 366-376, 2012
• 29 Signorelli SS, "Behaviour of some indicators of oxidative stress in postmenopausal and fertile women" 53 : 77-82, 2006
• 30 Kim MS, "Anti-obesity effects of alpha-lipoic acid mediated by suppression of hypothalamic AMP-activated protein kinase" 10 : 727-733, 2004
• 31 Zhang Y, "Amelioration of lipid abnormalities by α-lipoic acid through antioxidative and anti-inflammatory effects" 19 : 1647-1653, 2011
• 32 Lee WJ, "Alpha-lipoic acid increases insulin sensitivity by activating AMPK in skeletal muscle" 332 : 885-891, 2005
• 33 Hahm JR, "Alpha-lipoic acid attenuates adipocyte differentiation and lipid accumulation in 3T3-L1 cells via AMPK-dependent autophagy" 100 : 125-132, 2014
• 34 Bartelt A, "Adipose tissue browning and metabolic health" 10 : 24-36, 2014
• 35 Yang Q, "AMPK/α-ketoglutarate axis dynamically mediates DNA demethylation in the Prdm16 promoter and brown adipogenesis" 24 : 542-554, 2016
• 36 O’Neill HM, "AMPK regulation of fatty acid metabolism and mitochondrial biogenesis : implications for obesity" 366 : 135-151, 2013
• 37 Day EA, "AMPK as a therapeutic target for treating metabolic diseases" 28 : 545-560, 2017
• 38 Janovská A, "AMPK and ACC phosphorylation : effect of leptin, muscle fibre type and obesity" 284 : 1-10, 2008
• 39 Hardie DG, "AMPK : a key regulator of energy balance in the single cell and the whole organism" 32 (32): S7-S12, 2008
• 40 Boström P, "A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis" 481 : 463-468, 2012